Update on the Treatment of Chronic Viral Hepatitis - Gastroenterology Clinics of North America Vol 33 Issue 3

Gastroenterol Clin N Am 33 (2004) xiii–xv

Preface

Update on the Treatment of Chronic Viral Hepatitis

Norah A. Terrault MD, MPH Guest Editor

The burden of chronic liver disease caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) is substantial. Effective therapies aimed at reducing the rate of chronic infection and the risk of complications of cirrhosis are desirable. In the last few years, significant advances in the treatment of chronic HBV and HCV have been achieved. In this edition of Gastroenterology Clinics of North America, an update on treatment of these chronic viral infections is the focus. The issue is divided into three sections: the first on the management of chronic HCV; the second on management of chronic HBV; and the third on special treatment topics relevant to both viral infections. An overview of the general approach to patients with chronic HCV and HBV serves as the introduction to each of the treatment sections. These overview articles, written by Dr. Dove (HCV) and Drs. Ghany and Doo (HBV) provide details on the diagnostic work-up of infected individuals, recommendations for routine follow-up, and factors to consider when making decisions to treat patients. Subsequent articles are devoted to state-ofthe-art reviews on the treatment of treatment-naı¨ve and treatment-experienced patients, as well as special patient groups including those with HIV coinfection, cirrhosis, renal failure, and extrahepatic disease. Antiviral therapy for chronic hepatitis C has advanced to the point where viral eradication can be achieved in about half of the treated patients overall, albeit with significant variability by genotype and other factors. The improvement in treatment outcomes has led to recommendations to 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.05.001

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consider antiviral therapy in every person with chronic HCV infection. Therefore, it is more critical than ever that clinicians be updated on the latest approaches to treatment. The therapeutic options and factors influencing treatment decisions in treatment-naive HCV patients are reviewed by Drs. Oh and Afdhal. The next two articles focus on a growing group of patients in clinical practice, namely patients who have relapsed or not responded to prior treatment with interferon (IFN)-based therapy. Drs. Ahmed and Jacobsen look at the treatment of relapsers and provide an excellent and balanced prospective on the approach to this patient subgroup. Dr. Fontana addresses the treatment of nonresponders to prior combination therapy, the use of hepatic fibrosis as a treatment endpoint, and new therapeutic approaches for this patient group. The final articles in the HCV section are on the treatment of special patient populations. Dr. Khalili looks at treatment of HCV in patients with HIV coinfection, highlighting the issues of tolerability, efficacy, and drug interactions. Drs. Arenas and Vargas provide a comprehensive review of treatment of HCV in patients with cirrhosis. The number of therapeutic options for chronic HBV infection is greater than for chronic HCV infection. Three different drugs, IFN, lamivudine, and adefovir, are approved for treatment of HBV. The issues of who to treat and what drug to use for treatment are important. Both the American Association for the Study of Liver Diseases and American Gastroenterological Association (AGA) have published practice guidelines on the management of chronic HBV infection, in part prompted by the growing number of antiviral agents, evolving concepts of disease progression, and indications for treatment. Drs. Lau and Membreno provide a detailed review of treatment of patients who are naı¨ve to antiviral therapy. Drs. Hui, Zhang and G. Lau review the treatment of drug-experienced patients, an increasingly frequent occurrence in clinical practice. Dr. Benhamou reviews the unique challenges posed by the common occurrence of lamivudine resistance in HBV-infected patients with HIV, and the last article in this section by Dr. Lai and me looks at the treatment of chronic HBV infection in cirrhotic patients. The latter group has benefited significantly from the availability of safe and effective antiviral agents such as lamivudine and adefovir. The last section is devoted to special treatment topics. Drs. Fabrizi, Martin, and Bunnapradist look at the role of antiviral therapy in patients with renal disease, both those on dialysis and those who have undergone renal transplantation. Hepatocellular carcinoma is a serious risk for those with chronic viral hepatitis, and treatment options have expanded in recent years. Drs. Sherman and Takayama examine critically the role of hepatoma surveillance strategies for patients with chronic HBV and HCV and provide an overview of available treatment options and their outcomes. The final article in this section, by Drs. Kim and Sherker, is a review of the extrahepatic manifestations of chronic HCV and HBV and current treatment approaches. I hope that clinicians will find this issue of Gastroenterology Clinics of North America to be a useful update and reference on the management of

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patients with chronic viral hepatitis. I am extremely grateful to all the authors for their superb contributions. I would also like to acknowledge the excellent editorial support of Kerry Holland and the staff at Elsevier. Norah A. Terrault, MD, MPH

Division of Gastroenterology University of California, San Francisco, S357, 513 Parnassus Avenue San Francisco, CA 94142, USA E-mail address: [email protected]

Gastroenterol Clin N Am 33 (2004) 463–477

A general approach to the management of chronic hepatitis C Lorna M. Dove, MD, MPH Center for Liver Disease and Transplantation, Columbia University-College of Physicians and Surgeons, 622 West 168th Street, New York, NY 10128, USA

Chronic liver disease accounts for approximately 1% of all deaths in the United States. Of patients with chronic liver disease, hepatitis C virus (HCV) infection represents 40% of all cases, and this translates into 8000 to 10,000 deaths per year [1,2]. Although death from liver disease is uncommon in patients with HCV infection, approximately 3.9 million Americans have been infected, making it the most common chronic blood-borne infection in the United States [2]. Thus, HCV is a public health problem with great impact on individuals, the health care system, and health care resources. With 1.8% of the general population infected [3], health care providers in any discipline likely will encounter a patient infected with HCV. Therefore, having a general working knowledge of risk factors, indications for screening, clinical outcomes, and treatment is crucial in today’s medical practice.

Epidemiology and transmission If one were to identify a prototypical patient with HCV, he would be a 40- to 50-year-old man with a history of injection drug use decades before his first evaluation for liver disease. Although he represents a typical patient, the population of infected patients crosses all age, gender, ethnic, and racial groups [4]. New infection with HCV is seen mostly in younger patients between the ages of 20 and 39. The rate of new infection has decreased dramatically, however, since the early 1990s. Therefore, the highest prevalence of HCV antibody is seen in individuals between the ages of 30 and 49 [1]. The lack of symptoms associated with acute disease results in most evaluated patients

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falling in this older age group, and they present with complications of chronic liver disease. Men and patients of Latino ethnicity have a slightly higher incidence of acute infection [5]. When compared with Caucasians, the incidence of acute infection in African Americans is similar, but African Americans appear to be at higher risk of developing chronic infection (95% versus 85%) [6]. Parenteral exposures represent the greatest risk for infection. In the United States, injection drug use is the most common risk factor, accounting for 60% of new infections. Before the screening of blood, receiving a blood transfusion or clotting factor concentrate was of considerable risk; this risk is now negligible (0.001% per unit transfused) [7]. Other risk factors such as dialysis and nosocomial exposures have been identified, but they carry a significantly lower risk (Table 1). Intranasal cocaine use [8], acupuncture, and tattoos also have been suggested as potential risks, but they remain unproven. Finally, certain populations, such as Vietnam-era veterans [9] or those with a history of incarceration [10,11], have been shown to have an increased prevalence of HCV antibody. Whether these populations have unrecognized exposures to previously identified risk factors or independent risk factors is still a matter of debate. Clearly parenteral exposure is the greatest risk for HCV transmission, and avoiding blood exposure is understood well. In the hospital, universal precautions are practiced and are adequate for protection against HCV. Needle sticks and splashes are inevitable, however. The prevalence of HCV antibody among health care workers is not significantly different from that in the general populations, suggesting that risk of transmission to medical providers is low [2]. The risk of developing HCV after a needle stick, however, ranges from 3% to 10% in community studies [12,13]. Patients and family members have questions about casual contact and sexual exposure. Some small studies have demonstrated a higher prevalence of HCV antibody in the family members of patients with HCV, suggesting some increase in transmission within households [14]. These studies are small, however, and most of this transmission is likely secondary to inapparent blood exposure. In general, there are no additional precautions or recommendations for the family members of patients with HCV. Table 1 Prevalence of hepatitis C virus antibody in select high-risk groups Risk factor

Prevalence of HCV antibody (%)

Hemophilia with transfusion of products prior to 1987 Injection drug use Chronic hemodialysis Persons receiving transfusion prior to 1990 Infants of HCV þ mothers Men who have sex with men General population

87 79 10 6 5 4 1.8

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Vertical transmission of HCV is low, with most studies suggesting a risk of 5% to 6% in a mother without HIV [15–17] and 15% for the coinfected mother [18]. The impact of mode of delivery on the likelihood of transmission is still under investigation [19]. There are no currently accepted recommendations for interventions at the time of the birth. Infants born to a mother with HCV should be tested for HCV. Although there are no accepted guidelines for the method of testing, the practitioner should be aware that passively acquired HCV antibodies may persist in an infant for 12 months. Finally, there is no contraindication to breast feeding [17,20]. Sexual exposure represents a common risk factor for acute HCV [1], and patients with a history of multiple sexual partners have a higher prevalence of HCV antibody [14]. Longitudinal studies, however, suggest that sexual transmission between monogamous couples is low (less than 5% in most studies) [8,21]. Given this low transmission, there are no universal recommendations for barrier precautions within monogamous relationships. It is recommended, however, that individuals with HCV discuss the risk of transmission with their partner and consider barrier precautions.

Screening Routine screening for HCV antibody should be directed toward any group with a prevalence rate that is greater than that of the general population. Most agree that the following groups should be identified and screened [2,22]: all patients with a history of transfusion of clotting factor before 1987, patients who received blood products or an organ transplant before 1992, patients with a history of injection drug use, chronic dialysis recipients, infants born to mothers with HCV, and any patient with clinical evidence of liver disease (Box 1). In addition, all patients with HIV disease should be tested [23]. Given the similarity of risk factors, HIV coinfection occurs in anywhere from 10% to 30% of patients with HIV depending on the population studied [24]. Of the population with HCV, approximately 5% to 10% are infected with HIV [3].

Serologic and virologic tests Screening for HCV antibody with an immunoassay is the initial recommended test. These assays are designed to detect antibodies to HCV epitopes in the core, NS3, NS4, and NS5 proteins. The sensitivity and specificity of the currently available test (enzyme immunoassay [EIA] 2.0 and 3.0 ELISA) are 99% or greater [25,26]. With these tests, seroconversion occurs on average at 7 to 8 weeks and generally no later than 12 weeks [27,28]. Confirmatory testing beyond the initial antibody test is a matter of great controversy. The purpose of this article is not to make recommendations to laboratories but to give medical practitioners a guideline for evaluation.

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Box 1. Hepatitis C virus screening recommendations History of injection drug use Recipient of clotting factor before 1987 Recipient of blood transfusion or organ transplantation prior to July of 1992 History of chronic hemodialysis After known parenteral exposure (ie, needle stick) Children born to HCV-positive women Patient with persistently abnormal alanine aminotransferase (ALT) Unlike hepatitis B or HIV, most laboratories do not have a standard reflex protocol that is activated by a positive EIA antibody test [26]. In high-risk groups, the positive predictive value of the EIA is high because of the high prevalence of infection. In this group, a false-positive test is a rarity, and confirmatory testing should be directed at establishing chronic infection as opposed to documenting true exposure. To this end, follow-up testing with HCV RNA (qualitative) is appropriate. In low-risk populations (ie, patients without identifiable risk factors), false-positive tests are more common, and thus confirmatory testing probably prevents unnecessary medical evaluation. The strip immunoblot assay (RIBA) can be used for this purpose. This is a more common situation with blood donor screening or general population screening. It is unusual for the medial practitioner to order an antibody test in a patient with no risk factors and no clinical evidence of liver disease. Therefore, RIBA is rarely useful in the day-to-day clinical practice. More recently, the nucleic acid test (NAT) for RNA has been applied to the screening of blood donors. Although false-negative EIA tests are uncommon, patients with unexplained elevated aminotransferases or cryptogenic cirrhosis should have a qualitative HCV RNA test before HCV can be excluded. In addition, the negative predictive value of the test is diminished in immunocompromised patients, such as those with HIV infection or those on hemodialysis [29,30]. Thus, in these groups, the threshold for obtaining a qualitative HCV RNA should be lowered. Hepatitis C virus RNA is detectable in the serum within 1 to 2 weeks after infection. Testing for RNA is available as either a qualitative or a quantitative test, the former being more sensitive. Qualitative RNA testing is useful for documenting chronic infection. The currently available qualitative assays can detect RNA as low as 10 to 50 IU of HCV RNA per mL. The specificity of these tests is 98% to 99% [31]. Although less sensitive than qualitative tests (level of detection 30 to 615 IU/mL) [31], quantitative RNA testing is more useful for predicting response to therapy and monitoring the effects of therapy. For example, lower viral RNA levels are associated with increased

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response rates to therapy. Level of RNA has not been correlated with severity of illness or progression of liver disease; therefore, frequent monitoring in a patient not on therapy is of no benefit and is not recommended [22]. HCV RNA is a useful adjunct to the management of patients on treatment. Hepatitis C is a highly mutatable virus with several genetic variants. There are six major subtypes and subclassifications within these major variants [32]. Major variants are designated as genotypes and vary by approximately 30% in nucleotide and amino acid sequences. In the United States, approximately 75% of infected individuals have genotype 1 infection [2]. Genotype does not predict disease severity or risk of complications, but it is helpful to know when helping the patient contemplating treatment. Patients with non-1 genotypes have a higher likelihood of responding and have a different recommended course of therapy [33]. Therefore, genotype testing is crucial when making a decision about appropriateness or length of therapy. Natural history The appropriate evaluation of a patient with HCV is based on an understanding of the possible complications of chronic infection. Few patients with acute infection are symptomatic [34]; therefore, the medical practitioner rarely is evaluating this group. Natural history data suggest that progression of HCV is slow, and although the liver related mortality is increased in this population (4% versus 1%) [35], the overall mortality is not substantially different than age-matched controls without HCV [36]. The time course for the development of cirrhosis is estimated to be 20 to 30 years. The estimated risk of developing cirrhosis varies in different studies depending on the population studied. In a recent review of the literature, rates of cirrhosis after an estimated 20 years of infection ranged from as low as 4% in blood donor series to 24% in liver clinic series [37]. These differences are probably the result of selection bias in the study. Twenty percent of those with cirrhosis will develop the complications of portal hypertension, and 7% will develop hepatocellular carcinoma (HCC) [38]. Although these general statistics apply to the population at large, certain characteristics previously were identified as factors that accelerate the progression of liver disease including: older age at HCV infection, male gender, HBV or HIV coinfection, and heavy alcohol use [37,39–41]. No association has been demonstrated between level of HCV RNA, or ALT. Multiple studies have demonstrated an acceleration of fibrosis and increased risk of cirrhosis in patients that have a history of heavy alcohol use [39,42]. In these studies, the definitions of heavy alcohol use vary from 50 to 80 g of alcohol per day, but each suggests increased risk of end-stage liver disease. When compared with HIV-negative controls, patients with coinfection have accelerated fibrosis progression. They are more likely to have cirrhosis and develop this cirrhosis in an abbreviated time course [40,43]. There is no clear etiology for this increased rate of progression, as it

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is not related clearly to HCV RNA, HIV viral load, or level of immunosuppression [44,45]. Understanding where a patient is in the wide spectrum of disease is crucial in determining prognosis and making recommendations on the appropriateness of hepatoma screening or initiation of antiviral therapy. Clinical evaluation History and physical Most evaluations begin with a clinical history, physical exam, and laboratory testing. The clinical history is important, because here the practitioner may identify important clues that help date time of infection. Knowing the timing of acute disease helps the provider evaluate disease progression and give the patient a more accurate prognosis. A patient with a former history of injection drug use in the 1960s can be presumed to have had infection for over 30 years. This is based on data that show that in some environments half of injection drug users develop HCV within the first year of drug use [46,47]. Other helpful clues may be a history of transfusion, abnormal liver enzymes for many years without obvious cause, or known exposed contact. Although important to ascertain, many patients may have no identifiable risk factor, leaving the patient and practitioner unclear of the time of infection. Unfortunately, until a patient develops signs of cirrhosis and portal hypertension, the physical exam can be unrevealing, making it unreliable in determining prognosis. In one study, a hepatologist evaluating patients with HCV could predict stage of fibrosis accurately only 76% of the time after assessing all clinical data [48]. Presence of ascites and hepatic encephalopathy are diagnostic of hepatic decompensation. Splenomegaly, hepatic left lobe enlargement, firm liver edge, and spider nevi are suggestive but not diagnostic of cirrhosis and portal hypertension. Laboratory evaluation and histology Laboratory studies may help with assessing progression of liver disease. Each patient should have a complete blood count, prothrombin time (PT)/ international normalized ratio (INR), ALT, and bilirubin tests. Thrombocytopenia or elevated INR and increased bilirubin may represent signs of portal hypertension or impaired hepatic function, respectively. ALT is a marker of liver inflammation, and the usefulness of the test remains controversial. There is no correlation between degree of ALT elevation and natural history of HCV. Patients with persistently normal ALT (defined as normal on more than one visit separated by 6 months), however, represent 30% of patients who present with chronic HCV. In general, these patients have a more benign disease course. Although most will have chronic hepatitis on biopsy, few will have advanced fibrosis or cirrhosis [49,50].

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The additional testing for alternative etiologies of liver disease or coexisting illnesses is useful, and these tests should be directed by the epidemiology and clinical presentation of the patient. The use of HCV RNA and genotype were discussed previously. a-fetoprotein (AFP) as a marker of hepatocellular carcinoma is used widely for screening in patients with HCV. The usefulness of this test has been questioned [51], and further research is needed to establish its role in the patient with HCV and advanced fibrosis (stage 3 or 4) who is at risk for HCC. Liver biopsy remains the gold standard for assessing severity of liver disease associated with HCV [52]. The lack of sensitivity and specificity of individual laboratory or radiographic tests have left biopsy as the most reliable tool in assessing degree of fibrosis. Liver biopsy, however, is invasive and carries some risk. It is only beneficial if it will aid in patient education, or if the results will alter the treatment plan. Being able to assess degree of fibrosis without biopsy would simplify care and allow patients and practitioners to make medical decisions with less risk. Given this, there has been enormous interest in finding alternative tests or models that would yield the same information obtained from biopsy. A recent study demonstrated that the use of a simple noninvasive index that measures the aspartate aminotransferase (AST) to platelet ration index (APRI) was able to predict significant fibrosis and cirrhosis with a high degree of accuracy. Cirrhosis was predicted accurately in 81% of patients [53]. The results of this study are promising, but significant fibrosis (defined as Ishak score of 3 or more) was predicted in just more than half [53]. Furthermore, clinical decisions may be affected by less than significant fibrosis, and additional information may be noted on histology such as steatosis. Therefore, biopsy remains the most reliable means of prognosticating disease course. In experienced hands, the associated morbidity with biopsy is low [54]. The risks and benefits, however, must be explained to the patient before recommending the procedure. There are several different scoring systems for liver histology. Many centers have adopted a two variable scoring system that measures degree of inflammation and amount of fibrosis [55]. The development of this nomenclature has allowed practitioners to better explain findings to patients and to better follow their progression over time. In addition, it allows physicians to discuss histology with a common background understanding. An example of common histology nomenclature is noted in Tables 2 and 3. Radiographic tests Radiographic tests used for HCV include ultrasound, abdominal CT, MRI, and liver–spleen scans. The test chosen is driven by the information needed. Ultrasound is an adequate test if one is evaluating for the presence of portal hypertension (ie, splenomegaly, a recanalized umbilical vein) or evaluating the biliary tree or gall bladder. Both CT, with intravenous contrast, and MRI, however, have higher sensitivity for hepatocellular

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Table 2 Grading of disease activity in chronic hepatitis Grade

Portal inflammation

Lymphocytic lobular inflammation

Piecemeal necrosis and necrosis

0 1

None Minimal

None Minimal, patchy

2

Mild

3

Mild, involving some portal tracts Moderate

None Minimal: occasional spotty necrosis Mild

Moderate

4

Severe

Severe

Moderate with noticeable hepatocellular change Severe with prominent difuse hepatocellular damage

carcinoma [56,57]. Liver–spleen scans are useful if the only question is cirrhosis where a shift of colloid is suggestive of that diagnosis. In patients followed with HCV, imaging often is obtained early to evaluate for signs of portal hypertension. Once HCV is staged, imaging is useful for HCC screening. The benefit of screening remains unproven. If screening is to be adopted, however, it should be limited to those patients with HCV who have advanced fibrosis (stage 3 or 4). Hepatocellular carcinoma in HCV rarely is seen in patients with minimal fibrosis.

Treatment Antiviral therapy Every patient with chronic HCV is a potential treatment candidate. A patient’s decision to be treated is affected not only by the estimated likelihood of success but also by the severity of illness, the anticipated adverse effects, and the cost and availability of treatment. Given the number of variables that affect success of therapy and the potential adverse effects, the decision to treat is never black and white. It involves a good understanding of the issues, and it is a joint decision between patient and practitioner. The standard of care for therapy is weekly pegylated interferon (PEG IFN) and daily ribavirin (RBV). The effectiveness of this regime is anywhere Table 3 Stage of fibrosis Stage

Semi quantitative

Descriptive criteria

0 1 2 3

No fibrosis Portal fibrosis Periportal fibrosis Septal fibrosis

4

Cirrhosis

Normal connective tissue Fibrous portal expansion Periportal or rare portal septa Fibrous septa with architectural distortion; no obvious cirrhosis Cirrhosis

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from 40% to 80% depending on viral and patient characteristics [33,58]. Patients with non-1 genotypes and less fibrosis are more likely to respond. Patients with several decades of chronic infection but little fibrosis on biopsy, however, may never progress to cirrhosis. Given the data on treatment, a patient infected with genotype 2 disease and stage 3 fibrosis may be more likely to accept therapy as compared with a patient infected 25 years with genotype 1 disease and no fibrosis. Therefore, the decision to be treated often begins with determining genotype and staging liver fibrosis, the two factors which heavily influence treatment outcomes. The marked success of therapy in patients infected with genotypes 2 and 3, however, may lessen the importance of staging liver fibrosis. If a patient has a 60% to 80% chance of having a sustained viral response with therapy, treatment without regard for biopsy results may be appropriate (Fig. 1). Finally, some patients have clear contraindications to therapy. In this group, biopsy is useful only for patient education and for determining prognosis. Liver transplantation Despite some progress in the treatment of HCV, many patients will develop hepatic dysfunction with signs and symptoms of end-stage liver disease. Hepatitis C represents the most common indication for liver transplantation in the United States [59]. Although some will undergo transplantation, many will die each year waiting for an organ. Any patient who has demonstrated impaired synthetic dysfunction (decreased albumin without alternative cause, elevated PT or INR), hepatic decompensation with ascites, encephalopathy or variceal hemorrhage, or hepatocellular carcinoma within transplant criteria should be considered for referral to a transplant center. In the past, accrual of time on the wait list played a more important role in the transplantation. Now timing of transplantation is driven by mortality risk [60]. Health care providers should err on early referral, however. Transplant evaluation and education are extensive and may be prolonged. General measures in the management of hepatitis C virus Managing a patient with HCV does not end with staging of disease and counseling about the currently available US Food and Drug Administration (FDA)-approved treatments. Many patients will not be candidates for therapy or may not choose to pursue medications. They may be very interested, however, in maintaining general health and arresting progression of disease. In this regard, several nonmedication issues should be addressed as a part of patient education. Nutrition There are not sufficient data to support specific dietary recommendations in patients with chronic HCV. In general, patients do not need restrictions

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Screening for HCV (EIA) (Patients with risk factors or elevated aminotransferase activity) (+)

(-)

Qualitative or Quantitative RNA*

(-) Repeat in 6 months

Stop (unless unexplained liver disease then proceed with qualitative RNA)

(+)

Clinical Evaluation for Cirrhosis (Hx. of ascites, encephalopathy or variceal bleeding PE: caput, telangiectasia, palmar erythema, asterixis Labs: elevated INR, thrombocytopenia) (+) (-)

Consider Therapy and/or Transplant Referral (Antiviral therapy if no hx or signs of decompensation)

HCV Genotype

Genotype 1

Genotype 2 and 3 **

+/Liver Biopsy for Staging of Fibrosis***

Consider Therapy Decision dependent on stage, genotype, clinical characteristics and patient desire

Fig. 1. Screening for hepatitis C virus (EIA) (patients with risk factors or elevated aminotransferase activity).

unless they develop signs and symptoms of hepatic dysfunction with subsequent fluid overload or encephalopathy. In these latter situations, sodium, fluid or protein restriction may be appropriate. Maintaining a healthy well-balanced diet, however, probably contributes to overall good health and decreases the probability of obesity. Obesity is clearly a risk factor for steatosis [61]. The impact of concurrent steatohepatitis in patients with chronic HCV remains a matter of debate. Some data, however, suggest that steatosis accelerates fibrosis [62,63]. Therefore, as obesity and increased body mass index (BMI) contribute to HCV-associated steatosis [64], encouraging dietary discretion and exercise is prudent advice.

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Alcohol Though the criteria for heavy alcohol use may differ in different studies, most would agree that greater than 50 g per day of ethanol is more than what is consumed by the average patient. Advising patients to refrain from use at these levels is easy but probably not an issue for most. Therefore, the more pertinent question is the impact of smaller amounts of alcohol in the natural history of HCV. Unfortunately, this issue is not resolved [65]. Several studies have shown a trend of increased rate of fibrosis [66] or more evidence of end-stage liver disease [67] in patients who consume smaller amounts of alcohol. All of the studies have been retrospective, with inherent inaccuracies in calculating current or lifetime alcohol use. These difficulties make calculating a dose effect that contributes to fibrosis progression and cirrhosis nearly impossible. Prospective studies with accurate regular assessment of alcohol consumption and concurrent serial biopsies are needed to accurately answer this issue. Given the uncertainties, most practitioners choose to recommend complete abstinence. Prescription medications Almost all classes of drugs have some reported hepatotoxicity. Druginduced liver injury is the most frequently reported adverse event, representing anywhere from 3% to 10% of events depending on the drug class [68]. Many reactions are idiosyncratic, while others are dose-related. Having underlying liver disease may not increase the risk of drug-induced hepatotoxicity; however, patients with advanced fibrosis have little reserve for additional injury. Also, baseline abnormal liver enzymes may make early diagnosis of drug-induced liver injury difficult [68]. The practitioner prescribing a drug with reported hepatotoxicity should monitor patients closely when the drug is initiated and periodically check liver enzymes. Over the counter medications/vitamins Patients with HCV and end-stage liver disease should be counseled to read labels and take over-the-counter medications only after discussion with their health care provider. Although patients are aware of the problems of excessive acetaminophen, they are often not aware of the ingredients in combination cold and flu products, many of which contain acetaminophen. In addition, less than toxic amounts of acetaminophen may pose a problem to patients with advanced liver disease, especially in the setting of concurrent alcohol use [69]. Vitamin supplementation is usually safe, although benefits are unclear unless the patient has a demonstrated deficiency. Patients should be cautioned on the potential danger of iron supplementation. Although controversial, there is some suggestion of a synergistic effect of iron supplementation on the development of fibrosis. In addition, it may have a negative effect on the effectiveness of IFN [70].

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Complimentary and alternative medicine Although there are few data on the efficacy of alternative treatments, awareness of alternative medications is nearly universal [71]. In patients with chronic liver disease, the use of both milk thistle (sylibum marianum) and SAMe (s-adenosyl-L-methionine) is common. A recent meta-analysis of the small series of published data on milk thistle was unable to demonstrate a benefit from the supplement. Further research with randomized clinical trials is needed before health care providers can support the use of these therapies. Given the ubiquitous use, however, it is prudent to advise patients to be up-front about alternative treatments that are being used. Providers then may be able to research individual products and accurately counsel patients about potential risk and drug interactions if applicable. Immunization Patients with chronic HCV often have risk factors that put them at risk for other non-C viral hepatitides. Therefore, in a patient with known HCV, markers for previous exposure to hepatitis A and B should be checked. If not immune, patients should be vaccinated [2]. Evaluations and monitoring In the patient who has decided to defer therapy or who has not responded to therapy, periodic visits to assess for progression of liver disease are necessary. Clinical examination and laboratory testing were described previously. Liver biopsy is the only test to accurately determine progression of disease. There is an assumption that hepatic fibrosis is linear [39], although this may not be accurate. If a linear rate of fibrosis progression is assumed, patients are predicted to progress one stage approximately every 4 years. Therefore, repeat biopsy more frequently is unlikely to demonstrate significant progression. If a patient has other risk factors that may accelerate fibrosis progression (eg, HIV coinfection or alcohol use), however, repeat biopsy in a shorter period of time may be indicated. Summary Hepatitis C is a chronic illness that often is identified decades after infection. The natural history of disease is variable, but many patients have few or no complications. A quarter of the patients, however, may have progressive liver fibrosis and cirrhosis. This group is at risk for complications of end-stage liver disease and may eventually succumb to cirrhosis or require transplantation. The difficulty in identifying infected patients and the lack of clinical predictors make developing a careful screening and evaluation program is essential (see Fig. 1). Once patients are identified, accurate staging of disease and patient education should be the primary focus of the health care provider. The decision to be treated is complex and

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dependent on many viral and patient variables. All patients should be considered treatment candidates and given the information that allows them to make an informed decision about their care. References [1] Alter M. Epidemiology of Hepatitis C. Hepatology 1997;26(3):62S–5S. [2] MMWR Morb Mortal Wkly Rep. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. 1998;47(RR-19): 1–39. [3] Alter M, Kruszon-Moran D, Nainan O, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341(8):556–62. [4] Murphy EL, Bryzman S, Williams AE, et al. Demographic determinants of hepatitis C virus seroprevalence among blood donors. JAMA 1996;275(13):995–1000. [5] Alter M, Hadler S, Judson F, et al. Risk factors for acute non-A non-B hepatitis in the United States and association with hepatitis C virus infection. JAMA 1990;264(17):2231–5. [6] Howell C, Jeffers L, Hoofnagle JH. Hepatitis C in African Americans: summary of a workshop. Gastroenterology 2000;119(5):1385–96. [7] Schreiber G, Busch M, Kleinman S, et al. The risk of transfusion-transmitted viral infections. The Retrovirus Epidemiology Donor Study. N Engl J Med 1996;334(26): 1685–90. [8] Conry-Cantilena C, VanBaden M, Gibble J, et al. Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection. N Engl J Med 1996; 334(26):1691–6. [9] Briggs M, Baker C, Hall R, et al. Prevalence and risk factors for Hepatitis C virus infection at an urban Veterans Administration Medical Center. Hepatology 2001;34(6):1200–5. [10] Ruiz J, Molitor F, Plagenhoef J. Trends in hepatitis C and HIV Infection among inmates entering prisons in California 1994 vs. 1999. AIDS 2002;16(16):2236–8. [11] Baillargeon J, Wu J, Kelley M, et al. Hepatitis C seroprevalence among newly incarcerated inmates in the Texas correctional system. Public Health 2003;117(1):43–8. [12] Kiyosawa K, Sodeyama T, Tanaka E, et al. Hepatitis C in hospital employees with needlestick injuries. Ann Intern Med 1991;115(5):367–9. [13] Mitsui T, Iwano K, Masuko K, et al. Hepatitis C virus infection in medical personnel after needlestick accident. Hepatology 1992;16(5):1109–14. [14] Alter M, Gerety R, Smallwood L, et al. Sporadic non-A non-B hepatitis: frequency and epidemiology in an urban US population. J Infect Dis 1982;145:886–93. [15] Wejstal R, Widell A, Mansson AS, et al. Mother-to-infant transmission of hepatitis C virus. Ann Intern Med 1992;117:887–90. [16] Roudot-Thoraval F, Pawlotsky J, Thiers V, et al. Lack of mother-to-infant transmission of hepatitis C virus in human immunodeficiency virus-seronegative women: a prospective study with hepatitis C virus RNA testing. Hepatology 1993;17(5):772–7. [17] Ohto H, Terazawa S, Sasaki N, et al. Transmission of hepatitis C virus from mothers to infants. N Engl J Med 1994;330(11):744–50. [18] Pier-Angelo T, Palomba E, Ferraris G, et al. Increased risk of maternal-infant hepatitis C virus transmission for women coinfected with human immunodeficiency virus type 1. Clin Infect Dis 1997;25:1121–4. [19] Gibb DM, Goodall RL, Dunn DT, et al. Mother-to-child transmission of hepatitis C virus evidence for preventable peripartum transmission. Lancet 2000;356:904–7. [20] Zanetti A, Tanzi E, Paccagnini S, et al. Mother-to-infant transmission of hepatitis C virus. Lancet 1995;345:289–91. [21] Eyster M, Alter H, Aledort L, et al. Heterosexual cotransmission of hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Ann Intern Med 1991;115(10):764–8. [22] Management of hepatitis C: 2002. NIH Consensus State Sci Statements. 2002; Jun 10–12; 19:1–4.

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[46] Thomas DL, Vlahov D, Solomon L, et al. Correlates of hepatitis C virus infections among injection drug users. Medicine (Baltimore) 1995;74(4):212–20. [47] Lorvick J, Kral AH, Seal K, et al. Prevalence and duration of hepatitis C among injection drug users in San Francisco, Calif. Am J Public Health 2001;91(1):46–7. [48] Romagnuolo J, Jhangri GS, Jewell LD, et al. Predicting the liver histology in chronic hepatitis C: how good is the clinician? Am J Gastroenterol 2001;96(11):3165–74. [49] Pradat P, Alberti A, Poynard T, et al. Predictive value of ALT levels for histologic findings in chronic hepatitis C: a European collaborative study. Hepatology 2002;36:973–7. [50] Bacon B. Treatment of patients with hepatitis C and normal serum aminotransferase levels. Hepatology 2002;36:S179–84. [51] Gupta S, Bent S, Kohlwes J. Test characteristics of alpha-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C. A systematic review and critical analysis. Ann Intern Med 2003;139(1):46–50. [52] Dienstag J. The role of liver biopsy in chronic hepatitis C. Hepatology 2002;36:S152–60. [53] Wai CT, Greenson J, Fontana R, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003; 38(2):518–26. [54] Bravo A, Sheth S, Chopra S. Current concepts: liver biopsy. N Engl J Med 2001;344(7): 495–500. [55] Batts K, Ludwig J. Chronic hepatitis. an update on terminology and reporting. Am J Surg Pathol 1995;19:1409–17. [56] Harisinghani M, Hahn P. Computed tomography and magnetic resonance imaging evaluation of liver cancer. Gastroenterol Clin North Am 2002;31(3):759–76. [57] Laing AD, Gibson RN. MRI of the liver. J Magn Reson Imaging 1998;8(2):337–45. [58] Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358(9286):958–65. [59] UNOS. The US Scientific Registry of Transplant Recipients and the Organ Procurement and Transplantation Data 1989–1996. Washington, DC: US Department of Health and Human Resources; 1997. [60] Kamath P, Wiesner R, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001;33:464–70. [61] Reid AE. Nonalcoholic steatohepatitis. Gastroenterology 2001;121(3):710–23. [62] Hourigan LF, Macdonald GA, Purdie D, et al. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 1999;29(4):1215–9. [63] Czaja AJ, Carpenter HA, Santrach PJ, et al. Host- and disease-specific factors affecting steatosis in chronic hepatitis C. J Hepatol 1998;29(2):198–206. [64] Monto A, Alonzo J, Watson J, et al. Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus and alcohol. Hepatology 2002;36(3):729–36. [65] Peters M, Terrault N. Alcohol use and hepatitis C. Hepatology 2002;36(5):220–5. [66] Khan KN, Yatsuhashi H. Effect of alcohol consumption on the progression of hepatitis C virus infection and risk of hepatocellular carcinoma in Japanese patients. Alcohol Alcohol 2000;35(3):286–95. [67] Thomas DL, Astemborski J, Rai RM, et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA 2000;284(4):450–6. [68] Bissell D, Gores G, Hoofnagle J. Drug-induced liver injury: mechanisms and test systems. Hepatology 2001;33:1009–13. [69] Seef L, Cuccherini B, Zimmerman H, Adler E, Benjamin S. Acetaminophen hepatotoxicity in alcoholics. Ann Intern Med 1986;194:399–404. [70] Bassett S, di Besceglie A, Bacon B, et al. Effects of iron loading on pathogenicity in hepatitis C virus-infected chimpanzees. Hepatology 1999;29:1884–92. [71] Seeff L, Lindsay K, Bacon B, et al. Complementary and alternative medicine in chronic liver disease. Hepatology 2001;34:595–603.

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Treatment of the hepatitis C virus in patients coinfected with HIV Mandana Khalili, MDa,*, Nicole Proietti, PA-Ca a

University of California, San Francisco, San Francisco General Hospital, 1001 Potrero Avenue, NH-3D, San Francisco, CA 94110, USA

The quality of life and survival of individuals with HIV infection has improved significantly with use of potent antiretroviral regimens and continued prevention and treatment of opportunistic infections. Hepatitis C virus (HCV) infection now is considered an opportunistic infection in individuals with HIV, as liver-related complications are recognized increasingly as a contributing cause of morbidity and mortality in this population [1]. Additionally, coinfection with HIV and HCV is common, presumably because of shared modes of transmission of these viruses. In United States, it is estimated that the prevalence of HCV in individuals with HIV ranges from 16% to 25% [2,3]. There is substantial variability in HCV prevalence among different risk groups, however, with significantly higher rates in the intravenous drug users (50% to 90%) [4–7] and the hemophiliacs (up to 85%) [8]. In a representative cohort of 57,064 patients with HIV from the United States Adult AIDS Clinical Trials Group (ACTG), the overall HCV prevalence was estimated at 16% [2]. Among patients defined as being at risk (intravenous drug users and hemophiliacs), however, 73% were HCV-positive [2]. On the other hand, among those in the lower risk categories including men who have sex with men, persons with heterosexual exposure, and health care workers with exposure, the overall prevalence of coinfection was much lower at 3.5% [2]. In addition, HIV coinfection appears to enhance sexual and vertical transmission of HCV, and in turn the presence of HCV enhances vertical transmission of HIV [9–11]. Therefore, implementation of effective strategies for the management and prevention of HCV in the setting of HIV coinfection has become the focus of attention in the new millennium. Understanding the impact of HCV and HIV on the diagnosis and natural history of these viruses and their contribution to * Corresponding author. E-mail address: [email protected] (M. Khalili). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.04.002

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patient morbidity is essential in the management of HCV in individuals with HIV. Diagnosis of hepatitis C virus The approach toward HCV diagnosis is unchanged in the presence of HIV infection. The third-generation US Food and Drug Administration (FDA)-approved enzyme immunoassay (EIA) has a high sensitivity and specificity (greater than 99% and 99% respectively) and is suitable for screening at-risk populations [12]. Additionally, 60% to 90% of HIV coinfected HCV antibody-positive patients are viremic with detectable HCV RNA level by polymerase chain reaction (PCR) [13,14]. Despite the high sensitivity of these tests, EIAs can result in an estimated 4% false negative rate in the presence of HIV coinfection [15]. This false negative antibody rate may vary depending on the mode of acquisition of HIV [16], and it has been attributed to several possible factors, including impaired HCV antibody production with immunosuppression [14], more rapid decline in HCV antibody titer, an anti-HCV seroreversion into a negative state [17], and possible interaction between the two viruses. On the other hand, the hypergammaglobulinemia reported in HIV infection can lead to a false positive EIA anti-HCV result [18]. There are also inconsistencies in the results of the confirmatory recombinant immunoblot assay (RIBA) for HCV; 10% to 40% of RIBA results can be indeterminate in the setting of coinfection with HIV [19]. Therefore, while patients should be screened by an EIA assay, measurement of serum HCV RNA may be required for the diagnosis of HCV in individuals with undetectable antibody but evidence of chronic liver disease [1]. HCV RNA may be detected in individuals with HIV coinfection by either the more sensitive qualitative tests or quantified by means of target amplification (PCR or transcription mediated amplification) or signal amplification techniques (branched DNA assay) [20]. The quantitative HCV RNA assays are used before and during HCV therapy to evaluate treatment response. Hepatitis C virus viral replication in the setting of HIV Hepatitis C virus replication is enhanced in the presence of HIV. Among individuals with HCV, HCV RNA levels increase immediately after HIV seroconversion [21]. Additionally, serum and liver HCV RNA levels are generally higher in HIV-positive compared with HIV-negative individuals [2,13,14,21,22]. HIV also may affect hepatitis C viral heterogeneity, as HCV quasispecies selection has been attributed to immune status [23,24]. Immune restoration associated with successful antiretroviral therapy also may impact quasispecies diversity. In a retrospective study comparing HIV/ HCV coinfected patients with or without highly active antiretroviral therapy (HAART) and on either short-term or prolonged HAART therapy,

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prolonged HAART therapy and immune restoration resulted in an increased HCV viral load and quasispecies diversity [25]. The enhanced HCV viral replication and possible increased HCV diversity in individuals coinfected with HIV potentially can affect response to anti-HCV therapy.

Impact of HIV on the course of hepatitis C virus infection: implications for hepatitis C virus therapy HIV coinfection has been associated with a more rapid progression of liver disease and a higher prevalence of cirrhosis and hepatocellular carcinoma [26–29]. In parenterally acquired HCV infection, there is a significantly higher incidence of cirrhosis within the first 15 years of follow-up in HIVpositive compared with HIV-negative individuals (15% to 25% versus 2.6% to 6.5%; respectively, P less than 0.05) [30,31]. The overall relative risk of severe liver disease in patients with HIV/HCV coinfection is estimated to be 2.92 times higher than HIV-uninfected HCV-positive patients (95% confidence interval [CI], 1.70 to 5.01) [32]. The risk of end-stage liver disease appears to significantly increase with each decade of HCV infection (relative risk [RR], 2.26, 95% CI, 1.42 to 3.59, P = 0.0006) [33], resulting in a shorter time to cirrhosis in HIV-infected individuals (7 versus 23 years, P less than 0.001) [30]. Factors associated with an increased rate of liver fibrosis in the coinfected population included alcohol consumption greater than 50g per day, age at infection younger than 25 years, and CD4 counts less than 200 cells/lL [27]. Despite a more rapid rate of liver disease progression, the impact of coinfection with HIV on patient mortality is less clear and requires further study. Although some have reported a higher rate of liverrelated mortality in HIV/HCV coinfected patients [29,34], others have not shown any effect on survival [35,36]. The negative impact of HIV on the natural history of HCV, however, increases the necessity of HCV treatment in this population but can also influence HCV treatment response rates. Higher pretreatment fibrosis scores are associated with lower virologic response rates. It is also important to note that a significant proportion of coinfected patients with normal alanine aminotransferase (ALT) may have histologic advanced fibrosis, and no clear clinical or virologic factors appear to reliably identify patients with advanced fibrosis [37]. Therefore, liver biopsy is important in confirming the etiology and determining the severity of liver disease before HCV therapy in this population.

Impact of hepatitis C virus on HIV infection: implications for hepatitis C virus therapy Data regarding the influence of HCV infection on the natural history of HIV disease are conflicting. Most pre-HAART studies failed to show a direct alteration of the course of HIV in the presence of HCV coinfection.

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More recently in the post-HAART era, some have shown a negative impact of HCV on natural history of HIV [38,39], while others have failed to find an effect [40]. In the Swiss HIV cohort of over 3000 patients starting potent antiretroviral therapy, progression to an AIDS-defining clinical event or death was associated independently with HCV coinfection (RR, 1.7, 95% CI, 1.26 to 2.3). Additionally, HCV status was associated with a smaller CD4 count recovery with HAART [38]. In the urban United States cohort, however, HCV infection did not alter the risks of death, acquisition of an AIDS -defining illness, or response to HAART substantially, but HIV management was compromised by HCV coinfection [40]. HAART was less likely to be initiated (possibly because of known risk of HAART-induced hepatotoxicity) in patients with HCV, and duration of HAART was shorter in patients with HCV except in patient subgroups with CD4 counts below 50 cells/lL [40]. The influence of HCV coinfection on HIV management has been noted in other studies; patients with HIV infection alone were treated significantly more often and earlier than those without coinfection [29,41]. Additionally, HCV coinfection may decrease the tolerability of these medications further, resulting in an indirect adverse effect on the course of their HIV disease [42,43]. Controlled HIV disease is important when considering HCV treatment; higher CD4 counts have been associated with improved HCV treatment response [44,45]. The mechanism of HAART-associated hepatotoxicity is not defined clearly but is likely multifactorial, including immune-mediated with enhanced inflammatory responses following immune restoration, direct hepatotoxicity, or possible alteration in drug metabolism in the setting of liver dysfunction. The risk of severe hepatotoxicity, however, appears to be low. In a cohort of 141 HIV patients, use of ritonavir and saquinavir resulted in a greater than fivefold increase in serum transaminases in 10% of cases. The risk of hepatotoxicity was associated with pre-HAART abnormal liver enzymes and coinfection with chronic HCV or hepatitis B virus (HBV) (RR, 5.0, 95% CI, 1.5 to 16.9) [42]. Similarly, in a recent prospective cohort of 298 patients, the incidence of severe hepatotoxicity was approximately 10%, but this toxicity occurred more frequently with ritonavir compared with other protease inhibitors (PIs) such as indinavir and nelfinavir [46]. Data from the Swiss cohort study evaluating 1160 patients showed a comparable prevalence of severe and serious adverse events, including hepatotoxicity in single-PI and PI-sparing antiretroviral treatments (9% versus 16%, respectively) [47]. Compared with single-PI use, treatment with dual-PI and three-class-antiretrovirals was associated with higher prevalence of adverse events (odds ratio [OR] 2.0 and 3.9, respectively) [47]. Use of nonnucleoside reverse transcriptase inhibitors (NNRTIs), especially nevirapine, also has been associated with severe hepatotoxicity in some [48], but not all studies [49]. The risk of NNRTI-associated hepatotoxicity was twofold higher in coinfected individuals and in those who also received PIs [48]. The relationship between the observed elevations of liver enzymes with HAART

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and induction of acute liver failure is not defined well. In one study evaluating histologic and clinical outcomes in 755 HIV seropositive patients, the incidence of severe hepatotoxicity resulting in HAART discontinuation was 4.2 per 100 person-years of use of HAART, and this occurred mainly in those with viral hepatitis infection [50]. Liver failure, however, was rarely seen (1.1 per 100 person-years) [50]. Therefore, perhaps HAART can be continued in some patients despite elevation of liver enzymes [51]. It has been suggested that perhaps HAART may have beneficial or detrimental effects in various subgroups of HCV-coinfected individuals. For example, in one retrospective study, patients with higher ALT levels at the initiation of HAART showed a significant decrease in ALT, whereas those with normal ALT levels at baseline had a significant increase in ALT over time [36]. These factors may influence the priority of anti-HCV versus antiHIV therapy in coinfected individuals.

Priority of antiviral therapy in the hepatitis C virus/HIV coinfected individuals Several factors should be considered when discussing the priority of initiation of anti-HIV and anti-HCV therapy in the coinfected patient (Box 1). First, HIV therapy with HAART may have a beneficial impact on HCVinduced liver fibrosis progression [52,53]. Second, some have shown that

Box 1. Factors that may influence decision to initiate anti-HCV therapy Favoring therapy Stable HIV disease Higher CD4 counts Stable HAART regimen No active opportunistic infections More advanced stage of fibrosis on liver histology Compensated liver disease Favorable HCV genotypes (2 and 3) Inability to tolerate HAART because of underlying HCV disease (irrespective of CD4 counts) Favoring deferral of therapy Recent change in HAART or planning to change HAART HAART-related adverse effects likely to be exacerbated by anti-HCV therapy Inability to comply with anti-HCV treatment regime

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immune reconstitution associated with PI therapy can help to reduce HCV viral load [54], but the impact of HAART on HCV RNA levels in coinfected individuals remains to be defined clearly [55]. If indeed proven to be true, the reduction in HCV viral load in addition to HAART-induced immune restoration may result in improved efficacy of anti-HCV therapy, and therefore, initiation of HAART therapy should be a priority in managing the coinfected population. On the other hand, chronic HCV is an independent risk factor for HAART-induced hepatotoxicity, and previous treatment for HCV appears to be associated with a decreased rate of severe hepatotoxicity following initiation of HAART. In a recent prospective study, the rate of HAART hepatotoxicity was evaluated in 66 patients pretreated for HCV either with interferon (IFN) or in combination with ribavirin (36% of patients were sustained virologic responders) compared with 39 patients not treated for HCV [56]. Overall, 9.5% of patients experienced severe hepatotoxicity in this study. The rate of discontinuing HAART because of severe hepatotoxicity (defined as ALT at least five times upper limit of normal or a 3.5 times increase from baseline if ALT is elevated) was significantly higher in the HCV untreated group (RR, 10.4, 95% CI, 1.6 to 66; P = 0.01) after adjusting for baseline CD4 counts, ALT levels, histologic scores, HCV and HIV viremia, HCV genotype, and previous anti-HCV therapy [56]. Additionally, it has been shown that patients with HIV infection alone are treated significantly more often and earlier than those with HCV coinfection [29,40,41]. Therefore, HCV eradication may decrease the rate, albeit low, of severe HAART-induced hepatotoxicity and may influence initiation and duration of HAART therapy. Coinfected patients with stable HIV disease should be evaluated for HCV therapy. In some coinfected individuals with HAART-induced hepatotoxicity, HCV eradication may improve tolerability to HAART. Liver enzymes should be monitored carefully in patients on HAART, especially in the setting of viral hepatitis coinfection.

Hepatitis C virus therapy in HIV coinfected individuals The goals of HCV treatment in the presence of HIV include viral eradication, decreasing the rate of liver disease progression, and better tolerance of anti-HIV medications. These benefits must be weighed against the adverse effects of anti-HCV therapy and possible interactions of antiHIV and anti-HCV treatment. The 2002 National Institutes of Health Consensus Development Conference on the management of HCV recommends treatment of HCV in the HIV-coinfected individuals on a caseby-case basis [12]. Patients with adequately controlled HIV disease (CD4 counts greater than 150), compensated liver disease, and evidence of chronic hepatitis C on liver biopsy should be evaluated for HCV treatment. HCV therapy also may be considered in some patients with lower CD4 counts to allow for better tolerability of HAART. Liver biopsy aids in establishing the

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diagnosis of chronic HCV, excluding concurrent conditions such as drug hepatotoxicity, and identifying individuals at risk of progression of liver disease. These individuals must not have any evidence of active opportunistic infection and must be stable on antiretroviral therapy. Interferon monotherapy Studies assessing the role of IFN monotherapy in HIV/HCV coinfection have been predominantly of small sample size, nonrandomized, and uncontrolled (Table 1). Additionally, there is variation in the dosage and duration of IFN among studies, including IFN induction dosing and dose escalation. The end-of-therapy and sustained (6 months following end of therapy) biochemical and virologic response rates to IFN monotherapy, however, appear to be similar to individuals with HCV infection alone (4% to 55% and 0% to 29%, respectively). Factors associated with achieving a virologic response include higher baseline CD4 counts, lower baseline HCV RNA levels, and Table 1 Interferon monotherapy for Hepatitis C in HIV coinfected patients

Reference (number)

N

Interferon

Nardiello, 1992 [84] Boyer, 1992 [85] De Sancitis, 1993 [86] Marriott, 1993 [87] Marcellin, 1993 [88] Arcias, 1994 [89] Pol, 1995 [90] Soriano, 1996 [44]

21 12 20 14 20 10 31 80 HIV/HCV

3 MU
6 mo 1,3,5 MU
6 mo 3 MU
18 mo 9 MU
6 mo 3 MU
6 mo 3 MU
6 mo 3 MU
6 mo 5 MU
3 mo, then 3 MU
12 mo

Mauss, 1998 [45] Prestileo, 2000 [91] Bruno, 2000 [92]

End of Sustained therapy virologic response (%) response (%) 45 33 NA 55 30 40 23 32

27 8 25 44 15 20 0 22

27 HCV 17 27 50

37 47 4 20

26 29 4 NA

Causse, 2000 [93]

28

18

11

Hayashi, 2000 [94]

36 7

36 57

17 0

Beurton, 2001 [95]

58

N/A

14

Hanabusa, 2002 [96]

15

58

33

67

40

15

5 MU
12 mo 3–6 MU
6–12 mo 3 MU once daily
12 mo HIV/HCV 3 MU three times weekly
6 mo HCV 9 MU once daily
2 wk, then three times weekly
22 wk 3 MU three times weekly
12 mo HIV/HCV 9 MU once daily
2 wk, then three times weekly
22 wk HCV

Abbreviations: N, number of patients; MU, million units.

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genotype 3a [44,45]. Histologic responses also have been observed with IFN treatment. In a retrospective cohort of 79 patients comparing histologic response to IFN in patients with coinfection and those with HCV alone, the rate of histologic improvement (defined as at least a 2-point drop in total Knodell score on paired liver biopsies) was similar in the two cohorts, despite a lower sustained virologic responses in the coinfected group (6% versus 30%) [57]. Treatment with IFN does not appear to impact HIV parameters. CD4 cell counts may decrease in about 5% of individuals during HCV therapy [58], but the percentage of CD4 counts and HIV RNA levels remain unchanged [59]. Standard interferon and ribavirin combination therapy In patients with HCV infection alone, combination therapy with IFN and ribavirin has been associated with sustained hepatitis C virologic responses of approximately 40% overall [60]. Factors associated with a lower rate of virologic response to antiviral therapy are as follows: male gender, age older than 40 years, HCV genotype 1, high HCV viral load (greater than 2,000,000 copies/mL), and increased liver fibrosis [60]. Published reports evaluating the role of IFN in combination with ribavirin in patients with HIV coinfection are limited in number, and studies are of small sample size. Combination therapy appears to be tolerated reasonably well, however, and rates of sustained virologic response are better than those obtained with IFN alone (Table 2). The end-of-treatment and sustained virologic response rates vary from 13% to 73% and 13% to 40%, respectively [61–63]. In most series, however, the sustained virologic response with combination therapy is less than 25% in patients with HIV. Factors associated with sustained virologic response with combination therapy appear to be similar to that observed with IFN alone [64]. Recently, a large randomized controlled trial of 180 coinfected patients suggested that daily IFN in combination with Table 2 Interferon and ribavirin for hepatitis C in HIV coinfected patients

Reference

N

Interferon/ribavirin dosage

Morsica, 2000 [62]

12

Nasti, 2001 [97]

17

Sauleda, 2001 [63]

20

Landau, 2001 [64] Rockstroh, 2002 [61]

51 23

6 MU/800–1200 mg once daily
6 mo 3 MU/1000–1200 mg once daily
6 mo 3 MU/800mg once daily
12 mo 3 MU/1000–1200 mg
12 mo 5 MU once daily
10 wk, then three times weekly
36 wks/1200 mg once daily

Abbreviations: N, number of patients; MU, million units.

End of therapy virologic response (%)

Sustained virologic response (%)

73

NA

31

19

55

40

29 13

22 13

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ribavirin may be more effective in obtaining sustained virologic response than a standard IFN regimen administered three times weekly (43% versus 28%, P = 0.03) [65]. In this study, early virologic response at 12 weeks was a strong predictor of sustained virologic response (negative predictive value 94%) [65]. The discontinuation rate because of adverse effects was similar in both groups, and HIV RNA levels were not changed significantly. The impact of modified regimens of IFN in the coinfected population on HCV treatment response requires further assessment, but regimes using daily IFN have been superceded largely by those using pegylated IFNs. In coinfected individuals who have relapsed or not responded to IFN monotherapy, response to IFN and ribavirin combination therapy appears to be low. Zylberberg et al evaluated the efficacy of IFN and ribavirin combination therapy in 21 coinfected individuals with predominantly genotype non-1 infection (52%) on antiretroviral therapy, and prior IFN nonresponse or relapse [66]. After receiving combination therapy for a mean duration of 8.5 plus or minus 3 months, the end-of-therapy and sustained response rates were 28.5% and 14.3%, respectively [66]. In this study, anemia was a frequent adverse event associated with ribavirin, requiring dose reduction or discontinuation of ribavirin in approximately 10% of individuals [66]. The potential for drug–drug interactions can add to the complexity of HCV therapy in the coinfected population. There is evidence of increased mitochondrial toxicity during HCV combination therapy in the patients with HIV on HAART possibly related to ribavirin and its potential inhibitory effect on mitochondrial DNA polymerase [67]. For example, there are several reports of fatal lactic acidosis and severe pancreatitis with use of didanosine and ribavirin [67–69]. Ribavirin can facilitate intracellular phosphorylation of didanosine with conversion into its active metabolite. Consequently, the use of ribavirin should be avoided in patients taking didanosine [70]. Additionally, there are concerns about the potential for in vitro antagonism between ribavirin and pyrimidine nucleoside analogs used as part of HAART regimen [71]. In most clinical studies, however, there has been no significant effect on HIV parameters observed during HCV therapy [66,72]. The potential interactions of anti-HCV medications with HIV antiretroviral therapy remain an important area of study. Pegylated interferon (peginterferon) and ribavirin combination therapy Pegylation of IFN delays the clearance of the drug, permitting once weekly dosing. In patients with HCV infection alone, the combination of peginterferon and ribavirin has resulted in a higher overall sustained virologic responses of approximately 55% [73,74]. The efficacy of peginterferon therapy in coinfected individuals is being evaluated. In a recently published study of 68 patients, combination therapy with peginterferon alpha-2b (100 to 150 lg weekly) and ribavirin (800 mg daily) resulted in an overall sustained virologic response of 35% (24% in genotype 1 or 4 and

488

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52% in genotype 3) [68]. Although genotype 3 was the best predictor of end-of-treatment response, a low baseline HCV viral load (below 800,000 IU/mL) was the best predictor of sustained response [68]. Treatment was tolerated reasonably well; treatment discontinuation because of adverse effects occurred in 15% of patients. Severe pancreatitis and increase in lactate levels were noted in some patients taking didanosine or stavudine, however, emphasizing the need for caution with use of these medications in patients receiving ribavirin. Ribavirin dose reduction because of anemia was required in 5.5% of patients. In this study. ribavirin dosage was not a predictor of virologic response [68]. Preliminary results from large randomized controlled trials of peginterferon alone or in combination therapy in coinfected patients are available. In a United States national trial of 154 patients, peginterferon alpha-2a alone resulted in either the loss of HCV RNA or at least 2-log reduction in the HCV RNA levels in 38% of coinfected patients at 3 months of therapy, and 36% of those who responded at 3 months had a sustained virologic response [75]. The overall sustained virologic response, however, was low, at 14%. In this study, nearly all sustained virologic responders had at least a 2-log reduction in the HCV RNA by month 3 of therapy, and the addition of ribavirin to the nonresponder group resulted in only one additional sustained virologic response. Similar to previous reports, 16% of patients discontinued treatment because of adverse events [75]. The results from the ACTG trial evaluating 133 patients revealed that 27% of patients had virologic response after 48 weeks of peginterferon alpha-2a and ribavirin combination compared with 12% with standard IFN combination therapy (P = 0.03) [76]. In multivariate analysis, use of peginterferon, non-1 genotype, no prior injection drug use, and detectable base-line HIV RNA were associated with virologic response. Among virologic nonresponders, the week 24 biopsy showed a 36% histologic response [76]. Although severe adverse events were observed more frequently in the peginterferon group, the rates of treatment discontinuation were similar in both groups [76]. HIV parameters were not affected significantly in either of the studies. In the RIBAVIC study, 412 patients were randomized to standard IFN and ribavirin or peginterferon alpha-2b and ribavirin therapy. In an intention-to-treat analysis, virologic response was achieved in 18% of the standard IFN group and in 26% of the peginterferon group (P = 0.01) [77]. Patients with genotypes 1 and 4 had a lesser chance of response with peginterferon-based therapy (11% versus 43%) [77]. Significant adverse events occurred in 31% of patients and were similar in both groups [77]. Similarly in the APRICOT (AIDS Pegasys Ribavirin International Coinfection Trial) study of 868 patients, the combination of peginterferon alfa-2a and ribavirin was superior to conventional interferon and ribavirin combination therapy (40% versus 12%, P less than 0.0001) [78]. Based on these studies, peginterferon combination therapy appears to be more effective than standard IFN in patients coinfected with HIV, but overall

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the response rates are lower than observed in those with HCV infection alone. Several factors may contribute to the lower virologic responses to HCV therapy in the coinfected population. These include a high prevalence of the HCV genotype 1 (65% to 83%), higher HCV RNA viral levels (up to 66% with HCV RNA above 800,000 IU/mL), and a higher prevalence of advanced liver disease [2,68]. Given these evolving data, treatment of HCV in the setting of HIV needs to be considered on a case-by-case basis [12]. Barriers to hepatitis C virus treatment in the setting of HIV There are limited data on potential barriers to initiation of HCV therapy in patients with HIV coinfection. In one urban center with 1250 patients with HIV, only 30% of patients were eligible to receive IFN and ribavirin combination treatment [79]. The main barriers to treatment included missed clinic visits, active psychiatric illness, active drug or alcohol use, decompensated liver disease, and medical illness [79]. In another study, only 5 out of 51 coinfected patients enrolled for HCV treatment [80]. In this study, severe psychiatric illness (26%), current drug use or excessive alcohol use (20%), and cytopenias (15%) were among the major barriers to treatment. Additionally, 26% of patients chose not to participate because of the rigorous treatment regimen and time commitment [80]. Liver transplantation in HIV/hepatitis C virus coinfected individuals Hepatitis C virus coinfection results in higher incidence of cirrhosis and hepatocellular carcinoma in patients with HIV coinfection [26–29]. Although liver transplantation is considered the treatment of choice for those with end-stage liver disease caused by HCV, liver transplantation is considered experimental in patients with HIV coinfection. Several reports have emerged from large centers evaluating transplantation in the HCVcoinfected population. Researchers from the University of California at San Francisco recently summarized their kidney and liver transplantation experience in HIV-infected individuals. All patients had undetectable HIV RNA for at least 3 months before transplantation and CD4 counts greater than 200 cells/lL in kidney recipients and greater than 100 cells/lL in liver recipients before transplantation [81]. Ten patients underwent kidney transplantation (mean follow-up 480 days), and four received liver transplants (mean follow-up 380 days) with a 100% and 75% survival rates in the kidney and liver recipients, respectively [81]. There was no evidence of rejection in the liver recipients, and all patients had undetectable HIV RNA levels post-transplant [81]. Although the overall results from this study appear encouraging, only one patient was transplanted for HCV disease, and this patient died from recurrence of HCV. Similarly, the European experience has been disappointing, where three of the five patients with HCV/HIV coinfection died of severe HCV recurrence 12 to 25 months

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following transplantation [82]. These reports contrast with the experience of the universities of Miami and Pittsburgh [83]. Among the 10 HIV/HCV infected patients who underwent liver transplantation, 66% to 100% had HCV recurrence, and the 2-year actuarial survival was 80% [83]. Given the mixed results obtained, the role of liver transplantation in HCV/HIV coinfected individuals requires ongoing careful assessment. Summary Individuals with HIV infection should be screened for HCV and assessed for HCV treatment; additionally, the decision to treat should be determined on a case-by-case basis. The limited information to date indicates that HCV therapy in the HIV-infected individual is effective, and peginterferon in combination with ribavirin results in the greater virologic response compared with other regimens. The treatment response rates, however, are lower than those observed in individuals with HCV infection alone. The benefits of HCV therapy, including viral eradication and histologic improvement, should be weighed against the adverse effects of therapy and possible anti-HCV and anti-HIV drug interaction. There are emerging data on liver transplantation as a treatment modality in HCV/HIV infected individuals with end-stage liver disease, but long-term outcomes have not been defined, and HCV recurrence appears to be a significant problem following transplantation.

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[78] Torriani FJ, Rochstroh J, Rodrigue-Torres M, Lissen E, Gonzalez J, Lazzarin A, et al. Final results of APRICOT: A randomized, partially blinded, international trial evaluating peginterferon-alfa-2a þ ribavirin vs interferon alfa-2a þ ribavirin in the treatment of HCV in HIV/HCV co-infection. Presented at the 11th Conference on Retrovirus and Opportunistic Infections, February 8–11, 2004, San Francisco, CA. [79] Fleming CA, Craven DE, Thornton D, Tumilty S, Nunes D. Hepatitis C virus and human immunodeficiency virus coinfection in an urban population: low eligibility for interferon treatment. Clin Infect Dis 2003;36(1):97–100. [80] Taylor LE, Costello T, Alt E, Yates G, Tashima K. Psychiatric illness and illicit drugs as barriers to hepatitis C treatment among HIV/hepatitis C virus coinfected individuals. AIDS 2002;16(12):1700–1. [81] Stock PG, Roland ME, Carlson L, Freise CE, Roberts JP, Hirose R, et al. Kidney and liver transplantation in human immunodeficiency virus-infected patients: a pilot safety and efficacy study. Transplantation 2003;76(2):370–5. [82] Prachalias AA, Pozniak A, Taylor C, Srinivasan P, Muiesan P, Wendon J, et al. Liver transplantation in adults coinfected with HIV. Transplantation 2001;72(10): 1684–8. [83] Neff GW, Bonham A, Tzakis AG, Ragni M, Jayaweera D, Schiff ER, et al. Orthotopic liver transplantation in patients with human immunodeficiency virus and end-stage liver disease. Liver Transpl 2003;9(3):239–47. [84] Nardiello SGM, Pizella T, et al. Interferon treatment for chronic HCV and NANB hepatitis in HIV seropositive patients. In: Programs and abstracts of the 8th International Conference on AIDS; 1992. Amsterdam (The Netherlands): CONGREX Holland BV; 1992. p. A3373. [85] Boyer NMP, Degott C, Degos F, Saimot AG, Erlinger S, Benhamou JP, et al. Recombinant interferon-a for chronic hepatitis C in patients positive for antibody to human immunodeficiency virus. J Infect Dis 1992;165:723–6. [86] De Sanctis GMEG, Barbacini IG, Bergami N, Chireu LV. Long-term outcome of chronic hepatitis infection in HIV þ subject treated with interferon. In: Programs and Abstracts of the 9th International Conference on AIDS; 1993. Berlin: Institute for Clinical and Experimental Virology of the Free University of Berlin; 1993. p. A1822. [87] Marriott ENS, del Romero J, Garcia S, Castillo I, Quiroga JA, Carreno V. Treatment with recombinant a-interferon of chronic hepatitis C in anti-HIV-positive patients. J Med Virol 1993;40:107–11. [88] Marcellin PBN, Arejas J, Erlinger S, Benhamou JP. Comparison of efficacy of alpha interferon in former intravenous drug addicts with chronic hepatitis C with or without HIV infection. Gastroenterology 1993;106:A938. [89] Arcias JPI, Barrias S, Maros P, Freitas T, Saraiva AM. Pilot study of interferon 2b treatment of chronic hepatitis C in patients coinfected with human immunodeficiency virus. Hepatology 1994;20:A264. [90] Pol S, Thiers V, Trinh T, et al. Chronic hepatitis of drug users: influence of HIV infection. Hepatology 1995;22:A933. [91] Prestileo T, Mazzola G, Di Lorenzo F, Colletti P, Vitale F, Ferraro D, et al. Responseadjusted a-interferon therapy for chronic hepatitis C in HIV-infected patients. Int J Antimicrob Agents 2000;16:373–8. [92] Bruno R, Sacchi P, Filice C, Filice G. Aggressive daily interferon therapy in HIV–HCV coinfected patients. J Acquir Immune Defic Syndr 2000;25(4):372–3. [93] Causse X, Payen JL, Izopet J, Babany G, Girardin MF. Does HIV-infection influence the response of chronic hepatitis C to interferon treatment? A French multi-center prospective study. French Multicenter Study Group. J Hepatol 2000;32(6):1003–10. [94] Hayashi K, Fukuda Y, Nakano I, Katano Y, Yokozaki S, Toyoda H, et al. Poor response to interferon treatment for chronic hepatitis C in human immunodeficiency virus-infected haemophiliacs. Haemophilia 2000;6(6):677–81.

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[95] Beurton I, Bertrand MA, Bresson-Hadni S, Parquet-Gernez A, Goudemand J, Paris JC, et al. Interferon alpha therapy in haemophilic patients with chronic hepatitis C: a French multi-centre pilot study of 58 patients. Eur J Gastroenterol Hepatol 2001;13(7):859–64. [96] Hanabusa H. Efficacy of induction therapy with high-dose interferon for patients with hemophilia and human immunodeficiency virus–hepatitis C virus coinfection. Clin Infect Dis 2002;35(12):1527–33. [97] Nasti G, Di Gennaro G, Tavio M, Cadorin L, Tedeschi R, Talamini R, et al. Chronic hepatitis C in HIV infection: feasibility and sustained efficacy of therapy with interferon alfa-2b and ribavirin. AIDS 2001;15:1783–7.

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Antiviral therapy for treatment naı¨ ve patients with hepatitis C virus Sangik Oh, MD, MMSca,b, Nezam H. Afdhal, MDa,b,* a

Department of Medicine, Harvard Medical School, 25 Shattack Street, Boston, MA 02115, USA b The Liver Center, Beth Israel Deaconess Medical Center, 110 Francis Street, Suite 8E, Boston, MA 02215, USA

Chronic hepatitis C virus (HCV) infection is recognized as a global health problem, with 170 to 200 million people estimated to be infected worldwide. In the United States, chronic HCV is the most common cause of end-stage liver disease, hepatocellular cancer, and the most frequent indication for liver transplantation [1]. Data from the third National Health and Nutrition Examination Survey (NHANES III) estimated that 2.7 million Americans have active HCV infection [2]. This figure probably underestimates the true prevalence of chronic HCV infection, however, as the study excluded highrisk groups such as prisoners and homeless people. HCV infection generally is regarded as ‘‘a disease of decades,’’ as the most significant clinical consequences occur 20 to 30 years after the initial exposure. Approximately 10,000 HCV related deaths occur each year, mostly resulting from end-stage liver disease and development of hepatocellular carcinoma (HCC) [3]. The NHANES study also revealed that HCV prevalence was the highest in persons 30 to 49 years of age. Because of its slowly progressive natural history, the Centers for Disease Control and Prevention (CDC) predict that HCV-associated mortality might double or triple over the next 10 to 20 years [4]. Davis et al estimated that the need for liver transplantation will increase by 528%, and liver-related death might increase by 223% by 2008 [5]. One logical solution is early detection and aggressive antiviral treatment to eradicate HCV or to halt disease progression. This article focuses on the most recent therapies for patients with HCV who are naı¨ ve to therapy. The primary end point for the treatment of naı¨ ve HCV patients is viral eradication or a sustained virological response (SVR), which is defined as the absence of HCV in the serum, as detected by * Corresponding author. E-mail address: [email protected] (N.H. Afdhal). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.04.003

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a sensitive polymerase chain reaction (PCR) test, 24 weeks after stopping antiviral therapy. Recent data suggest that an SVR can be equated with a biochemical, virological, and histological response that is sustained for up to 5 years and is conceptually a cure of HCV in 90% of patients [6]. Some patients fail to clear HCV by PCR while on treatment, and these are classified as nonresponders (NR). Additionally, there is a final group of relapsers, who are able to clear HCV on treatment, but in whom HCV reappears within 24 weeks of stopping treatment. These definitions of patient responses are used in the clinical trials discussed in this article.

Patient selection The indications for therapy for naı¨ ve patients have undergone many revisions over the last 10 years (Box 1). Patients who are HCV-positive by PCR test with an elevated alanine aminotransferase (ALT) and necroinflammation and fibrosis on liver biopsy are obvious candidates for treatment. At the National Institutes of Health (NIH) consensus conference in 2002, however, there was a strong movement toward expanding the number of potential treatment candidates to include people with controlled depressive illness, methadone users, and patients who had stopped using alcohol recently. The other controversial area is whether to treat patients with persistently normal ALT. In the era of interferon (IFN) monotherapy, several case series suggested that patients with normal ALT might experience ALT flares and have a reduced SVR rate if treated with IFN [7,8]. Larger studies with IFN and ribavirin (RBV), however, have shown that ALT flares are not common and that the SVR rate is similar in patients with normal ALT compared with those with elevated ALT [9,10]. The current recommendation is that treatment of patients with normal ALT be considered on an individual basis, and it is believed that these patients will respond equally well to IFN and RBV combination therapy. There remain some absolute contraindications to treatment, and these are listed in Box 1. In particular, therapy should not be undertaken in patients with decompensated liver disease and with active manic depressive disease or recent suicidal ideation. RBV is contraindicated specifically in patients with hemolytic disease, unstable cardiac disease, renal disease with a creatinine above 2.0 mg/dL, and in patients who are pregnant or contemplating pregnancy.

Historical perspective The efficacy of alpha interferon for treatment of HCV first was recognized when Hoofnagle et al published their preliminary findings in 1986 when HCV was known as non-A, non-B hepatitis [11]. They treated 10 patients with chronic non-A, non-B hepatitis with varying doses (0.5 to

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Box 1. Indications and contraindications to therapy Indications Elevated/normal ALT Necro-inflammation and fibrosis on liver biopsy Hepatitis C virus RNA positive Extrahepatic manifestations (renal disease, cryoglobulinemia, porphyria cutanea tarda) Patient preference Contraindications Absolute Severe uncontrolled depression Unstable cardiac disease Uncontrolled concomitant disease Pregnancy Hemolytic diseases Renal disease; creatinine greater than 2 mg/dL Seizure disorder Relative Active drug and alcohol use Moderate depression/situational suicidal ideation Decompensated liver disease Autoimmune diseases

5 million U) up to 12 months. The aminotransferases levels improved in 8 of 10 patients and in 3 patients who had follow-up biopsies done after 1 year of therapy showing marked improvement in liver histology. Several subsequent studies, including a large, multi-center, randomized clinical trial in the United States by Davis et al confirmed the initial finding that long-term IFN therapy improved liver function tests and liver histology [12]. The US Food and Drug Administration (FDA) approved alpha interferon monotherapy for the treatment of chronic HCV infection in 1993. In 1997, The NIH released the consensus statement recommending alpha interferon monotherapy at a dose of 3 million U three times weekly for 48 weeks as the standard of care for patients with chronic HCV infection. There are three IFNs approved for monotherapy in the United States, including IFN alfa 2b, IFN alfa 2a, and consensus IFN (CIFN). Multiple clinical trials of IFN monotherapy have been published using different doses and schedules, and overall there have been no major clinical differences in SVR between the different IFNs. Overall, the rates of SVR have been limited to 6% to 16%. The optimal duration of treatment is 48 weeks for IFN monotherapy. In view of this relatively low response rate, higher doses, longer duration,

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induction doses, and dose escalation have been tried to increase SVR, but none of these variations has been shown prospectively to significantly increase response.

Combination therapy of interferon with ribavirin A major advance occurred when IFN was combined with RBV in the pivotal studies of McHutchison et al [13], and SVR was increased from 13% to 38%. RBV is a nucleoside analog that putatively acts by means of inhibition of RNA-dependent RNA polymerase, depletion of intracellular guanosine triphosphate pools, and by altering Th1 and Th2 cytokine balance in the liver. Initial studies of RBV monotherapy in HCV resulted in biochemical but not histological response [14–16]. Two large randomized controlled clinical trials comparing IFN/RBV combination therapy with IFN monotherapy in HCV infection demonstrated a significant improvement in SVR for combination therapy (Fig. 1) [13,17]. Combination IFN/ RBV therapy became the standard of care for naı¨ ve patients, with a 24-week course of treatment for genotyped 2 and 3 patients and a 48-week course for genotype 1 patients.

70 60 50

S 40 V 30 R 20

Geno 1 Geno Non-1

10 0

IFN 24 wks

IFN 48wks IFN/RBV 24wks

IFN/RBV 48wks

Fig. 1. SVR rates according to genotype for naı¨ ve patients receiving IFN alfa-2b versus combination IFN alfa-2b plus 1000/1200 mg ribavirin daily. In genotype non-1 patients, 24 weeks of combination IFN/RBV was equivalent to 48 weeks with a 62% SVR. For genotype 1 patients, SVR was 29% with 48 weeks of combination therapy (P less than 0.008 compared with IFN monotherapy for 48 weeks). (Adapted from McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998;339(21):1485–92; Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of interferon alfa-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alfa-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998;352(9138):1426–32.)

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501

Pegylated alfa interferon monotherapy Pegylation is a process by which a polyethylene glycol molecule is attached to a protein or drug to decrease renal clearance and increase bioavailability and efficacy. The renal clearance and short half-life of alfa interferons necessitated their administration three times a week and made them an excellent target molecule for pegylation. A critical concept with pegylation of biologically active proteins is the need to achieve a balance between increasing the half-life while maintaining biological activity. Increasing the size of the pegylated component can decrease renal clearance but also reduces the biological activity of the IFN component. There are two forms of peginterferons that have been approved by the FDA for use in chronic HCV; PEG-IFN 2a (Pegasys) IFN and PEG-IFN 2b (PEGINTRON). PEG-IFN 2a has a 40kDa branched chain PEG attached to IFN alfa 2a, and PEG-IFN 2b has a 12kDa straight chain PEG attached to IFN alfa 2b. Both PEG-IFNs retain reduced but effective biological activity while having a favorable pharmacological profile that allows for once weekly administration. These PEG-IFNs have replaced IFN as the preferred form of IFN for use in treatment of HCV infection. Clinical trials have confirmed a twofold increase in efficacy of PEG-IFNs compared with standard IFN in HCV treatment-naı¨ ve patients (Table 1). Zeuzem et al showed that in the SVR was 39% in patients treated with PEGIFN 2a at a dose of 180 lg for 48 weeks compared with 19% in patients taking standard interferon 2a at a dose of 6 mU three times weekly for 12 weeks then 3 mU three times weekly for 36 weeks [18]. In this trial, 62% of the subjects had genotype 1 HCV, and 7% had cirrhosis. In their multivariate analysis, use of PEG-IFN 2a, younger age, smaller body surface area, absence of cirrhosis or bridging fibrosis, a lower HCV RNA level, and a nongenotype 1 infection were associated with higher SVR. Subsequent studies using PEG-IFN 2a have shown a somewhat reduced SVR of 29%. The results are similar in a study from Lindsay et al comparing there doses of PEG-IFN 2b (0.5, 1.0 and 1.5 lg/kg per week) with standard IFN alfa 2b at 3 mU three times weekly for 48 weeks [19]. The SVR was only 12% with standard IFN but 18%, 25%, and 23%, respectively with escalating doses of PEG-IFN 2b. In this study, two pretreatment variables were associated with higher SVR when a multivariate analysis was performed: nongenotype 1 and HCV RNA less than 2 million copies/mL. In a difficult-to-treat population of naı¨ ve patients with advanced fibrosis, defined as bridging fibrosis or cirrhosis, PEG-IFN 2a again demonstrated superior SVR compared with IFN alfa 2a. Heathcote et al randomized 271 patients with cirrhosis or bridging fibrosis into one of three groups: standard IFN alpha-2a at a dose of 3 mU three times weekly; PEG-IFN 2a at a dose of 90 lg; and PEG-IFN 2a at a dose of 180 lg for 48 weeks [20]. The SVR was 30% with PEG-IFN 2a at 180 lg compared with 8% for standard IFN alfa 2a.

502

Study

Zeuzem et al, 2000

Heathcote et al, 2000

Lindsay et al, 2001

Type of IFN

IFN a-2a

PegIFN a-2a

IFN a-2a

PegIFN a-2a

PegIFN a-2a

IFN a-2b

PegIFN a-2b

PegIFN a-2b

PegIFN a-2b

Dose and duration

6 mU for 12 weeks, then 3 mU for 36 weeks

180 lg for 48 weeks

3 mU for 48 weeks

90 lg for 48 weeks

180 lg for 48 weeks

3 mU for 48 weeks

0.5 lg/kg/wk

1.0 lg/kg/wk

1.5 lg/kg/wk

Number of patients

264

267

88

96

87

303

315

297

304

Sustained virological response (95% CI)

19% (14 to 24%)

39% (33% to 45%)

7% (4 to 16%)

15% (9 to 23%)

30% (21% to 40%)

12% (9% to 16%)

18% (14% to 23%)

25% (20 to 30%)

23% (19% to 28%)

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Table 1 Randomized controlled trials of peginterferon monotherapy

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In summary, the pegylation of interferons has resulted in improving the pharmacokinetic (PK) profile, allowing for once weekly administration while improving the biological activity and doubling the SVR rates for IFN alfa 2a and 2b. Pegylated interferon and ribavirin combination therapy A logical extension of the PEG-IFN monotherapy trials was to combine PEG-IFN with RBV, and two large prospective studies have compared combination PEG-IFN/RBV with IFN/RBV. Both trials have demonstrated a significant benefit of the PEG-IFN/RBV combination over standard combination therapy, and PEG-IFN/RBV is the standard of care for naı¨ ve chronic HCV patients currently. Manns et al conducted a randomized clinical trial with PEG-IFN 2b involving 1530 HCV patients from Europe, North America, and Australia [21]. They were randomized into one of three groups: IFN alfa 2b (3 mU three times weekly) with RBV (1000 to 1200 mg daily based on body weight) for 48 weeks, PEG-IFN alfa-2b at 1.5 lg/kg/week with RBV 800 mg daily for 48 weeks, or PEG-IFN alfa-2b at 1.5 lg/kg/week for 4 weeks and then 0.5 lg/kg/week for 44 weeks with standard doses of RBV. The group receiving highest dose of PEG-IFN alfa-2b with RBV achieved highest rate of SVR (54%) when compared with the group that received lower dose of PEG-IFN (47%) and standard IFN (47%) combined with RBV (Table 2). Fried et al conducted a comparable study with PEG-IFN alfa-2a in combination with RBV [22]. A total of 1121 patients were assigned randomly to one of three groups: standard IFN alfa-2b (3 mU three times weekly) with RBV (1000 to 1200 mg daily based on body weight), PEG-IFN alfa-2a (180 lg weekly) with RBV (1000 to 1200 mg daily based on body weight), or PEG-IFN alfa-2a (180 lg weekly) with placebo. All patients were treated for 48 weeks. The SVR was the highest in the group that Table 2 Results from the two clinical trials of peg-interferon and ribavirin Study

Manns et al 2001

Fried et al 2002

Interferon

INF a-2b

PegIFN

PegIFN

IFN a-2b

PegIFN

PegIFN

Regimen

3 mU tiw

a-2b 1.5 lg/ 1.5 lg/ kg/wk kg/wk

3 mU tiw

a-2a 180 lg

a-2a 180 lg

Ribavirin

1000 or 1000 or 1200 mg 1200 mg

800 mg

1000 or Placebo 1200 mg

1000 or 1200 mg

Number of patients

505

511

444

453

514

Sustained 47% 47% viral response (42 (43% (95% CI) to 51%) to 52%) Abbreviation: tiw, three times weekly.

224

54% 44% 29% 56% (49% (40% (24% (52% to 58%) to 49%) to 36%) to 61%)

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received PEG-IFN in combination with RBV (56%) compared with IFN alfa 2b and RBV (45%) and PEG-IFN alfa 2a alone (30%) (Table 2). A third large randomized controlled study has been performed by Hadziyannis et al [23]. The study design was to examine the effect of duration of therapy (24 versus 48 weeks) and of RBV dose (800 mg versus 1000 or 1200 mg) on SVR using fixed-dose PEG-IFN alfa 2a. A total of 1284 patients were stratified, based on their genotype and pretreatment viral load, and randomized into one of four groups: PEG-IFN alfa-2a (180 lg weekly) and RBV at 800 mg daily for 24 weeks, PEG-IFN alfa-2a (180 lg weekly) and RBV at 1000 or 1200 mg daily for 24 weeks, PEG-IFN alfa-2a (180 lg weekly) and RBV at 800 mg daily for 48 weeks or PEG-IFN alfa-2a (180 lg weekly) and RBV at 1000 to 1200 mg daily for 48 weeks. The genotype-specific SVR is shown in Fig. 2 for the four groups. In patients with genotype 1, the highest SVR was obtained in the group that was treated with highest dose of RBV for the longer duration. In contrast, the SVR did not differ significantly among patients with genotypes 2 or 3 regardless of dose of RBV or the duration of therapy. These findings suggest that patients with genotypes 2 and 3 can be treated effectively with PEG-IFN and lower doses of RBV (800 mg) for 24 weeks, whereas patients with genotype 1 should be treated with higher doses of ribavirin (1000 to 1200 mg) for a longer duration. Pretreatment predictors of response Analysis of the clinical trials has identified pretreatment predictors of response to PEG-IFN and RBV (Box 2). The major predictor is genotype, with genotype 1 patients having a markedly reduced response (42% to 46%) compared with patients with genotypes 2 and 3 (76% to 82%). After genotype, multiple other factors have lesser predictive value but can still be clinically important when one is individualizing therapy. Clinically relevant predictors that indicate a more difficult-to-treat patient include viral load greater than 2 million by PCR test, presence of advanced fibrosis or cirrhosis, high body mass index, and African American race. Posthoc analysis of the clinical trials has suggested that PEG-IFN alfa 2b, which is dosed on a weight basis at 1.5 lg per kg, may be more effective in patients with a body weight of greater than 75 kg. Similar analyses have suggested that PEG-IFN alfa 2a may be better for genotype 1 patients with high viral load. All analyses suggest that a weight-based dose of RBV should be used for genotype 1 patients, and the authors recommend 12 to 15 mg of RBV per kilogram. Early virological response Although useful, the baseline predictors highlighted are a general guideline for discussion with patients as to the likelihood of response to treatment. Once

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505

Genotype 1

SVR %

100 24 Weeks Treatment

80

48 Weeks Treatment

60

51 41

40

40

29 20

N=101

N=118

N=250

PEG-IFN α-2a 180 µg + RBV 1000-1200 mg

PEG-IFN α-2a 180 µg + RBV 800 mg

N=271

0 PEG-IFN α-2a 180 µg + RBV 800 mg

PEG-IFN α-2a 180 µg + RBV 1000-1200 mg

Genotype 2 and 3 SVR % 24 Weeks Treatment

100 82

48 Weeks Treatment

81

80

76

76

60 40 20 N=96

0

PEG-IFN α-2a 180 µg + RBV 800 mg

N=144

N=99

PEG-IFN α-2a 180 µg + RBV 1000-1200 mg

PEG-IFN α-2a 180 µg + RBV 800 mg

N=153 PEG-IFN α-2a 180 µg + RBV 1000-1200 mg

Fig. 2. SVR for four different treatment regimens of PEG-IFN alfa-2a with either RBV 800 mg or 1000/1200 mg given for 24 or 48 weeks. Optimal SVR for genotype 1 is seen with 48 weeks treatment with RBV 1000/1200mg daily. For genotypes 2 and 3, 24 weeks with 800 mg of RBV are equivalent to longer duration of therapy and higher RBV doses. (Adapted from Hadziyannis SJ, Cheinquer H, Morgan T, Diago M, Jensen DM, Sette H. Peginterferon alfa 2-a (40kD) (PEGASYS) in combination with ribavirin (RBV): efficacy and safety results from a phase III randomized double-blind multi-centre study examining effect of duration of treatment and RBV dose. J Hepatol 2002;36(Suppl 1):3.)

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Box 2. Factors predicting increased SVR Fixed
Genotype 2,3
Low viral load (less than 2 million copies/mL)
No or minimal fibrosis
Achieving EVR
Female gender
Short duration of disease
Race (non-African American) Variable
Increasing physician experience
PEG-IFN/RBV therapy (weight-based dosing; 24 weeks for Genotype 2,3; 48 weeks for Genotype 1)
Adherence to therapy

treatment starts, however, one can use viral kinetic responses in the early stages of treatment to predict response. This is applicable to genotype 1 patients where early virological response (EVR) has been used to predict who is unlikely to have an SVR, a so-called stop rule. The advantages of EVR are that it reduces the morbidity and cost of treatment by stopping treatment in patients who are unlikely to respond [24]. To use viral kinetics, however, one needs to have reproducible and quantitative measurement of HCV RNA with no more than 0.5 log10 variability. Recent PCR tests are able to provide this accurate level of HCV RNA quantitation enabling physicians to use EVR for treatment decisions. The other important factor is to determine the primary goal of treatment, which is whether SVR alone is the endpoint of treatment or whether secondary benefits of therapy such as slowing disease progression or improving liver histology are applicable in the individual patient. Early virological response is defined for treatment with both PEG-IFNs and RBV as either a 2 log10 unit reduction or loss of detectable HCV RNA at 12 weeks. When EVR does not occur, the chance of SVR being achieved by continuing the same treatment for 48 weeks is reduced to 1% to 3%, and an individualized decision can be made as to whether to stop treatment. For those patients who achieve EVR, there is an increased likelihood (65% to 70%) that they will have an SVR (Table 3). Adherence to treatment Another factor that has been reported to effect outcome is whether patients are able to tolerate therapy and are adherent to the planned treatment dose and duration. McHutchison looked at the effect of adherence in patients treated with IFN/RBV and used the simple adherence parameters

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507

Table 3 Effect of achieving EVR on hepatitis C virus treatment response Treatment response Early virological response (n)

SVR

NR

PEG-IFN alfa2b þ RBV EVR ACHEIVED (388) No EVR (124)

70% 1%

30% 99%

PEG-IFN alfa2a þ RBV EVR ACHIEVED (390) NO EVR (63)

65% 3%

35% 97%

of whether patients were able to take 80% of their IFN, 80% of their RBV for 80% of the time, the 80/80/80 rule [25]. Approximately 30% of patients were unable to adhere to the treatment regimen, usually secondary to adverse effects of therapy. Inability to comply with therapy resulted in an overall loss of response that was more marked in genotype 1 patients, where SVR in the adherent group was 51% and fell to 34% in the patients who were dose-reduced or stopped therapy prematurely (Fig. 3). Factors that affect adherence include patient education and motivation, physician experience with adverse effect management, and positive reinforcement by physicians to the patient. The most successful centers treating HCV patients have incorporated these factors into overall management and often use

70 60 50

S 40 V 30 R 20 10 0 All patients ITT

Compliant Patients

Fig. 3. Effect of adherence on SVR in patients treated with Peg-IFN alfa 2b 1.5 lg/kg and RBV 800 mg. The left panel shows the SVR for patients on intention-to-treat analysis (ITT), with the gray bars representing all patients and the black bars representing genotype 1 patients. Patients compliant to treatment by 80/80/80 rule had an increased SVR. All patients 54% to 63%, p 0.01; genotype 1 patients 42% to 51%, P greater than 0.03. (Adapted from McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002;123(4):1061–9.)

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physician extenders successfully in the role of primary caregivers to manage HCV adverse effects.

Adverse effect management The adverse effects of IFN and RBV are shown in Box 3, although a detailed discussion is beyond the scope of this article. One of the most frequent causes of dose reduction is the cytopenias associated with combination therapy. Thrombocytopenia with platelet counts of less than 50,000 usually is treated with dose reduction of IFN and is only seen in 1% to 4% of patients [26]. Neutropenia with neutrophils less than 750 per cc is seen in up to 20% of patients. No increased risk of bacterial infections has been reported with neutropenia, but dose reduction of IFN should be considered. Alternatively, use of growth factors such as granulocyte colony stimulating factor may be considered. Finally, anemia is common with

Box 3. Common adverse effects of interferon/ribavirin therapy Interferon Bone marrow suppression
Anemia
Thrombocytopenia
Neutropenia Neuropsychiatric syndromes
Depression
Mood swings
Anxiety/mania
Neurocognitive dysfunction Flulike syndrome Nausea/gastrointestinal upset Thyroid disease /thyroiditis Alopecia Neuropathy Retinopathy Injection site reactions Ribavirin Hemolytic anemia Teratogenic Dyspnea/cough Rash/pruritis Insomnia Nausea/gastrointestinal upset

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509

combination therapy, with 50% of patients having a reduction of 3 g/dL in hemoglobin or a fall in hemoglobin to less than 12 g/dL [27]. Recent studies have shown that epoetin alfa at 40,000 U weekly can maintain RBV dose, improve hemoglobin by a mean of 2 g/dL, and improve quality of life in patients with IFN/RBV-induced anemia [28,29]. Interferon also is associated with several neuropsychiatric syndromes, including depression, mood swings, mania, anxiety, and neurocognitive dysfunction. Aggressive management of these side effects is necessary to maintain compliance to therapy. In summary, remarkable improvements have been achieved in efficacy of treatment of naı¨ ve patients with HCV over the last decade, with SVR rates going from 10% to 50% with the current recommended PEG-IFN/RBV combination therapy. The success of therapy is dependent on many variables, and physicians who treat HCV should become very familiar with adverse effect management to achieve the results in clinical practice that have been demonstrated in the clinical trials to date.

Benefits and cost effectiveness of antiviral therapy Follow-up of patients who have had an SVR for up to 10 years suggests that there is a persistent biochemical, virological, and histological remission in 95% of patients. This probably represents a true cure of HCV. It remains unknown if this translates into a reduction in the development of cirrhosis, liver failure, and HCC or translates into an improvement in survival. Economic and cost-effectiveness analyses have suggested that treatment of HCV has future cost savings comparable with many other accepted medical practices such as screening for colorectal cancer or hypertension and coronary artery bypass graft [30]. Finally, patients who have an SVR also have been shown to have significant improvements in health related quality of life, representing another strong argument for treating patients with HCV [31].

References [1] Annual report of the US scientific registry for transplant recipients and the organ procurement and transplantation network-transplant data: 1988–1994. Richmond, VA: United Network for Organ Sharing and the Division of Organ Transplantation, Bureau of Health Resources Development. [2] Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341(8):556–62. [3] Alter MJ. Epidemiology of hepatitis C. Hepatology 1997;26:62S–5S. [4] Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 1998;47(RR-19):1–39.

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[5] Davis GL, Albright JE, Cook S, Rosenberg D. Projecting the future healthcare burden from hepatitis C in the United States. Hepatology 1998;28:390A. [6] Marcellin P, Boyer N, Gervais A, Martinot M, Pouteau M, Castelnau C, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med 1997;127(10):875–81. [7] Marcellin P, Levy S, Erlinger S. Therapy of hepatitis C: patients with normal aminotransferase levels. Hepatology 1997;26:133S–6S. [8] Sangiovanni A, Morales R, Spinzi G, Rumi M, Casiraghi A, Ceriani R, et al. Interferon alfa treatment of HCV RNA carriers with persistently normal transaminase levels: a pilot randomized controlled study. Hepatology 1998;27(3):853–6. [9] Jacobson IM, Russo MW, Lebovics E, Esposito S, Tobias H, Klion F, et al. Interferon alfa-2b and ribavirin for patients with chronic hepatitis C and normal ALT: final results. Gastroenterology 2002;122:627. [10] Sponseller C, Koehler KM, Hoffman JA, Strinko JM, Bacon BR. Use of interferon alpha2b and ribavirin for treatment of patients with chronic hepatitis C with normal ALT levels. Hepatology 2002;36:579A. [11] Hoofnagle JH, Mullen KD, Jones DB, Rustgi V, Di Bisceglie A, Peters M, et al. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon. A preliminary report. N Engl J Med 1986;315(25):1575–8. [12] Davis GL, Balart LA, Schiff ER, Lindsay K, Bodenheimer HC Jr, Perrillo RP, et al. Treatment of chronic hepatitis C with recombinant interferon alfa. A multi-center randomized, controlled trial. Hepatitis Interventional Therapy Group. N Engl J Med 1989; 321(22):1501–6. [13] McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998;339(21):1485–92. [14] Di Bisceglie AM, Conjeevaram HS, Fried MW, Sallie R, Park Y, Yurdaydin C, et al. Ribavirin as therapy for chronic hepatitis C. A randomized, double-blind, placebocontrolled trial. Ann Intern Med 1995;123(12):897–903. [15] Dusheiko G, Main J, Thomas H, Reichard O, Lee C, Dhillon A, et al. Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study. J Hepatol 1996; 25(5):591–8. [16] Bodenheimer HC Jr, Lindsay KL, Davis GL, Lewis JH, Thung SN, Seeff LB. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multi-center trial. Hepatology 1997;26(2):473–7. [17] Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of interferon alpha-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998;352(9138): 1426–32. [18] Zeuzem S, Feinman SV, Rasenack J, Heathcote EJ, Lai MY, Gane E, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000;343(23):1666–72. [19] Lindsay KL, Trepo C, Heintges T, Shiffman ML, Gordon SC, Hoefs JC, et al. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa2b as initial treatment for chronic hepatitis C. Hepatology 2001;34(2):395–403. [20] Heathcote EJ, Shiffman ML, Cooksley WG, Dusheiko GM, Lee SS, Balart L, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000;343(23):1673–80. [21] Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358(9286):958–65.

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[22] Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347(13):975–82. [23] Hadziyannis SJ, Cheinquer H, Morgan T, Diago M, Jensen DM, Sette H. Peginterferon alfa-2a (40kD)(PEGASYS) in combination with ribavirin (RBV): efficacy and safety results from a phase III, randomized, double-blind multi-centre study examining effect of duration of treatment and RBV dose. J Hepatol 2002;36(Suppl 1):3. [24] Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003;38(3):645–52. [25] McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002;123(4):1061–9. [26] Afdhal NH, Geahigan T. Supporting the patient with chronic hepatitis during treatment. In: Koff RS, Wu GY, editors. Clinical gastroenterology: diagnosis and therapeutics. Totowa (NJ): Humana Press. P. 211–32. [27] Maddrey WC. Safety of combination interferon alfa-2b/ribavirin therapy in chronic hepatitis C-relapsed and treatment-naive patients. Semin Liver Dis 1999;19(Suppl 1): 67–75. [28] Dieterich DT, Wasserman R, Brau N, Hassanein TI, Bini EJ, Sulkowski M. Once-weekly recombinant human erythropoietin (Epoetin Alfa) facilitates optimal ribavirin (RBV) dosing in hepatitis c virus (HCV) infected patients receiving interferon-alpha-2b (IFN)/ RBV combination therapy. Gastroenterology 2001;120:340. [29] Afdhal NH, Dieterich DT, Pockros PJ, Schiff ER, Shiffman M, Sulkowski M. Epoetin alfa treatment of anemic HCV-infected patients allows for maintenance of ribavirin dose, increases hemoglobin levels and improves quality of life vs. placebo: a randomized, doubleblind, multi-center study. Gastroenterology 2003;124:714. [30] Siebert U, Sroczynski G, Rossol S, Wasem J, Ravens-Sieberer U, Kurth BM, et al. Costeffectiveness of peginterferon alpha-2b plus ribavirin versus interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C. Gut 2003;52(3):425–32. [31] Bonkovsky HL, Woolley JM. Reduction of health-related quality of life in chronic hepatitis C and improvement with interferon therapy. The Consensus Interferon Study Group. Hepatology 1999;29(1):264–70.

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Treatment of relapsers after combination therapy for chronic hepatitis C Furqaan Ahmed, MD, Ira M. Jacobson, MD* Division of Hepatology and Gastroenterology, Weill Medical College of Cornell University, 450 East 69th Street, New York, NY 10021, USA

The treatment for chronic hepatitis C (CHC) has evolved over the last decade from standard interferon (IFN) monotherapy to combination therapy with standard IFN and ribavirin (RBV) and more recently, pegylated (PEG) IFN and RBV combination therapy. As each successive regimen has led to improved sustained virologic response (SVR) rates, the issue of retreating those patients who did not achieve a sustained response with previous therapy arises. A relapse after therapy is defined as viral clearance with a negative hepatitis C virus (HCV) RNA by polymerase chain reaction (PCR) during therapy and reappearance of the virus after treatment is discontinued. This article focuses on the treatment of patients who have relapsed after being treated with IFN or a combination of IFN and RBV. Relapse to PEG IFN and RBV will also be discussed.

Rates of relapse Studies with standard IFN monotherapy at 3 million units thrice weekly have demonstrated SVR rates after 24 and 48 weeks of therapy to be 6% and 13% to 19%, respectively [1,2]. RBV was approved by the US Food and Drug Administration (FDA) for the treatment of CHC in combination with IFN in 1998. RBV’s mechanism of action, a nucleoside analog, has still not been elucidated firmly. Postulated mechanisms include inhibition of host inosine monophosphate dehydrogenase, enhancement of host T-cell mediated immunity against HCV, direct HCV inhibition, and increased HCV RNA mutagenesis leading to error catastrophe [3,4]. Although ineffective in the treatment of CHC as monotherapy [5–7], when administered with IFN, Dr. Jacobson is a consultant and has received research support from Schering-Plough. * Corresponding author. E-mail address: [email protected] (I.M. Jacobson). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.04.004

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RBV increases SVR rates by increasing response rates and, even more notably, by decreasing the rate of post-treatment relapse in patients who become HCV RNA-negative on therapy. The combination of standard IFN and RBV therapy for 24 weeks in naı¨ ve patients results in end-of-treatment viral clearance rates of 53% to 57% and SVR rates of 31% to 35% [1,2]. Combination therapy for 48 weeks results in end-of-treatment response rates of 50% to 52% and SVR rates of 38% to 43% [1,2]. The incremental efficacy of 48 weeks versus 24 weeks of therapy appears to be limited to patients with HCV genotype 1 infection. Pegylated IFNs, recently developed by the covalent attachment of a polyethylene glycol molecule to standard IFN, have a longer half-life and increased therapeutic efficacy. PEG IFN alfa-2b and alfa-2a have been approved by the FDA recently for the treatment of CHC in combination with RBV, and this therapy represents the current standard of care for CHC. Two landmark studies evaluated the efficacy of PEG IFN alfa-2a and alfa-2b and RBV treatment. PEG IFN alfa-2b at 1.5 lg/kg per week and RBV (800 mg per day) in naı¨ ve patients led to end-of-treatment response rates of 65% and SVR rates of 54% [8]. PEG IFN alfa-2a at 180 lg per week and RBV (1000 to 1200 mg) resulted in end-of-treatment response rates of 69% and SVR rates of 56% [9]. Even with these newer treatment regimens that result in higher SVR rates, a significant number of patients relapse when therapy is stopped. The relapse rates are lower than they were with older forms of therapy, however.

Mechanisms of relapse The precise reason for HCV relapse is likely multifactorial and may result from host-, viral-, and treatment-related factors. Differences in HCV genotypes influence response to therapy. Genotype 1 is more resistant to therapy than genotypes 2 and 3, and patients with genotype 1 who achieve a response on treatment have slightly higher rates of relapse after discontinuation of therapy, even with PEG IFN alfa-2b and RBV [10]. Similarly, patients with advanced fibrosis have higher rates of relapse, particularly with IFN monotherapy [10]. The host immune response plays a pivotal role in determining the ultimate outcome of therapy. Also, factors including age, ethnicity, and the degree of liver fibrosis influence treatment outcome. The development of anti-IFN neutralizing antibodies may play a role for some patients who have viral breakthrough during therapy [11,12]. The importance of these antibodies in patients who relapse after therapy is discontinued is doubtful, however. Other host factors not yet identified also may predispose some patients to fail to clear the virus completely from the liver. A two-phase model of viral clearance after initiation of IFN therapy has been described [13]. The first phase, consisting of a rapid decline in viremia, results from IFN-induced inhibition of HCV virion production. The second

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and more gradual decline in viremia represents HCV-infected cell death (Fig. 1). This model suggests that relapsers are patients who have not cleared all virus-infected hepatocytes at the time their treatment is stopped. Because of the practical obstacles to serial liver biopsy and the challenges in quantifying intrahepatic virus, it is unknown whether there is progressive attrition of infected cells or whether, in some patients, the process achieves a plateau beyond which further clearance does not occur. Similarly, it is unknown whether the mechanism of intrahepatic viral persistence represents some form of latency or simply very low viral replication undetectable in serum. As a flavivirus, however, it is presumed that HCV is not capable of genomic integration, as is the case with HIV and hepatitis B virus (HBV).

Retreatment of interferon monotherapy relapsers with interferon and ribavirin Several studies have evaluated retreatment of patients who relapsed after IFN monotherapy. Retreating patients who relapsed after a course of standard IFN at 3 million units three times weekly for 24 weeks with the same regimen has not been shown to be efficacious, with SVR rates of only 0% to 5% [14–16], although a few studies have reported higher SVR rates [17,18]. Treatment with standard IFN at 3 million units three times weekly but for a longer duration results in higher SVR rates. Forty-eight weeks of therapy has led to SVR rates of 29% to 36% [17,18]. Treatment for 96 weeks has resulted in SVR rates of 68% [17]. Other investigators have retreated relapsers with higher doses of standard IFN for 24 weeks. IFN doses of 4.5 to 5 million units three times weekly for 24 weeks were reported to induce an SVR in 35% to 38% of monotherapy relapsers [14,19]. Studies using even higher doses of IFN,

Fig. 1. Two phase model of viral clearance with interferon therapy. The first, steeper phase is thought to be related to inhibition of viral production, while the second, more gradual phase, represents clearance of infected hepatocytes. (From Gerond Lake-Bakaar, MD.)

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however, have reported lower SVR rates. One study using 6 million units three times weekly resulted in an SVR in 5% of patients [20], and a dose of 10 million units resulted in an SVR of 18.5% [18]. Cavaletto et al treated 25 patients with an 8-week induction phase of 6 million units three times weekly, followed by 3 million units for 24 weeks and reported an SVR rate of 16% [21]. It is unclear why the highest doses of IFN therapy resulted in lower SVR rates. Chow et al combined both approaches to the retreatment of patients who have relapsed to prior therapy using both a higher dose of IFN and a longer duration of therapy [14]. They treated 11 patients with 5 million units of IFN three times weekly for 48 weeks and reported an SVR rate of 27%, which was lower than the SVR rate in patients treated with 5 million units of IFN for 24 weeks (35%). Retreatment of IFN monotherapy relapsers with combination standard IFN and RBV results in higher SVR rates than retreatment with IFN alone. Davis et al retreated patients with IFN (3 million units three times weekly) and RBV for 24 weeks and reported an SVR rate of 49%, markedly higher than SVR rates in patients who were retreated with IFN monotherapy for 24 weeks (5%) [15]. Similar SVR rates of 25% to 40% have been reported in most studies retreating IFN monotherapy relapsers with IFN and RBV combination therapy [20,22–24]. One study reported an SVR rate of 75% in 20 patients treated with this regimen [25]. Similar or slightly higher rates of SVR (29% to 49%) have been reported when patients are treated with higher doses of IFN (5 to 6 million units three times weekly) and RBV for 24 weeks [19,24,26]. Reported SVR rates after 48 weeks of IFN at 3 million units three times weekly and RBV range from 40% to 67% [22,24,27]. Forty-eight weeks of high-dose (5 to 6 million units) IFN and RBV therapy resulted in SVR rates of 47% to 72% [24,26,27]. Cavaletto treated 25 patients with an 8-week induction phase of 6 million units three times weekly, followed by 3 million units of standard IFN in addition to RBV (1000 to 1200 mg per day) for 24 weeks and reported an SVR rate of 44% [21]. Shiffman et al randomized patients with an end-of-treatment virologic response after 24 weeks of IFN and RBV to either discontinue therapy or continue RBV monotherapy for 24 additional weeks [25]. Of the 46 patients with an end-of-treatment response, SVR rates were 75% in the group that discontinued therapy and 50% in the group treated with RBV monotherapy, indicating that continuing RBV monotherapy after achieving a virologic response does not increase the likelihood of an SVR. Krawitt et al treated 17 IFN monotherapy relapsers with PEG IFN alfa-2b (100 to 150 lg per week) and RBV (1000 mg daily); 53% had an SVR [28]. In conclusion, retreatment with the same treatment regimen for the same duration of therapy has not been shown to result in significant SVR rates in patients who have relapsed after a previous course of therapy previously. In contrast, higher doses, and, more importantly, longer duration of therapy

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lead to significant SVR rates in these groups. It is also important to remember that when IFN monotherapy relapsers are treated with IFN and RBV therapy, much of the increase in SVR rates undoubtedly reflects the incremental increase in SVR associated with combination therapy regardless of whether treatment duration is extended. Factors predicting sustained virologic response in prior relapsers In HCV treatment-naı¨ ve patients, SVR has been associated with age younger than 40, genotypes 2 and 3, non-African American race, low serum HCV RNA levels (less than 2 million copies/mL), the absence of bridging fibrosis or cirrhosis, and the absence of coinfection with HIV. During treatment, adherence to therapy and a decline in HCV RNA by over 2 logs at 12 weeks of therapy also are associated with achieving an SVR [29,30]. A smaller body of data suggests similar predictors of response in prior relapsers (Box 1). Data on favorable predictors of SVR in prior relapsers are available mostly from patients in studies on relapsers to IFN monotherapy given combination therapy with IFN and RBV; further data on predictors of SVR in combination therapy relapsers given PEG IFN and RBV are needed. Genotype 1 clearly is associated with lower response rates in most studies [15,18,19,24,26]. Low pretreatment viral load (less than 2 million copies/mL) [15,18,25,26] and lesser degrees of fibrosis on liver biopsy [18,24,25] are predictors of a favorable treatment response, although not all investigators have shown this [14,15,20,22,27]. Older age at treatment and African-American race are associated with poorer response rates [25,26]. An early virologic response is also a strong predictor of a virologic cure [15,20]. Longer duration of treatment (24 versus 48 weeks) [17,18,26], particularly for genotype 1 patients with a high viral load, is associated with a better chance for SVR [22,24] in IFM mono-therapy relapsers given IFN and RBV. Higher doses of IFN have not been associated with higher response rates in most studies [18,24,27]. Saracco et al found that the cumulative dose of IFN during the initial course of therapy or retreatment did not predict a favorable response to therapy [24]. Increased dose or duration of therapy in patients with genotypes 2 and 3 is not associated with higher SVR rates [22,24,26].

Box 1. Predictors of response in prior relapsers to interferon Genotype non-1 Low viral load No or mild fibrosis Age greater than 40 Non-African-American ethnicity Early virologic response to therapy

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Treatment of patients who have relapsed after interferon and ribavirin combination therapy Data on the retreatment of patients who have relapsed after combination therapy with standard IFN and RBV are more limited. There are no data on retreating these patients with regimens of standard IFN and RBV. In a few studies reported in abstract form, combination relapsers have been retreated with PEG IFN and RBV (Table 1). Jacobson et al randomized patients who had relapsed after IFN and RBV therapy to receive 48 weeks of either PEG IFN alfa-2b 1.0 lg/kg per week and RBV 1000 to 1200 mg per day or PEG IFN alfa-2b 1.5 lg/kg per week and RBV 800 mg per day [31]. Twenty five patients received the higher dose of RBV, and 30 patients were in the group that received the higher dose of IFN. Overall, 65% (36/55) of patients had an end-of-treatment response. Only 42% (23/55), however, had SVR. There was a trend toward higher SVR rates in patients who received a higher dose of PEG IFN (50% versus 32%), although this difference did not reach statistical significance. SVR rates were lower in genotype 1 patients than in those with other genotypes (38% versus 63%). In this study, patients who were nonresponders to IFN monotherapy or combination IFN and RBV therapy also were treated. SVR rates in prior nonresponders were significantly lower than in patients who had relapsed to therapy previously. Krawitt et al retreated 68 combination standard IFN and RBV relapsers with a regimen of PEG IFN alfa-2b (100 to 150 lg per week) and ribavirin (1000 mg per day) [28] (E.L. Krawitt, MD, unpublished data, 2003). In this group of patients, the overall end-of-treatment response rate was 66% (45/ 68), and the SVR rate was 54% (37/68). Genotype 1 and genotype non-1 patients had similar end-of-treatment (67% and 65%, respectively) and sustained response (55% and 53%) rates. SVR rates were higher in patients who had previously relapsed to therapy than in those who were previous nonresponders. Gaglio et al treated patients with PEG IFN alfa-2b (1.5 lg/kg per week) and fixed-dose (800 mg) or weight-based (800 to 1400 mg) RBV for 48 weeks [32] (P.J. Gaglio, MD, unpublished data, 2003). Of the patients who have completed therapy and reached 24 weeks of follow-up, 78% had an end-oftreatment response, and 56% achieved an SVR. The SVR rate was lower in genotype 1 patients than in those with other genotypes (50% versus 60%). In another study by Portal et al in 46 patients, the efficacy of an induction dose of PEG IFN and RBV was compared with a fixed lower dose of PEG IFN and RBV [33]. One group of patients received PEG IFN alfa-2b 1.5 at lg/kg per week plus RBV (800 to 1000 mg per day) for 8 weeks followed by PEG IFN alfa-2b 0.7 lg/kg per week and RBV therapy for 40 weeks. The second group of patients received low-dose PEG IFN alfa-2b 0.7 at lg/kg/ week and ribavirin (800 to 100 mg per day) for 48 weeks. The end-oftreatment response rate was 94.1% in the induction group and 88.2% in the

Table 1 Combination peginterferon and ribavirin for relapses to standard interferon and ribavirin

Patient number

Krawitt [28]

68

Jacobson [31]

25

Gaglio [32]

30 128

Portal [33]

24

Lawitz [34]

22 60

Freilich [35]

65 12

Herrine [36]

11 32 29 31 31

Treatment regimen PEG IFN a-2b (100–150 lg/week) þ RBV 1000 mg daily
48 weeks1 PEG IFN a-2b 1.0 lg/kg/week þ RBV 1000–1200 mg daily
48 weeks1 PEG IFN a-2b 1.5 lg/kg/week þ RBV 800 mg daily
48 weeks1 PEG IFN a-2b 1.5 lg/kg/week þ RBV 800–1400 mg daily
48 weeks PEG IFN a-2b 1.5 lg/kg/week þ RBV 800–1000 mg daily
8 weeks, then PEG IFN a-2b 0.7 lg/kg/week þ RBV 800–1000 mg daily
40 weeks PEG IFN a-2b 0.7 lg/kg/week þ RBV 800–1000 mg
48 weeks PEG IFN a-2b 1.5 lg/kg/week þ RBV 1000–1200 mg daily
12 weeks, then PEG IFN a-2b 1.0 lg/kg/week þ RBV 800 mg daily
36 weeks PEG IFN a-2b 1.0 lg/kg/week þ RBV 800 mg daily
48 weeks PEG IFN a-2b 1.0 lg/kg/week þ RBV 1000 mg daily þ AMD 200 mg daily
48 weeks PEG IFN a-2b 1.0 lg/kg/week þ RBV 1000 mg daily
48 weeks PEG IFN a-2a 180 lg/week þ RBV 800–1000 mg daily
48 weeks PEG IFN a-2a 180 lg/week þ MMF 2000 mg daily
48 weeks PEG IFN a-2a 180 lg/week þ AMD 200 mg daily
48 weeks PEG IFN a-2a 180 lg daily þ RBV 800–1000 mg daily þ AMD 200 mg daily
48 weeks

Overall SVR

Genotype 1 SVR

66%

54%

55%

53%

52%

32%

27%

67%

77% 78%

50% 56%

48% 50%

60% 60%

94%

69%

69%

67%

88% 55%

67% 30%

73% 30%

50% NA

58% NA

37% 50%

36% 25%

NA 100%

NA 59% 72% 42% 71%

36% 38% 17% 10% 45%

40% NA NA NA NA

33% NA NA NA NA

Genotype non-1 SVR

519

Abbreviations: AMD, amantadine MMF; mycophenolate mofetil. 1 HCV RNA by PCR was determined at 24 weeks of therapy. If PCR was positive, treatment was discontinued; if PCR was negative, treatment was continued for 48 weeks.

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Author

Overall end of treatment response

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group that did not receive induction therapy. SVR rates were similar in both groups (68.7% and 66.7% in the induction and noninduction groups, respectively). SVR rates in this study were unexpectedly higher in patients with genotypes 1 and 4 (69.2% to 72.7%) than in patients with genotypes 2 and 3 (50% to 66.7%). The authors reported that tolerance was similar in both groups, although flu-like symptoms were more frequent in the induction group. The degree of liver fibrosis, as measured by Metavir staging, decreased in approximately 50% percent of patients regardless of the treatment regimen or the ultimate outcome of treatment. In this study, low-dose PEG IFN and RBV therapy was as efficacious as induction-dose therapy. The efficacy of induction versus fixed-dose PEG IFN and RBV therapy compared was assessed by Lawitz et al in 125 patients [34]. One group of patients received PEG IFN alfa-2b at 1.5 lg/kg week and RBV (1000 to 1200 mg per day) for 12 weeks followed by PEG IFN alfa-2b 1.0 lg/kg per week and a reduced dose or ribavirin (800 mg per day) for 36 weeks. The second group of patients received PEG IFN alfa-2b 1.0 lg/kg per week and RBV (800 mg per day) for 48 weeks. End-of-treatment (58% versus 55%) and sustained virologic response (37% versus 30%) rates were slightly but not significantly higher in the patients receiving induction dosing. Overall SVR rates, as well as SVR rates in patients with genotype 1 with advanced fibrosis (Metavir stage 3-4) were higher in patients who had relapsed after a prior course of therapy than those who were nonresponders to IFN monotherapy or combination IFN and RBV therapy.

Adjunctive therapies for patients who have relapsed after interferon and ribavirin combination therapy In an effort to improve SVR rates in this population, some investigators have evaluated adjunctive therapies in addition to PEG IFN and RBV. Freilich et al assessed the benefit of adding amantadine to PEG IFN and RBV therapy in treating patients who previously had relapsed to therapy [35]. They compared PEG IFN (1.0 lg per week) and RBV (1000 mg per day) with a regimen of PEG IFN (1.0 lg/kg per week) and RBV (1000 mg per day) plus amantadine (200 mg per day). The overall SVR rate presented from interim data in 23 patients was 43%. The addition of amantadine was not beneficial in genotype 1 relapsers. The SVR rate in genotype 1 relapsers was 25% (2/8) in patients treated with amantadine and 40% (2/5) in those treated with standard PEG IFN and RBV combination therapy. In contrast, the addition of amantadine may have led to superior treatment efficacy in nongenotype 1 patients. All of the genotype non-1 patients treated with amantadine had an SVR, compared with only 33% (two of six) of patients treated with PEG IFN and RBV alone, but final data from this study are not available, and the number of patients is too small to draw any definitive conclusions.

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Herrine et al assessed the efficacy of mycophenolate mofetil and amantadine in addition to PEG IFN and RBV in a pilot study [36] (S.K. Herrine, MD, unpublished data, 2003). They treated 124 patients (106 relapsers, 18 breakthrough relapsers) who were randomized to receive PEG IFN alfa-2a 180 lg once weekly in addition to one of four following treatment arms: (1) RBV at 800 to 1000 mg daily, (2) mycophenolate at 1000 mg twice daily, (3) amantadine at 100 mg twice daily, or (4) amantadine at 100 mg twice daily and RBV at 800 to 1000 mg daily. End-of-treatment response rates were highest in patients who were treated with PEG IFN and mycophenolate (72.4%) and PEG IFN, RBV, and amantadine (71%). Patients who received PEG IFN, RBV, and amantadine had the highest SVR rates (45%), followed by those who received PEG IFN and RBV (38%). Treatment with PEG IFN and either amantadine or mycophenolate alone resulted in lower SVR rates (10% and 17%, respectively), as in other trials. Thus, RBV appears to exact its benefit by preventing relapse. Tolerance of the medications was similar in the different treatment groups, except for the more significant decline in hemoglobin seen in patients who received ribavirin.

Approach to the retreatment of patients who relapse after interferon and ribavirin combination therapy Patients who relapse after standard IFN and RBV should be considered strongly for retreatment with PEG IFN and RBV because of their significant chance of SVR (30% to 70%). The available data are derived from studies in which 48 weeks of retreatment with PEG IFN and RBV was given. In these studies, however, relapse even after PEG IFN and RBV occurred in significant numbers of patients. Current viral kinetic models suggest that a gradual second phase of HCV-infected cell death occurs, ultimately leading to viral eradication in patients who achieve an SVR [13]. It is thought that patients who relapse may have a more prolonged period of elimination of infected cells, which may not have been completed when a standard course of IFN and RBV therapy ends. Therefore, in these patients with a previously demonstrated proclivity to relapse, longer courses of therapy than the standard duration of 48 weeks may be worth consideration in the retreatment of selected patients, with a goal of maximizing the chance of eventual eradication of all virally infected cells. Such patients might include those with genotype 1, high viral load, and advanced fibrosis, or those with a delayed response to therapy. However, controlled trials demonstrating the efficacy of such prolonged therapy have not been reported. Adherence to intended doses of PEG IFN and RBV during prior therapy also should be considered. In treatment naı¨ ve patients, dose reductions of either drug, and particularly both drugs, have a significant impact on

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attainment of early virologic response (EVR) after 12 weeks (80% EVR with full doses versus 60% to 70% and 33% with dose reduction of either or both drugs, respectively) [37]. In patients who attain EVR, the chance of SVR is adversely affected by dose reductions or discontinuation of therapy beyond the 12-week timepoint. Although comparable data do not exist for the relapse population, these same principles may well apply. Accordingly, every effort must be made to maintain optimal dosing during the retreatment of patients who have relapsed to a prior course of therapy. Patients who had dose reduction during prior therapy for depression, anemia, or neutropenia may be considered for antidepressants, granulocyte colony stimulating factor therapy, or erythropoietin, respectively, as appropriate during retreatment. It must be recognized, however, that while recent studies on erythropoietin show an effect on successful maintenance of ribavirin dose [38], no prospective trials have demonstrated the use of adjunctive factors to enhance SVR.

Treatment of patients who have relapsed after pegylated interferon and ribavirin combination therapy Patients who have relapsed after a course of PEG IFN and RBV pose a difficult problem, because more effective therapy is not available. There are no data on the efficacy of higher doses of drugs, leaving a repeat course of more prolonged therapy as the major option. Goncales et al treated naı¨ ve patients with either 24 or 48 weeks of combination PEG IFN alfa-2a and RBV. Patients who received 24 weeks of therapy and relapsed were eligible to enter a retreatment study consisting of PEG IFN alfa-2a (maximum dose of 180 lg per week) and RBV (1000 to 12000 mg per day) for 48 weeks [39]. PEG IFN and RBV doses were adjusted by the investigators according to the patients’ tolerance of the medications during the initial course of therapy. Preliminary data from this study on 59 patients indicate high end of treatment virologic response rates of 90% (88% in genotype 1 patients; 93% in patients with genotype 2 and 3) with retreatment. SVR rates from this study are awaited. Because most patients who relapse after a course of PEG IFN and RBV will have received 48 weeks of therapy, the only realistic option is to consider a repeat course for a longer duration (eg, 72 to 96 weeks). In apparent conformity with concepts of the kinetics of viral clearance, patients who clear HCV RNA on their initial course of PEG IFN and RBV have an enhanced risk of post-treatment relapse if clearance of HCV RNA requires longer than 12 weeks of therapy [29]. The concept of modifying the duration of therapy according to a patient’s virologic response pattern to PEG IFN and RBV therapy has been evaluated in a preliminary study of nine HCV genotype 1, treatment-naı¨ ve patients [40]. These nine patients all had delayed virologic clearance; they were positive

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for HCV RNA by PCR but had a 2 log decline in HCV RNA by week 12 of therapy and had cleared virus by week 24. Patients were treated for 72 weeks, and 88% (7/8, with one lost to follow-up) had an SVR. As in patients with relapse after a course of standard IFN and RBV, this approach to therapy needs to be evaluated further in patients who have relapsed after a prior course of PEG IFN and RBV, particularly patients with genotype 1, high viral load, and cirrhosis, or patients in whom clearance of HCV RNA was delayed beyond 12 weeks.

Future directions In addition to the options of PEG IFN and RBV for relapsers to previous combination therapy, or prolonged courses of PEG IFN and RBV in relapsers to previous PEG IFN and RBV therapy, new therapies on the horizon for treatment-naı¨ ve patients with chronic hepatitis C include genome sequence-based therapies, viral enzyme inhibitors, and immunomodulatory agents may be efficacious in patients who have relapsed to previous therapy also [41–45]. Patients with mild liver disease or those who had great difficulty tolerating interferon-based therapy may wish to defer retreatment as novel therapies are awaited. In the authors’ practice, however, it is felt that most patients with relapse after standard IFN and RBV should be offered a course of PEG IFN and RBV.

Summary Sustained virologic response rates are significantly higher in patients who have relapsed after a previous course of therapy compared with patients who did not respond. A meta-analysis of combination therapy in patients who failed IFN monotherapy reported SVR rates of 52% in relapsers to prior therapy and 16% in nonresponders [46]. Similarly, relapsers after a combination standard IFN and RBV therapy have higher SVR rates than combination of therapy nonresponders when treated with pegylated interferon and ribavirin [28,31–34]. For this reason, patients who relapse after a previous course of therapy should be considered potential candidates for retreatment. Factors that have been associated with SVR in these patients include genotype non-1, low viral loads, and lesser degrees of fibrosis. The course of treatment in all patients who have relapsed after prior therapy should be reviewed to identify possible reasons for failure to achieve an SVR. In particular, optimal dosing of PEG IFN and RBV and the occurrence and timing of treatment dose reductions during prior therapy should be reviewed. The reasons for dose reduction should be addressed before initiating another course of therapy in an effort to optimize the chance for a SVR. Patients who had dose reduction for depression, anemia, or neutropenia, should be considered for antidepressants, erythropoietin, or,

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if neutropenia is severe, granulocyte colony stimulating factor therapy, respectively, during retreatment. Prolongation of therapy beyond 48 weeks in patients with relapse after a standard course of PEG IFN and RBV may offer a chance of SVR.

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Nonresponders to hepatitis C virus antiviral therapy: pegylated interferons and beyond Robert J. Fontana, MD Department of Medicine, Division of Liver Transplantation, University of Michigan Medical School, 3912 Taubman Center, Ann Arbor, MI 48109-0362, USA

Great advances in the diagnosis, natural history, and management of chronic hepatitis C (CHC) have been realized over the past 15 years [1]. A sustained virological response (SVR), defined as undetectable hepatitis C virus (HCV) RNA 6 months after completion of antiviral therapy, is achieved in 54% to 56% of previously untreated CHC patients receiving pegylated interferon (PEG IFN) and ribavirin (RBV) combination therapy [2,3]. The number of virological nonresponders and relapsers to prior antiviral therapy, however, continues to increase. Because many nonresponders and relapsers with advanced fibrosis may be at risk of developing progressive liver disease and/or hepatocellular cancer (HCC), management strategies that delay or reduce fibrosis progression are needed. In this article, the host, treatment, and environmental factors associated with a lack of virological response to antiviral therapy will be discussed. In addition, the utility of PEG IFN and RBV in prior nonresponders to standard IFN and IFN and RBV combination therapy will be reviewed. Lastly, the natural history and medical management of nonresponders will be discussed with an emphasis on investigational therapies, such as maintenance PEG IFN, in this challenging patient population.

Antiviral therapy in previously untreated patients Interferon-based antiviral therapy has been used in CHC patients since the late 1980s. Standard IFN a2a, IFN a2b, and consensus IFN treatments given as three times weekly injections for 12 months were associated with an SVR of 5% to 15% [4]. In 1998, standard IFN monotherapy was supplanted E-mail address: [email protected] 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.04.005

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by IFN and RBV combination therapy because of the significant improvement in SVR rates when given to previously untreated and IFN relapser patients [5,6]. More recently, the development of PEG IFNs with improved bioavailability and antiviral efficacy in combination with RBV have led to further improvements in SVR rates compared with standard IFN and RBV. Specifically, PEG IFN and RBV combination therapy is associated with a SVR of 42% to 46% in HCV genotype 1 and 75% to 82% in HCV genotype 2 and 3 patients [2,3]. In addition, 24 weeks of treatment with PEG IFN a2a plus RBV in genotype 2 and 3 patients is associated with a comparable SVR to that seen with 48 weeks of treatment [7]. Retrospective analyses have demonstrated that the lack of an early virological response at week 12 is associated with a high likelihood of nonresponse to PEG IFN and RBV treatment (negative predictive value of 97%) [3,8]. Therefore, current recommendations are to use one of the approved PEG IFN formulations plus low-dose RBV for 24 weeks in genotype 2 and 3 patients and 48 weeks of PEG IFN and full-dose RBV in genotype 1 patients [1]. HCV RNA levels should be determined at baseline, week 12, week 24, end of treatment, and 6 months after completion of treatment. Genotype 1 patients who fail to achieve an early virologic response defined as a
2 log drop of HCV RNA level by week 12 or persistently detectable HCV RNA at week 24 should have therapy discontinued [8].

Identification of prior nonresponders To determine if retreatment with PEG IFN and RBV is worthwhile, the duration and type of response to prior antiviral therapy should be reviewed. Several patterns of response are observed during primary antiviral treatment of CHC (Fig. 1). Patients with an SVR following completion of standard IFN and RBV combination therapy have a greater than 95% chance of sustained virologic cure at 4 years [9]. Recent follow-up studies also demonstrate stable or improved liver histology in some long-term sustained responders to IFN monotherapy [10,11]. Many CHC patients, however, either will not respond or relapse following antiviral therapy. Nonresponders can be categorized as null nonresponders who suppress HCV RNA less than 1 log during treatment and partial nonresponders who suppress HCV RNA greater than 1 log but not to undetectable levels by the end of treatment. Most studies demonstrate that a few patients will suppress HCV RNA to undetectable levels but then experience a virological breakthrough during treatment. Virological relapsers are patients who suppress HCV RNA to undetectable levels at the end of treatment but then develop detectable HCV RNA during post-treatment follow-up. Unfortunately, many CHC patients treated during the early and mid1990s were monitored by biochemical endpoints (ie, improvement or normalization in serum ALT) rather than virological endpoints (ie, loss of

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“Flat” Non-responder

106

“Partial” Non-responder

HCV-RNA

“Late” Breakthrough

Relapser Sustained responder

Lower limit of detection

0 0

Time

Fig. 1. Patterns of response to antiviral therapy in chronic hepatitis C. SVR suppresses HCV RNA to undetectable levels during and for at least 6 months following treatment, while a relapser develops detectable HCV RNA during post-treatment follow-up. Null nonresponders are patients who fail to suppress HCV RNA by greater than 1 log from baseline during treatment, while partial nonresponders suppress HCV RNA greater than 1 log but not to undetectable levels during treatment. A minority of patients who initially suppress HCV RNA to undetectable levels may experience virologic breakthrough, with reappearance of HCV RNA by the end of treatment.

detectable HCV RNA). This was in part because of a lack of widely available and standardized HCV RNA assays and the historical reliance on serum ALT as a surrogate marker of liver injury. Subsequent studies have demonstrated that qualitative and quantitative HCV RNA assays are more sensitive and specific than ALT monitoring during antiviral treatment [2– 5,12]. Therefore, HCV RNA testing before, during, and following treatment are recommended to assess response in all CHC patients [1]. With several hundred thousand Americans having received IFN monotherapy in the 1990s, however, there are large numbers of nonresponders to prior IFN alone. In addition, because HCV genotype 1 patients have only a 25% to 30% likelihood of SVR with standard IFN and RBV combination therapy, there is a large number of combination therapy nonresponders in the United States.

Predictors of response to combination antiviral therapy Consistent pretreatment predictors of SVR to IFN and ribavirin combination therapy include HCV genotype non-1 and low baseline HCV RNA level (Table 1) [5,6,13]. Other predictors of SVR include female gender and the absence of cirrhosis. Retrospective analysis of the end of treatment

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Table 1 Independent predictors of sustained virological response to standard and pegylated Interferon and ribavirin combination therapy Standard IFN þ Ribavirin Study Davis [5] Population n=345 Treatment1 IFN a2b þ RBV 1.0–1.2 Independent Genotype 2, 3 \2 predictors of  106 copies/ mL SVR2

Pegylated IFN þ Ribavirin Study Manns [2] Population n=1428 Treatment1 PEG IFN a;2b 1.5 þ RBV 0.8

Independent predictors of SVR

McHutchinson [6] n=912 IFN a2b þ RBV 1.0–1.2 Genotypes 2,3 \2  106 copies/ mL no cirrhosis female gender

Poynard [13] n=832 IFN a2b þ RBV 1.0–1.2 Genotype 2,3 \2  106 copies/ mL age \40 minimal fibrosis female gender

Fried [3] n=1121 PEG IFN a2a 180 þ RBV 1.0–1.2

Hadziyannis [7] n=1284 PEG IFN a2a 180 þ RBV 0.8 or 1.0–1.2 PEG IFN a2a 180 þ RBV 0.8 or 1.0–1.2

PEG IFN a2b 1.0 þ RBV 0.8

IFN a2b þ RBV 1.0–1.2

IFN a2b þ RBV 1.0–1.2 Genotypes 2,3 \2 million/mL minimal fibrosis body weight lower age

PEG IFN a2a 180 Genotypes 2,3 Age \40 Body weight \75 kg

Genotypes 2,3 age no cirrhosis

1 IFN a2b dose is 3 MU three times weekly, PEG IFN a2a dose is lg/ week; PEG IFN a2b dose is lg/kg week; RBV dose is grams per day. 2 Using multivariate or logistic regression analyses.

and SVR in African American and Caucasian CHC patients suggest that patient race also may influence the response to standard IFN and RBV [14,15]. Less than 5% of the patients enrolled in the registration trials were African American, however, and African Americans have a higher prevalence of HCV genotype 1 compared with Caucasians (95% versus 70%). Ongoing studies that include a larger proportion of African Americans and control for HCV genotype also suggest lower response rates with PEG IFN and RBV treatment in African Americans [16–18]. The pretreatment factors associated with a SVR to PEG IFN and RBV are similar to those reported for standard IFN and RBV (Table 1). Subject body weight also may be an important predictor of response, but prospective studies are needed of weight-based ribavirin dosing [19]. Treatment-related factors such as medication adherence also have been shown to significantly influence the likelihood of SVR when using standard and PEG IFN and RBV combination therapy. A multitude of dosedependent adverse effects are encountered commonly when administering

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standard and PEG interferon and RBV that lead to dose reductions or early discontinuation in 20% and 10% of treated patients, respectively [2,3,20]. Retrospective analysis has shown that HCV genotype 1 patients who receive at least 80% of the prescribed standard IFN and RBV dose for at least 80% of the intended duration are more likely to achieve an SVR than those who do not (IFN a2b plus RBV 1.0 to 1.2 g, 39% versus 31%, P = 0.15) [21]. Similar findings have been reported from retrospective analysis of the large PEG IFN and RBV registration trials (PEG IFN a2b 1.5 lg/kg plus RBV 0.8 g, 51% versus 34%, P = 0.011) [21,22]. Several ongoing studies are investigating the use of adjuvant approaches such as prophylactic antidepressants and intensive clinical monitoring to improve medication adherence and SVR rates, but the benefit remains unclear [23,24]. Similarly, although adjuvant erythropoietin may lead to fewer RBV dose reductions, the unknown benefit of this expensive agent in improving SVR leads it to be considered an unproven, investigational therapy at this time [25]. Selection of prior nonresponders for retreatment Even if medication adherence was 100%, there still would be a large group of nonresponders to antiviral therapy. Not all of these patients may need additional treatment, however. Therefore, before considering retreatment with newer therapies, the history of prior antiviral treatment and tolerance should be assessed carefully (Box 1). In particular, the prior dose and duration of antiviral therapy and the prior response to treatment should be reviewed (see Fig. 1). As previously mentioned, many patients treated with IFN monotherapy may not have undergone HCV RNA testing before, during, and after treatment. Because virological relapsers are more likely to respond to retreatment than true nonresponders, it is important to locate and review all available treatment records. In addition, many patients may have had treatment prematurely discontinued for laboratory abnormalities or adverse events, which now can be managed through dose modification or adjuvant treatments. For example, experienced hepatologists are comfortable tolerating lower levels of neutropenia (eg, absolute neutrophil count greater than or equal to 500 per mL) and thrombocytopenia (eg, platelets greater than or equal to 60,000 per mL) during treatment, because studies demonstrate a low rate of infections and bleeding complications, respectively [19,26]. In addition, RBV in combination with standard or PEG IFN leads to less thrombocytopenia and neutropenia than IFN alone because of the release of endogenous hematopoietic growth factors to compensate for the hemolytic anemia [5,6]. Nonetheless, patients who developed severe idiosyncratic adverse events with prior antiviral therapy, such as allergic reactions, pulmonary toxicity, retinal toxicity, or severe neuropsychiatric toxicity (eg, seizures, suicidal gesture, or hospitalization) should not be offered retreatment [27]. In addition, patients who experienced exacerbations of underlying autoimmune disorders should not be retreated.

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Box 1. Considerations for retreatment in prior interferon and interferon and ribavirin nonresponders Prior treatment Type and duration of prior treatment Virologic response Medication adherence/adverse effects Current status HCV genotype Severity of liver disease Medical and psychiatric comorbidities Patient preference The need for or urgency for retreatment with newer therapies is driven largely by the severity of underlying liver disease. In cases of uncertainty, a liver biopsy can be performed to assess hepatic fibrosis if not previously done or if a substantial amount of time has lapsed since the prior biopsy (ie, more than 5 years) [28]. The anticipated likelihood of response to retreatment with PEG IFN and RBV also may influence both the physician’s and patient’s enthusiasm to be retreated. Pegylated interferon and ribavirin in prior nonresponders Several recent meta-analyses have demonstrated that the likelihood of an SVR in prior IFN nonresponders when retreated with standard IFN and RBV for 48 weeks varies between 15% and 30% [29,30]. Collectively these studies demonstrate that patients with HCV genotypes 2 and 3 are more likely to respond than HCV genotype 1 and that 12 months of therapy is preferred over 6 months in prior IFN nonresponders. In addition, patients with a partial virological response to prior treatment are more likely to respond to retreatment compared with flat nonresponders. The author and others also have shown that viral clearance is more likely in relapsers compared with nonresponders and that high daily doses of standard IFN (ie, induction dosing) does not provide incremental benefit [29–31]. Furthermore, development of the PEG IFNs with their improved antiviral efficacy and bioavailability largely has supplanted the theoretical benefit of high daily dose standard IFN therapy. Several ongoing studies are exploring the potential benefit of PEG IFN and ribavirin for 48 weeks in prior IFN and IFN/RBV nonresponders (Table 2). The largest study addressing this issue is the ongoing Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial, wherein prior nonresponders to IFN or IFN and RBV combination therapy with bridging fibrosis or early cirrhosis (ie, Ishak fibrosis score greater than or

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equal to 3) initially are given PEG IFN a2a and RBV for 24 weeks [32]. Patients with undetectable HCV RNA at week 20 are eligible for a full 48 weeks of PEG IFN and RBV combination therapy. Preliminary results show that approximately 37% of patients are achieving a virological response at week 20. In the patients who receive 48 weeks of treatment, 9% are developing virological breakthrough on treatment, and over 50% of the end-of-treatment virological responders are relapsing after cessation of therapy. Therefore, the overall projected SVR in this group of prior nonresponders is approximately 18%. Baseline factors predictive of an SVR include HCV genotypes 2 and 3, prior treatment with IFN alone, and non-African American race. Preliminary analysis also suggests that patients who are able to receive full dose RBV may be more likely to achieve an SVR compared with patients requiring a RBV dose reduction. Subject age, severity of liver fibrosis, gender, and body weight were not predictive of SVR. Overall, therapy has been tolerated well, but PEG IFN and RBV dose reductions are common in these patients because of the inclusion of patients with early portal hypertension and hypersplenism. Other ongoing trials of PEG IFN and RBV combination therapy in prior nonresponders also demonstrate low end-of-treatment and SVR rates (Table 3) [33–39]. Most patients in these trials were either IFN or IFN and RBV nonresponders, and a small proportion of relapsers were enrolled in some studies. Relapsers consistently have a higher end of treatment and SVR compared with prior nonresponders. In addition, patients with HCV genotypes 2 and 3 have a significantly greater likelihood of SVR compared with HCV genotype 1 patients in all of the trials. The ALAMO study group has demonstrated that patients who had at least a 1 log drop in HCV RNA during prior IFN and RBV treatment (ie, partial nonresponders) are more likely to respond to retreatment compared with prior null nonresponders [34]. Another ongoing study suggests that prior IFN and RBV nonresponders who suppress HCV RNA to undetectable levels achieve greater histological benefit compared with patients who remain viremic at the end of 48 weeks [39]. Nonresponders involved in ongoing trials of PEG IFN and RBV retreatment are a heterogeneous group with an overrepresentation of HCV genotype 1 patients because of their poor response to prior antiviral therapy. The likelihood of an on-treatment response and SVR is highly variable and primarily determined by HCV genotype and the type of prior treatment received. In all of these trials, a high rate of virological relapse after cessation of treatment has been reported, leading to a low projected SVR (HCV genotype 1, 5% to 10%; HCV genotypes 2 and 3, 20% to 30%). This observation suggests that prolonged treatment with PEG IFN and RBV therapy extending to 18 or 24 months may be worthwhile in these refractory CHC patients, and trials to test this hypothesis are being developed. Clinicians should consider retreating prior nonresponders on a case-bycase basis after reviewing their prior treatment history and liver disease

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severity (see Box 1). Although most of the ongoing trials compare varying doses of PEG IFN and RBV, none of them are demonstrating a significant difference in safety or efficacy based upon treatment assignment. Therefore, standard-dose PEG IFN and full-dose ribavirin are recommended when retreating prior nonresponders. The value of early virologic response rules at week 12 in retreating nonresponders is an important unanswered question [35]. It is recommended that PEG IFN and RBV be used for at least 24 weeks before discontinuing treatment in prior nonresponders. Careful clinical and laboratory monitoring is required, particularly in patients with more advanced fibrosis who may experience more frequent adverse events and medication dose reductions [32]. Natural history of nonresponders The natural history of disease progression in CHC patients is highly variable and dependent upon a multitude of host and environmental factors. Subject age, gender, immune status, disease duration, and alcohol use have been shown to significantly influence fibrosis progression rates. The effect of prior antiviral therapy on the natural history of fibrosis progression has not been prospectively studied in a large group of CHC patients, however. Although histological improvements may be seen in up to 30% of nonresponders during short-term follow-up, the durability of this benefit remains unclear. In addition, some prior nonresponders to combination antiviral therapy have persistently lower serum ALT levels compared with pretreatment, suggesting less active liver disease, but long-term follow-up of biochemical responders versus nonresponders is lacking [5,6]. Nonresponders to antiviral therapy can be categorized conceptually into patients with mild and advanced hepatic fibrosis. Patients with mild fibrosis have an excellent short-term prognosis independent of antiviral therapy and are not at risk for HCC in the absence of cirrhosis. Therefore, the urgency for retreatment or use of investigational therapies is reduced, but these patients should be monitored for disease progression [40]. In contrast, patients with bridging fibrosis or cirrhosis are at significant risk for developing complications of liver failure and HCC. Fattovich et al described the natural history of 384 patients with compensated CHC cirrhosis who were followed for a median of 5 years [41]. During follow-up, 8% developed liver cancer, and 13% died. In addition, 18% developed decompensation and the overall probability of survival after the first episode of clinical decompensation was only 50% at 5 years. Similarly, Hu et al identified a 22% likelihood of decompensation and a 10% risk of HCC in 112 American CHC cirrhotics who were followed over 5 years [42]. In both of these studies, a history of prior IFN therapy was not predictive of survival or protection from complications. Therefore, nonresponders with advanced fibrosis need to be monitored carefully and prioritized for additional therapy or enrollment into clinical trials.

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Hepatic fibrosis as an endpoint of treatment Viral eradication is likely to be attained in only a minority of nonresponders retreated with PEG IFN and RBV (see Table 2). Alternate clinical endpoints such as improvements in liver histology and prevention or delay in development of HCC or decompensation may be more applicable for chronic anti-inflammatory or antifibrotic treatments in these refractory patients. Because CHC patients with advanced fibrosis and cirrhosis are likely to develop these complications within a short time period, clinical trials may be designed to assess these endpoints. Development of progressive hepatic fibrosis in CHC is the main determinant of subsequent complications of portal hypertension such as ascites, hepatic encephalopathy, and gastrointestinal bleeding. In addition, progressive hepatic fibrosis is linked to the risk of HCC in CHC patients. Liver biopsy is considered the gold standard for assessing disease stage and activity in CHC patients [28]. Liver biopsy, however, is subject to sampling error and inter- and intraobserver variability [43]. In particular, small fragmented biopsies less than 2 cm in length and those with fewer than three portal triads may be understaged [44]. In addition, liver biopsy is associated with serious but infrequent complications, patient inconvenience, and substantial cost. Therefore, physicians and patients may be reluctant to pursue periodical liver biopsy to monitor disease progression. Alternative noninvasive assessments of hepatic fibrosis such as quantitative liver function tests and serum fibrosis markers are being developed [40]. Until validation studies are completed, however, these tests remain investigational and are not recommended for estimating initial hepatic fibrosis stage or changes over time. The Knodell, Ishak, and METAVIR histological scoring systems have been used most commonly in studies of CHC patients (Table 3). However, all of the scoring systems are semiquantitative and rely upon subjective interpretation of stained liver biopsy samples, leading to substantial intraand interobserver variability [43,45]. In clinical practice, a uniform scoring system for staging hepatic fibrosis in CHC has not been defined. Before hepatic fibrosis can become a recognized clinical endpoint for antiviral therapy, a consensus regarding a fibrosis scoring system that is accurate, reproducible, and clinically relevant must be established.

Maintenance pegylated interferon in prior nonresponders Continuous, low-dose or maintenance PEG IFN therapy has been proposed as a possible treatment option for prior nonresponders with advanced fibrosis. The rationale for maintenance therapy is based upon the observation that up to 30% of virological nonresponders achieve discernible histological benefit after 48 weeks of treatment. In addition, hepatic fibrosis has been shown to be reversible during short-term follow-up, particularly in

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Table 2 Ongoing studies of pegylated interferon and ribavirin in prior interferon and interferon and RBVavirin nonresponders and relapsers N (% NR/ Rel)

Treatment1

ETR (%)

SVR (%)

Predictors of SVR

HALT-C [32]

1400 (100/0)

PEG IFN a2a 180 þ RBV 1.0 –1.2

36%

18%

RENEW [33]

845 (100/0)

Week 24 VR 23%, 39%, and 53% respectively

NA

ALAMO [34]

720 (80/20)

PEG IFN a2b 0.5 þ wt based RBV versus PEG IFN a2b 1.0 þ wt based RBV versus PEG IFN a2b 1.5 þ wt based RBV Induction PEG IFN a2b 1.5 þ RBV 1.0–1.2 versus PEG IFN a2b 1.0 þ RBV 0.8

Genotype 2,3 IFN > IFN/ RBV NR Caucasian RBV dose NA

IFN RBV NR 9% to 13% IFN NR 23% to 27% Rel 30 to 37%

Genotype 2,3 Caucasian Prior virologic response in IFN/ RBV NR

Hepatitis Resource Network [35]

517 (70/30)

15% to 25% IFN/RBV NR 30% to 34% IFN NR 55–58% Rel NR 20% Rel 35%

NR 7% Relapser 21%

Genotype 2,3 Caucasian Rel > NR Low viral load

PEG IFN a2b 1.5 þ RBV 0.8 versus PEG IFN a2b 100 or 150 þ RBV 0.8

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Study

321 (83/17)

Krawitt [37]

205 (67/33)

Frelich [38]

158 (78/22)

Hassanein [39]

193 (100/0)

PEG IFN a2b 1.0 þ RBV 1.0–1.2 versus PEG IFN a2b 1.5 þ RBV 0.8 PEG IFN a2b 100 þ RBV 1.0 versus PEG IFN a2b 150 þ RBV 1.0 PEG IFN a2b 1.0 þ RBV or PEG IFN a2b 1.0 þ RBV þ amantadine 200 PEG IFN a2b 1.5 þ RBV 0.8 or PEG IFN a2b 1.0 þ RBV 1.0–1.2

IFN/ RBV NR 16% IFN NR 36% Rel 65%

IFN/ RBV NR 8% IFN NR 21% Rel 42%

Genotype 2,3 Rel > NR

NR 31% Rel 66%

NA

Genotype 2,3 Rel > NR

NA

NR 9% Rel 43%

Genotype 2, 3 Rel > NR

16%

5%

Not reported

Abbreviations: ETR, end of treatment response; NR, non-responder; Rel, relapser; VR, virological response. 1 PEG IFN a2a dose is lg/week, PEG IFN a2b dose is lg/kg per week, RBV dose is grams per day.

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New York [36]

537

538

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Table 3 Semi-quantitative histopathological scoring systems for hepatic fibrosis in chronic hepatitis C Descriptor

Ishak

Metavir

Knodell

Absent Periportal fibrosis (some) Periportal fibrosis (most) Bridging fibrosis (few) Bridging fibrosis (many) Incomplete cirrhosis (Septa) Cirrhosis

0 1 2 3 4 5 6

0 1 1 2 3 4 4

0 1 1 3 3 4 4

patients who clear HCV RNA [46]. In a single-center, randomized study, Shiffman et al examined the effects of standard IFN a2b maintenance therapy on the inhibition of histological progression in previous IFN nonresponders [47]. Fifty-three patients who failed to clear HCV RNA after a 6-month course of IFN with a demonstrated histological benefit were randomized to continue IFN a2b 3 million units three times weekly for 24 months or receive no additional therapy. After 30 months of maintenance IFN, the Knodell fibrosis score had declined from 2.5 pretreatment to 1.7, and 80% of the treated patients had histological improvement. In contrast, the mean fibrosis scores had increased from 2.2 to 2.4 in the untreated group, and histological worsening was noted in 20% of patients. Similarly, Alric et al have demonstrated histological improvement in biochemical responders who remained viremic with standard IFN a2b maintenance therapy for 12 months compared with untreated controls [48]. In addition, several studies suggest that IFN therapy may reduce the likelihood of liver cancer in CHC patients, particularly in those who achieve a sustained virologic or biochemical response [49]. A recent review suggests that IFN therapy may prevent or delay HCC in some CHC patients, but the potential for selection bias in most of these nonrandomized retrospective studies is problematic [50]. Taken together, these preliminary studies suggest that maintenance IFN therapy may be a viable option for virological nonresponders with advanced fibrosis to prevent or delay fibrosis progression and clinical complications. Because of the cost, inconvenience, and poor tolerability of IFN, and the slow rate of hepatic fibrosis progression in CHC, however, large randomized controlled trials with adequate follow-up are needed to determine if this approach is safe and effective. Maintenance pegylated interferon trials Three large, prospective multi-center trials are examining the effects of maintenance PEG IFN on the development of HCC and other complications of portal hypertension in CHC patients with advanced fibrosis (Table 4). The National Institutes of Health (NIH)-sponsored HALT-C trial is an ongoing, multi-center US trial designed to examine the effect of maintenance

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539

Table 4 Ongoing trials of maintenance pegylated Interferon in prior nonresponders

Sponsor Sample size Sites Inclusion criteria Treatment

Endpoints

Status as of 8/03

HALT-C

COPILOT

EPIC3

National Institute of Health 1400

Schering-Plough

Schering-Plough

800

11 US Ishak fibrosis
3 NR to IFN CTP \7 Lead-in PEGIFNa2a 180 þ RBV 1.0–1.2  24 weeks Randomized PEGIFNa2a 90 versus no therapy  3.5 years

45 US Ishak fibrosis
3 NR to IFN CTP \8 Lead-in (None)

700 noncirrhotics 1000 cirrhotics 140 international Metavir fibrosis
2 NR to IFN/RBV CTP \7 Lead-in PEGIFNa2b 1.0 þ RBV 0.8  12 weeks

Noncirrhotic
2 Ishak fib * Cirrhotic ascites encephalopathy variceal bleed CTP
7 HCC liver transplant death Enrollment completed

Noncirrhotic
2 Ishak fib * Cirrhotic variceal bleed
2 point CTP * HCC liver transplant death

Randomized Colchicine 0.6 mg bid versus PEGIFNa2b 0.5  4 years

Enrollment ongoing

Randomized Non-cirrhotic PEGIFNa2b 0.5 versus no therapy  3 years Cirrhotic PEG IFN a2b 0.5 versus no therapy  5 years Noncirrhotic >1 Metavir fibrosis * Cirrhotic ascites encephalopathy variceal bleed CTP
10 HCC liver transplant death

Enrollment ongoing

* PEG IFN a2a dose is lg/w, PEG IFN a2b dose is lg/kg per week, RBV dose is grams per day.

PEG IFN a2a on the prevention of fibrosis progression and clinical decompensation in patients with advanced fibrosis and no response to prior antiviral therapy [32]. Virologic nonresponders to the 24 week lead-in phase of PEG IFN and RBV treated within the trial (lead-in nonresponders) or treated in the community (express patients) are eligible for randomization to either PEG IFN a2a 90 at lg per week or no further antiviral therapy for 3.5 years. The study endpoint of fibrosis progression will be determined at repeat liver biopsies obtained at years 2 and 4, while clinical endpoints will be determined throughout the 4-year trial. The Colchicine versus Peg-Intron LOng-Term trial (CO-PILOT) is another ongoing, multi-center US study testing the safety and efficacy of PEG IFN a2b at 0.5 lg/kg per week versus oral colchicine in nonresponders

540

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with advanced fibrosis [51]. A maximum of 800 nonresponders with advanced fibrosis will be followed for 4 years until they achieve a clinical endpoint of a CTP score increase of at least 2 points or clinical decompensation. Preliminary data in 287 randomized patients indicate a trend toward a lower frequency of clinical events in the PEG IFN a2b arm, but the study is ongoing. The Efficacy of Peg Interferon in Chronic Hepatitis C patients nonresponsive to Combination therapy trial (EPIC3) is another multi-center trial being conducted in Europe and the United States that is designed to determine the potential benefit of PEG IFN a2b at 0.5 lg/kg per week compared with no additional antiviral therapy in two groups of patients who have failed to respond to prior IFN and RBV combination therapy. There are plans to enroll 700 noncirrhotic nonresponders with a Metavir fibrosis score of at least 2 and 1000 compensated cirrhotic nonresponders who will be treated initially with PEG IFN a2b and RBV in the lead-in phase. Persistently viremic patients at week 12 will be eligible for randomization to either maintenance PEG IFN a2b or no further antiviral therapy. Endpoints for the noncirrhotic patients include fibrosis progression at the year 3 biopsy and development of decompensation or HCC in the cirrhotic group over the 5-year study period. The results of all three of these large, maintenance trials are awaited. In the interim, it is recommended that maintenance PEG IFN be reserved for patients in clinical trials, because the risk/benefit ratio of prolonged therapy is unknown.

Other Investigational treatments for nonresponders In addition to maintenance PEG IFN, several other medical therapies are being tested to determine their benefit in slowing liver disease progression in nonresponders to antiviral therapy. Antifibrotics Hepatic fibrosis in CHC occurs as a result of increased collagen fiber deposition, which is mediated by hepatic stellate cells [52]. As fibrosis progresses, the extracellular matrix surrounding hepatocytes becomes denser, and the cross-linked collagen becomes less amenable to remodeling. Recent advances in the understanding of the cellular and molecular events associated with the initiation, proliferation, and apoptosis of activated hepatic stellate cells has provided several potential therapeutic targets to treat hepatic fibrosis. In particular, reducing the transformation of quiescent stellate cells to activated myofibroblasts is an attractive strategy. In addition, treatments that suppress necroinflammation preferably through direct antiviral mechanisms are desirable [53]. IFN has been shown to not only reduce liver inflammation but also reduce the number and activity of hepatic stellate cells in CHC patients [54]. Other agents that may prove useful as antifibrotics in CHC include vitamin E (antioxidant), thiazolidinediones (proliferator-

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activated receptor gamma ligands down-regulate stellate cell activation), pentoxifylline (inhibits stellate cell proliferation), angiotensin converting enzyme inhibitors (antifibrogenic), and gliotoxin (stimulate stellate cell apoptosis) [54,55]. Each of these agents, however, must undergo careful stepwise evaluation in phase I safety testing and phase II dosing studies. In addition, these agents must demonstrate unequivocal efficacy in stabilizing or reversing hepatic fibrosis as a primary endpoint in large, placebo-controlled phase III trials. For example, although interleukin-10 (IL-10) showed great promise in a small, pilot study of IFN nonresponders, large randomized clinical trials have failed to demonstrate efficacy and safety [56]. An oral, well-tolerated antifibrotic agent will prove very useful for the growing population of CHC nonresponders with advanced fibrosis but likely will take several years to develop. Interferon gamma (c) Interferon gamma (IFNc) is a potent proinflammatory cytokine produced by lymphocytes that enhances cellular immunity. Low levels of IFNc production have been noted in patients who develop chronic hepatitis B virus (HBV) infection, and polymorphisms in IFNc expression recently have been described [57,58]. IFNc has been shown to inhibit stellate cell activation in in vitro cell culture systems and experimental animal models and therefore has been proposed as a potential antifibrotic therapy for CHC patients [59]. Clinical trials of IFNc in chronic HBV patients have demonstrated a lower efficacy and greater toxicity compared with standard IFNa [60]. Two pilot studies exploring the utility of IFNc in CHC patients were reported recently [61,62]. A 4-week course of IFNc given three times weekly had no demonstrable biochemical or virological benefit in 11 prior nonresponders [61]. Similarly, a 24-week course of IFNc given three times weekly did not reduce hepatic fibrosis as measured by image analysis or light microscopy in 20 IFN nonresponders [62]. The results of a large, ongoing, multi-center trial wherein nonresponders are randomized to either IFNc or placebo are awaited to determine if this agent is safe and effective. Antitumor necrosis factor antibodies High circulating levels of tumor necrosis factor alpha (TNFa) have been reported in CHC patients who are nonresponders to antiviral therapy [63]. In addition, TNFa has been implicated in enhancing fibrogenesis in CHC [63]. One ongoing pilot study is exploring the potential safety and efficacy of etanercept (Enbrel), an anti-TNFa antibody approved for the treatment of rheumatoid arthritis [64]. Preliminary data demonstrate that CHC patients receiving etanercept injections twice weekly in combination with standard IFN a2b and ribavirin have a higher week 24 virological response rate compared with patients treated with standard IFN and RBV. Although post-treatment liver histology and SVR data are pending, this study suggests

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that biological response modifiers may have a role in the future management of CHC patients. Phlebotomy Increases in serum transferrin saturation and ferritin levels are found in up to 40% of CHC patients, but most of these patients have little or no evidence of increased hepatic iron stores [65]. Patients with genetic hemochromatosis and CHC have been shown to be at increased risk of liver disease progression through cytopathic and immunopathic mechanisms [66]. In CHC patients, elevated iron levels are associated with increased serum aminotransferase levels, hepatic fibrogenesis, cirrhosis, and an increased risk of HCC [67,68]. Elevated hepatic iron levels also have been associated with a lower rate of sustained response to IFN monotherapy and more recently to combination therapy. Depletion of iron stores by therapeutic phlebotomy is associated with reduced serum aminotransferase levels in CHC patients and improvements in liver histology [69,70]. Phlebotomy, however, does not improve the response to IFN monotherapy in previously untreated or prior IFN nonresponders consistently [70,71]. Japanese investigators are conducting a prospective trial of maintenance phlebotomy therapy in 25 IFN nonresponders [72]. The preliminary results of this pilot study demonstrate the safety and tolerability of maintenance phlebotomy and stabilization of liver histology and improved aminotransferases. Although phlebotomy is an attractive adjuvant therapy for nonresponders because of its simplicity, low cost, and wide availability, large, placebo-controlled trials with adequate follow-up are needed [73]. In the interim, it is recommended that unnecessary iron supplementation be avoided in all CHC patients to minimize oxidative stress. Protease and polymerase inhibitors Because of the limited efficacy and tolerability of IFNs and the worldwide burden of CHC-related liver disease, intensive laboratory investigation to identify newer antiviral compounds with a more favorable adverse effect profile is underway. One of the major barriers to new drug development has been the lack of a small animal model and in vitro test system to assess antiviral efficacy [74]. Recently, a HCV replicon system that replicates in the Huh7 hepatoma cell line was developed [75]. Although a therapeutic vaccine is not anticipated because of the high rate of mutation in the HCV envelope protein, the structure and identity of several key enzymes involved in the HCV life cycle have been identified [74]. Protease inhibitors that bind to the NS3 protease may prove beneficial. BILN 2061 is an orally administered protease inhibitor that recently has been tested in CHC patients. In phase I pilot studies, dramatic declines in HCV RNA levels were observed after 48 hours of dosing in genotype 1 nonresponders to IFN [53,76]. Further studies are required, however, to optimize its absorption and demonstrate activity

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with prolonged dosing. As a double stranded RNA virus, HCV replication also may be targeted by means of inhibition of its helicase activity. Polymerase inhibitors that directly inhibit the viral RNA-dependent RNA polymerase in the NS5B region also may prove useful, because host enzymes are not involved in this replication step; several are now under development [77,78]. Although the development of antiviral compounds that directly inhibit HCV specific targets is awaited, it likely will be several years before these compounds are ready for testing in large-scale, clinical trials. Summary Although the likelihood of a SVR with antiviral therapy has improved markedly over the past 15 years, there are many CHC relapsers and nonresponders to earlier treatment who may benefit from retreatment with PEG IFN and RBV. Before pursuing retreatment, the type of prior treatment, tolerability, and prior virological response should be reviewed. In addition, the urgency for retreatment based upon the severity of liver disease and the likelihood of a response should be considered. Although 20% to 40% of prior nonresponders may achieve an end-of-treatment response with 48 weeks of PEG IFN and RBV, only 5 to 20% will achieve an SVR. Unresolved questions in the use of PEG IFN and RBV for prior nonresponders include the use of early virological response rules, the optimal dose and duration of retreatment, and the potential histological benefit of retreatment. Three, large ongoing controlled trials of maintenance PEG IFN in nonresponders with advanced fibrosis that have both histological and clinical endpoints should be completed in the next 5 years. In the interim, other novel antiviral and antifibrotic approaches are being developed to delay or prevent disease progression. Until additional data are available regarding the safety and efficacy of pegylated IFN and RBV in prior nonresponders, however, retreatment should be considered in selected CHC patients on a case-by-case basis. References [1] National Institutes of Health Consensus Development Conference statement: management of hepatitis C: 2002. Hepatology 2002;36:S3–20. [2] Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358:958–65. [3] Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–82. [4] National Institutes of Health Consensus Development Conference Panel statement. Management of hepatitis C. Hepatology 1997;26:2S–11S. [5] Davis GL, Esteban-Mur R, Rustgi V, Hoefs J, Gordon SC, Trepo C, et al. Interferon apha-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. N Engl J Med 1998; 339:1493–9.

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Hepatitis C virus antiviral therapy in patients with cirrhosis Juan I. Arenas, MD, Hugo E. Vargas, MD* Mayo Clinic, Scottsdale, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA

Hepatitis C virus (HCV) is the leading cause of chronic liver disease. Almost 4 million people in the United States have detectable HCV antibodies, and approximately 2.7 million are chronically infected [1]. Most of these patients do well and have a mild long-term disease course. The greatest concern is the group of patients who develop cirrhosis and its lifethreatening complications, which may include variceal bleeding, recurrent ascites, hepatorenal syndrome, or hepatocellular carcinoma (HCC). Once the patient has decompensated cirrhosis, the most reliable and successful treatment may be liver transplantation. The great shortage of donor organs has led to an estimated 10,000 deaths per year as a result of HCV-associated chronic liver disease [2]. The ideal situation would be to identify patients with HCV who are likely to develop cirrhosis and treat them aggressively early on, when the chances of response may be better. Because of its slow progression, and despite significant progress in limiting infection through screening the blood supply and other risk reductions measures, there currently is a large wave of newly identified chronic infections. The major effects of HCV infection on health care resources likely remain to be seen [3,4]. In a recent study, Davis et al [5] predicted a decline in prevalence of chronic hepatitis C infection by 2040 using a mathematical model. The proportion of patients with cirrhosis, however, will increase from 16% to 32% by 2020 in an untreated population. Their model examined the effect of treating variable proportions of the population with chronic hepatitis C. Their projections showed that treating 10%, 50%, or 70% of all hepatitis patients with compensated liver disease would decrease complications of cirrhosis after 20 years by 5%, 24%, and 34%, respectively. Moreover, because most of the morbidity and mortality occur when patients develop cirrhosis, they concluded that HCV treatment * Corresponding author. E-mail address: [email protected] (H.E. Vargas). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.04.006

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accounted for the reduction in disease complication and hepatic death in their model. This article discusses the treatment of HCV in patients with cirrhosis and different stages of disease and how treatment may affect the natural history of HCV-related cirrhosis and its complications based on the limited information available.

Prognosis of patients with hepatitis C virus-related cirrhosis The progression of hepatic fibrosis and development of regenerative nodules define the progression from chronic hepatitis to cirrhosis. Knowledge about the natural history of HCV-related cirrhosis is crucial before consideration of antiviral therapy. Patients with high-grade necroinflammatory scores or high stage of fibrosis have a higher risk of developing cirrhosis in the next decade than patients without these histological features [6]. The most reliable information comes from a European multi-center study in which the investigators prospectively followed 384 patients with compensated HCV-related cirrhosis for a mean period of 5 years [7]. During the observation period, 8% of the patients developed HCC, with a yearly incidence of 1.4% during the first 5 years. Of the patients who remained tumor free, 18% developed at least one episode of decompensation, defined as ascites, jaundice, hepatic encephalopathy, or variceal bleeding. Mortality was 1.9% per year during the first 5 years, and the probability of survival after the onset of the first major complication of the disease was 50% at 5 years. Patients with no decompensation had a probability of survival of 91% [7]. Thus, survival in patients with compensated cirrhosis caused by HCV is good, and this population should be targeted to receive treatment that may impact the development of major complications in the future.

Influence of antiviral therapy on fibrosis progression Antiviral therapy with interferon (IFN) has been associated with improvement in fibrosis in patients with sustained virological response (SVR) and also in nonresponders [8–10]. The establishment of combination IFN (standard or pegylated (PEG)) and ribavirin (RBV) as effective antiviral therapy has revolutionized the management of chronic HCV [11–13]. Patient data from several large trials recently have permitted the evaluation of the effect of these new regimens on the progression of fibrosis. Poynard et al reviewed data from 3010 patients with chronic hepatitis C infection who had paired liver biopsies from four published randomized trials [14]. Necrosis and inflammation improvement ranged from 39% in patients receiving standard IFN for 24 weeks to 73% in patients receiving PEG-IFN a-2b plus RBV (P less than 0.001) [14]. Patients with worsening fibrosis varied from 23% in the standard IFN group to 8% in the PEG-IFN a-2b

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plus RBV group (P less than 0.001), and the most encouraging result was the reversal of cirrhosis observed in 49% of 153 patients who had baseline cirrhosis [14]. One third of patients with cirrhosis reversal were sustained responders, and all were treated for 48 weeks. They were also younger and had significant improvement in the histological activity grade compared with patients without cirrhosis reversal. Although these results are encouraging, studies with expanded follow-up are needed to confirm these observations. The tantalizing possibility of reversing fibrosis has focused attention on the fibrogenesis process in HCV.

Treatment of patients with cirrhosis Antiviral treatment in patients with cirrhosis has been controversial because of reports in the era of IFN monotherapy of very limited success after treatment accompanied by a significant adverse effect profile [15,16]. Despite recent improvements in response rates and a shift in risk–benefit ratio, solid data are limited because of the small number of randomized controlled trials in patients with cirrhosis. Patients with compensated cirrhosis, patients with decompensated cirrhosis, and patients with recurrent disease after liver transplantation are three groups of patients with advanced HCV-related liver disease that present specific challenges and require distinct management approaches. Antiviral therapy in patients with compensated hepatitis c-related cirrhosis Some of the challenges to treatment of cirrhotic patients and the reasons for the limited amount of data are related to the stringent criteria needed to accrue valid data. In most studies of compensated cirrhosis, the inclusion criteria include biopsy-proven cirrhosis in the preceding year with absence of clinical complications of liver disease such as ascites, variceal hemorrhage, and encephalopathy. Most antiviral treatment clinical trials require adequate blood cell counts to allow treatment. The definition of compensated cirrhosis also necessitates preserved hepatic synthetic function as demonstrated by levels of albumin of at least 3.5 g/dL, bilirubin of at least 1.5 mg/ dL, and international normalized ratio of at least 1.5. In patients with cirrhosis, SVR may be difficult to achieve, and alternate endpoints have been applied. Improvements in histology, prevention (or delay in development) of HCC, and delay of decompensation are some of the targets that have been used as surrogates to SVR in this difficult population. The first reports of treating HCV in cirrhotic patients with IFN were very discouraging. The first randomized controlled trial was done by Nishiguchi et al [17], and the primary goal was to see if patients treated with IFN had less incidence of HCC. Ninety cirrhotic patients were allocated randomly to receive IFN-a or symptomatic treatment. At the end of follow-up and HCV RNA was negative in 16% of the treatment group and in none of the control

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group. HCC was detected in two a-IFN treated patients and in 17 controls, demonstrating a risk ratio to develop HCC of 0.067 for patients treated with a-IFN. So, even when virological responses are not good, antiviral therapy in these patients might be helpful in achieving this significant end goal. In another multi-center RCT done by Valla et al [18], however, 99 patients with biopsy-proven cirrhosis were randomized to receive a-IFN 2b for 48 weeks or no treatment. Only 39 patients in the control group and 37 patients in the IFN group finished the study, and only two treated patients attained SVR, versus none in the control group. No differences were seen with respect to the incidence of HCC between both groups [18]. Since the introduction of combination therapy with RBV and the introduction of PEG-IFN, the SVR rates have increased significantly in patients with chronic HCV and also in patients with cirrhosis. The data for patients with cirrhosis in large registration trials are limited, since enrollment was limited a priori in this subgroup for the reasons outlined previously [11,13]. Table 1 shows the SVR rate in patients with cirrhosis or bridging fibrosis in the three major randomized controlled trials. The only prospective study focused on patients with cirrhosis was conducted by Heathcote et al [19]. The investigators included 271 patients who received three different treatment regimens for 48 weeks. The treatment arms consisted of PEG-IFNa-2a dosed at 90 lg weekly (n = 87), 180 lg weekly (n = 96), and IFNa-2a given 3 times a week (n = 88). Patients had biopsy-

Table 1 Sustained virological response in hepatitis C virus patients with cirrhosis or bridging fibrosis

Study

Number of patients with bridging fibrosis/cirrhosis

Heathcote et al (2000) [19]

271

Manns et al (2001) [13]

414

Fried et al (2002) [11]

161

Treatment regimens Peginterferon-a2a 90 lg Peginterferon-a2a 180 lg IFN-a2a IFN-a2b plus RBV 1000–1200 mg/d Peginterferon-a2b (1.5 lg/kg) plus RBV 800 mg/d Peginterferon-a2b (0.5 lg/kg) plus RBV 1000–1200 mg/d IFN-a2b plus RBV 1000–1200 mg/d Peginterferon-a2a plus placebo Peginterferon-a2a 180 lg plus RBV 1000–1200 mg/d

Sustained virologic response in cirrhosis/bridging fibrosis patients 15% 30% 8% 41% 44%

43%

33% 21% 43%

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proven cirrhosis (67%) or bridging fibrosis (33%), and none had received previous treatment with IFN. Patients who received the highest dose of PEG-IFNa-2a had an SVR rate of 30% versus 8% in the group treated with standard IFN (P = 0.001) [19]. PEG-a 2a also was associated with a higher response at the end of treatment; only 14% of the patients receiving IFN were HCV RNA negative, as compared with 42% and 44% of the patients receiving PEG-IFN a 2a at 90 lg and 180 lg dose levels, respectively (P = 0.001). These improvements in response in part may be caused by the impressive response of nongenotype 1-infected patients, who had an SVR rate of 51% (at the 180 lg per week dose level). The SVR rate was only 12% for those with genotype 1 infection. The histologic response for the 184 patients who had paired liver biopsies was reviewed as an end point of treatment. A histologic response at week 72 was defined as a decrease of at least 2 points in the total histological activity index (HAI) [20]. The proportion of patients who had a histologic response was lower among patients treated with IFN (31%) than those treated with PEG-IFN at 90 lg per week (44%) and those treated with 180 lg per week (54%). Moreover, a histologic response also was seen in patients who did not have SVR, ranging from 26% to 35% regardless of the treatment regimen. There are no randomized controlled trials using combination therapy of IFN and RBV focused on cirrhotic patients alone or even patients with bridging fibrosis. The available data are from subgroup analyses of patients enrolled in large randomized controlled trials of combination therapy. The first large trial with combination therapy was by McHutchison et al [12], where 912 patients with chronic HCV were assigned to receive standarddose IFNa-2b alone or in combination with RBV for 24 or 48 weeks. There were 250 patients with cirrhosis or bridging fibrosis, and the rate of SVR for combination therapy given for 24 weeks was significantly higher than IFN alone given for 48 weeks (29% versus 13%, P = 0.01). The SVR rate was even higher if combination therapy was administered for 48 weeks (38% versus 13%, P less than 0.001). Logistic regression analyses, however, revealed that greater efficacy was associated with the absence of cirrhosis at baseline. Data from two large randomized controlled trials using combination therapy with PEG-IFN and RBV are now available. In the study by Manns et al [13], 1530 patients with chronic HCV were assigned to receive IFN-a 2b (3 MU subcutaneously three times a week) plus RBV 1000 to 1200 mg per day, PEG-IFNa-2b 1.5 lg/kg per week plus ribavirin 800 mg per day, or PEG-IFNa-2b 1.5 lg/kg per week for 4 weeks then 0.5 lg/kg per week plus RBV 1000 to 1200 mg per day for 48 weeks. The proportion of patients with cirrhosis or bridging fibrosis was similar in all three groups, ranging from 28% to 30%; only 5% to 7% were well-compensated cirrhotic patients. Overall, the SVR rate at end of follow-up was significantly higher for the group receiving PEG-IFNa-2b at the 1.5 lg/kg per week dose level than for the other two treatment groups. The response rate in patients with cirrhosis

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or bridging fibrosis was similar in the three groups, ranging from 41% in the IFN group to 44% in the higher dose of PEG-IFN. In the group with no fibrosis or minimal fibrosis, the higher dose of PEG-IFNa-2b had a better SVR compared with the standard IFN (57% versus 49%, P = 0.04). Using univariate logistic regression to examine the influence of potentially important prognostic factors on SVR, the absence of cirrhosis was likely to affect the response, but it did not reach statistical significance (P = 0.07), probably because of the small sample size. On the other hand, the absence of bridging fibrosis/cirrhosis was an independent predictor of SVR (P = 0.001). As already mentioned, patients with advanced liver disease had no differences in SVR regardless of the treatment. In a large multi-center trial by Fried et al [11], 1121 treatment-naı¨ ve patients with chronic hepatitis C infection were randomized to one of three regimens. The first arm received 180 lg of PEG-IFN a-2a once weekly plus daily RBV (1000 or 1200 mg, depending on body weight). The second arm received PEG-IFN a-2a 180 lg plus daily placebo, and the last arm received 3 million units of IFN alfa-2b three times a week plus daily RBV (1000 to 1200 mg) for 48 weeks. Among patients with cirrhosis or bridging cirrhosis (13% of the total), 43% of the patients treated with PEG-IFN a-2a plus RBV had SVR compared with 33% of those treated with IFN a-2b and RBV. This is in contrast to 21% in the group that received PEG-IFN monotherapy [11]. The differences between the combination therapy with PEG-IFN and the IFN group were not significant, probably because of a small sample size. Nevertheless, overall, including patients with mild or no fibrosis, those receiving PEG-IFN a-2a plus RBV had the highest response rate compared with the other two regimens. There were three factors that independently and significantly increased the chances of attaining SVR: HCV genotype other than 1, younger age, and body weight of 75 kg or less. In this study, the presence of cirrhosis or bridging fibrosis was not a significant predictor of SVR, most likely because of the small number of patients with stage 3 or 4 of fibrosis. Another large multi-center trial, which has been presented in abstract form, examines the efficacy and safety of treatment durations and doses of RBV in combination with PEG-IFN a-2a. This study by Hadziyannis et al [21] with 1284 patients had four treatment arms. All patients received PEGIFN a-2a in a dose of 180 lg weekly with two different doses of RBV (800 mg per day versus 1000/1200 mg per day) and with two treatment durations (24 weeks versus 48 weeks). One of the purposes of the study was to evaluate response rates by genotype, comparing genotype 1 against the other genotypes. In this study, overall SVR rate cannot be evaluated across the study because of the planned unequal distribution of genotypes in the treatment arms [21]. For patients with genotype other than 1, there was no difference between 24 weeks of treatment or 48 weeks, and they had an overall SVR of 73% to 78%. Patients with genotype 1 needed a full course and a higher dose of RBV to achieve the best SVR rate (51%). Patients with

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cirrhosis or bridging fibrosis comprised 26% of the genotype 1 cohort receiving PEG-IFN a-2a and high doses of RBV for 48 weeks. The SVR for patients with cirrhosis or bridging fibrosis was 50% compared with 65% for patients without cirrhosis. Long-term (maintenance) therapy There is an ongoing multi-center United States trial called Hepatitis C Long-term Treatment against Cirrhosis (HALT-C), designed to determine the effect of maintenance PEG-IFN on the prevention of fibrosis progression and clinical decompensation in patients with advanced fibrosis who failed combination therapy. Following treatment with PEG-IFN-a2a weekly and RBV at 1000 to 1200 mg per day for 6 months, nonresponders with advanced fibrosis or cirrhosis are being randomized to receive either 90 lg of PEG-IFN a-2a weekly for 3.5 years or no further antiviral therapy. The study endpoints include histological progression, development of HCC, decompensation, or the need for liver transplant. Results from a lead-in phase with 212 patients have been presented in abstract form [22]. SVR was achieved in 20% and was greater in patients previously treated with IFN monotherapy than with combination IFN and RBV. Patients with a non-1 genotype had a greater SVR rate. Another large multi-center trial (Co-PILOT) is testing the safety and efficacy of PEG-IFN a-2b at 0.5 lg/kg per week versus colchicine in previous nonresponders with advanced fibrosis. Data of the first 250 patients who have entered the study focusing on year 1 outcome are available [23]. Although no long-term conclusions can be drawn from these data, a trend toward lower viral load is being seen in the PEG-IFN group [23]. Recommendations for maintenance therapy should be reserved, as the benefit of therapy has not been established. Safety of antiviral therapy in patients with compensated cirrhosis Patients with HCV-related cirrhosis or advanced fibrosis are difficult to treat. Adverse effects of combination therapy in these patients are more frequent than in the preliver transplant chronic hepatitis C patient [11,13]. Furthermore, patients receiving PEG-IFN have a higher incidence of dose reduction than those receiving standard IFN because of greater hematological adverse effects such as neutropenia, thrombocytopenia, and anemia. Regardless of the type of IFN, patients with advanced fibrosis should be monitored closely to prevent serious adverse effects secondary to severe cytopenias. Growth factors have not been shown to increase virological response, and their use has not been proven to be cost-effective. Recommendations on the use of these agents cannot be made until large trials are completed.

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Antivirals in decompensated hepatitis C-related cirrhosis Therapy with IFN has been avoided in patients with decompensated cirrhosis, normally defined as those patients with a Child-Pugh score of at least 7. Pre-existing leukopenia, thrombocytopenia, and manifestations of end-stage liver disease have resulted in poor drug tolerance. Truly limited data are available, as decompensated cirrhosis was an exclusion criterion for large randomized controlled trials. Once a patient with cirrhosis develops a significant complication, such as ascites, hepatic encephalopathy, variceal bleeding, hepatorenal syndrome, or HCC, the only proven therapy to prolong survival is liver transplant. Therefore, because the treatment in these patients is not tolerated well, the primary goal of therapy may be different than for the noncirrhotic chronic hepatitis C population. The target in patients with advanced liver disease should be the prevention or slowing of clinical disease progression (including reducing the development of HCC) while awaiting liver transplant. The best result would be the viral clearance, potentially leading to liver transplant with undetectable viral counts. Box 1 summarizes the potential pros and cons of antiviral therapy in patients with decompensated cirrhosis.

Box 1. Arguments for and against antiviral therapy in patients with advanced liver disease contrasted with those for and against therapy after liver transplant Treatment of hepatitis C virus before liver transplant Pro HCV clearance may translate into postliver transplant clearance Potentially higher SVR rates May be able to maximize RBV doses No concern about rejection of IFN Con Limited by degree of decompensation High risk of infection High risk of bone marrow treatment-limiting adverse effects Treatment of hepatitis C virus after liver transplant Pro Patient potentially more tolerant of treatment No concerns about porter hypertension (particularly ascites) Con Adverse effects may limit number of patients Theoretical risk of rejection Risk of RBV toxicity because of limited renal function

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In a multi-center small pilot study, Crippin et al randomized patients with decompensated cirrhosis awaiting liver transplant to receive three different regimens of IFN a-2b with and without RBV [24]. Only 15 patients met the inclusion criteria, with thrombocytopenia and leukopenia the most common reasons for exclusion. Three patients received IFN a-2b 1 MU once daily, six received 3 MU three times a week, and six were treated with combination IFN at 1 MU daily plus RBV at 400 mg per day. All patients were HCV RNA positive at baseline, and treatment was planned until the patient underwent liver transplant. Five (33%) patients became HCV RNA negative during treatment even with the low dose IFN. Adverse events, however, occurred in 13 (86%) patients. Thrombocytopenia (n = 8), leukopenia (n = 4), hepatic encephalopathy (n = 3), and nausea and vomiting (n = 2) were seen. Of the 23 adverse effects, 20 were classified as severe. Infectious complications occurred in two patients, and although the investigators’ goal was to enroll 60 patients, the study was terminated early after the second major bacterial infection, which was a culture-negative empyema resulting in death. The authors concluded that despite response rates similar to those in patients with more compensated disease, the rate of adverse effects makes the value of antiviral therapy in patients with decompensated cirrhosis very limited [24]. A similar multi-center study conducted in Spain and presented in abstract form by Garcia-Retortillo et al [25] includes 25 HCV RNA-positive cirrhotic patients awaiting liver transplant. The indication for liver transplant was decompensated cirrhosis in 10 patients and HCC in 15. Patients were treated with IFN at 3 MU per day and RBV at 400 mg twice daily until they underwent liver transplantation. All patients were transplanted before 5 months from the first dose of therapy. At liver transplant, HCV RNA was negative in seven (28%) patients. HCV RNA reappeared in four patients and remained undetectable in three (follow-up at 4, 20 and 36 weeks). Dose reduction was necessary in 16 (64%) patients because of adverse effects and was discontinued in one patient because of severe thrombocytopenia [25]. A different approach, labeled LADR (low-accelerating-dose regimen) and consisting of slowly escalating the dose of standard IFN a-2b plus RBV in the treatment of moderately decompensated cirrhosis, has been reported by Everson et al [26]. A total of 102 patients were started with IFN a-2b at a dose of 1.5 MU three times a week plus 600 mg per day of RBV, and doses were increased slowly every 2 weeks as tolerated. Mean child-turcotte pugh score was 7.1 plus or minus 2 with approximately 50% stage A and 50% stage B or C. Growth factors such as granulocyte colony stimulating factor and erythropoietin were administered as needed to maintain absolute neutrophil count greater than 800 and Hgb greater than 10. Outcome was reported for 91 of 102 treated patients. SVR was achieved in 22% (20/91). The two factors correlated with response to treatment were the ability to achieve full-dose therapy and non-1 genotype. Eight patients who reached SVR and underwent liver transplant, and none of them recurred after liver

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transplant. In contrast, all patients who did not clear the virus pretransplant remained HCV RNA positive after transplant. Results from both the LADR protocol and the study by GarciaRetortillo reflect a less stringent selection process, with a significant number of patients with compensated cirrhosis. At this time, with only limited data, antiviral therapy for patients awaiting liver transplant can be recommended only if careful patient selection is performed to exclude patients with ascites and significant thrombocytopenia or granulocytopenia. There is no published information on the use of PEG-INF. Because of the frequency of hematological adverse effects with standard IFNs, it is reasonable to recommend caution in the use of pegylated agents in this population. Antiviral therapy for hepatitis C virus recurrence after liver transplantation The natural history of HCV after transplantation is very diverse. Viral recurrence is universal, and a significant percentage of these patients develop advanced fibrosis and cirrhosis within 5 years after transplantation [27]. Moreover, the natural history of HCV cirrhosis after transplantation is also more aggressive, and patients who develop cirrhosis after transplantation should be listed for retransplantation, if considered, as soon as they develop their first decompensation [28]. Furthermore, HCV-positive patients have an inferior survival after transplantation than HCV-negative patients [29], so treatment of HCV in the post-transplant setting is necessary. Antiviral therapy of recurrent HCV has not shown promising results, however, probably because of required immunosuppression. In addition, the tolerability of combination therapy is limited in this population, frequently requiring dose reductions and discontinuations of therapy because of bone marrow toxicity. Patients also receive several medications, such as calcineurin inhibitors, which impair renal function, thus limiting the use of RBV (Box 1). Various strategies have been considered to limit the recurrence of HCV after liver transplant, including pre-emptive antiviral therapy and selective therapy based on histological recurrence. The first studies published in this area made use of IFN monotherapy, and the results were poor, with viral clearance during treatment a rare event, and only one patient experiencing SVR in these series [30–33]. Furthermore, some investigators were concerned about the risk of IFN-related chronic and acute rejection [31]. Because the combination of IFN and RBV is more effective in immunocompetent patients, it would be expected to be true in liver transplant recipients also. As already mentioned, adverse effects of RBV are greater in renally compromised patients, and this appears to be the major limitation to successful therapy. Several uncontrolled studies with small numbers of patients have been published, and SVR rates range from 5% to 30% [34–39]. Recently, Samuel et al [40] published a randomized controlled study

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of treatment with combination therapy (n = 28) with IFN a-2b (3 MU three times a week) plus RBV (1000 to 1200 mg per day) for 1 year versus no treatment (n = 24) in liver transplant recipients infected with HCV. The primary endpoint was the negativity of HCV RNA 6 months after the end of treatment. HCV RNA was undetectable in nine patients (32%) at the end of the treatment in the treated group, and in six (21%) of those patients at the end of the follow-up. No patient in the control group lost the HCV RNA at any point during the observation period. A higher number of patients in the treatment group experienced improvement in their histological scores as compared with the control group (54% versus 21%). At the end of the follow-up period, however, the difference was undetectable (25% versus 21%). Tolerance was an important limiting factor to completion of therapy. Anemia caused by RBV was the main reason for withdrawal from the study, and this occurred in seven treated patients (25%) versus none in the control group. Chronic rejection was observed in one patient in the treated group and in none in the placebo group. Other adverse effects were comparable with the nontransplant population. Antiviral therapy after liver transplant may achieve SVR in a small percentage of patients. If the incidence of anemia is decreased by adjusting the initial dose of RBV to the patient’s weight and renal function and by adding erythropoietin, fewer patients might withdraw treatment, and response rates might increase. Data from a pilot study about efficacy and safety of PEG-IFN and RBV after liver transplant are available from a small single center study of 37 liver transplant recipients [41]. Patients started PEG-IFN a-2b at a dose of 0.5 lg/kg per week and progressively increased toward a maximum dose of 1.5 lg/kg per week. RBV was started at a dose of 400 mg per day toward a maximum of 1000 mg per day, as tolerated. Patients were treated for 1 year after they became RT-PCR negative or therapy was discontinued if there was no virological response at 48 weeks. Nineteen patients completed therapy, with 37% of the patients achieving an end-of-treatment response, and 26% achieving SVR. Growth factors such as erythropoietin and granulocyte colony stimulating factor were used in this trial to improve tolerability to PEG-IFN and RBV.

Summary Treatment of HCV infection in the setting of cirrhosis remains a challenge. In patients with compensated cirrhosis, combination therapy is the preferable choice, although the optimal regimen has not been defined. Some general recommendations can be made. Patients with genotype 1 should be treated for a total of 48 weeks with high doses of RBV and high doses of either PEG-IFN a-2a or PEG-IFN a-2b. There is no difference in efficacy between the two regimens, although it is important to consider that patients

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with cirrhosis are more likely to suffer from hematological adverse effects, which are more common with PEG-IFN. Patients with genotype non-1 may require lower doses of RBV, and 24 weeks of treatment duration might be enough. In cases where RBV is contraindicated, patients should be treated with PEG-IFN alone. The treatment for patients with decompensated cirrhosis remains controversial, and antiviral therapy should not be used outside a clinical trial, and then only with very close monitoring by experts in the field. Management of hepatitis C after liver transplant is also an area to be explored. Although treatment should be offered to patients, the ideal regimen and dosage remain undefined. Combination therapy with PEGIFN and RBV along with judicious growth factor use appears to hold the greatest promise.

References [1] Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341(8):556–62. [2] Alter MJ. Epidemiology of hepatitis C. Hepatology 1997;26:62S–65S. [3] Seeff LB, Buskell-Bales Z, Wright EC, et al. Long-term mortality after transfusionassociated non-A, non-B hepatitis. The National Heart, Lung, and Blood Institute Study Group. N Engl J Med 1992;327(27):1906–11. [4] El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340(10):745–50. [5] Davis GL, Albright JE, Cook SF, et al. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl 2003;9(4):331–8. [6] Yano M, Kumada H, Kage M, et al. The long-term pathological evolution of chronic hepatitis C. Hepatology 1996;23(6):1334–40. [7] Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology 1997;112(2): 463–72. [8] Poynard T, Leroy V, Cohard M, et al. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: effects of dose and duration. Hepatology 1996;24(4):778–89. [9] Camma C, Giunta M, Linea C, et al. The effect of interferon on the liver in chronic hepatitis C: a quantitative evaluation of histology by meta-analysis. J Hepatol 1997;26(6): 1187–99. [10] Sobesky R, Mathurin P, Charlotte F, et al. Modeling the impact of interferon alfa treatment on liver fibrosis progression in chronic hepatitis C: a dynamic view. The Multivirc Group. Gastroenterology 1999;116(2):378–86. [11] Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347(13):975–82. [12] McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998;339(21):1485–92. [13] Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358(9286):958–65. [14] Poynard T, McHutchison J, Manns M, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002; 122(5):1303–13.

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[15] Janssen HL, Brouwer JT, Nevens F, et al. Fatal hepatic decompensation associated with interferon alfa. European concerted action on viral hepatitis (Eurohep). BMJ 1993; 306(6870):107–8. [16] Nevens F, Goubau P, Van Eyken P, et al. Treatment of decompensated viral hepatitis B-induced cirrhosis with low doses of interferon alpha. Liver 1993;13(1):15–9. [17] Nishiguchi S, Kuroki T, Nakatani S, et al. Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 1995;346(8982):1051–5. [18] Valla DC, Chevallier M, Marcellin P, et al. Treatment of hepatitis C virus-related cirrhosis: a randomized, controlled trial of interferon alfa-2b versus no treatment. Hepatology 1999; 29(6):1870–5. [19] Heathcote EJ, Shiffman ML, Cooksley WG, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000;343(23):1673–80. [20] Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22(6):696–9. [21] Hadziyannis S, Cheinquer H, Morgan T, et al. Peginterferon alfa-2a (40KD) (Pegasys) in combination with ribavirin (RBV): efficacy and safety results from a phase III, randomized, double-blind, multi-centre study examining the effect of duration of treatment and RBV dose [abstract]. J Hepatol 2002;36(Suppl 1):3. [22] Shiffman M. Retreatment of HCV nonresponders with peginterferon and ribavirin: results from the lead-in phase of the hepatitis c antiviral long-term treatment against cirrhosis (HALT-C) trial. Hepatology 2002;36(4):295A. [23] Afdhal NH, Levine R, Black M. Colchicine versus PEG-intron long-term: 1 year data from the copilot study [abstract]. Gastroenterology 2002;122:218. [24] Crippin JS, McCashland T, Terrault N, et al. A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus-infected patients awaiting liver transplantation. Liver Transpl 2002;8(4):350–5. [25] Garcia-Retortillo M, Forns X, Suarez F, et al. Efficacy and safety of combined interferon and ribavirin therapy in cirrhotic patients infected with hepatitis C virus (HCV) awaiting liver transplantation [abstract]. Hepatology 2002;36:177A. [26] Everson G, Trotter JMK. Long-term outcome of patients with chronic hepatitis C and decompensated liver disease treated with the LADR protocol (low-accelerating-dose regimen). Hepatology 2002;36:297A. [27] Berenguer M. Natural history of recurrent hepatitis C. Liver Transpl 2002;8:S14–8. [28] Berenguer M, Prieto M, Rayon JM, et al. Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation. Hepatology 2000;32: 852–8. [29] Forman LM, Lewis JD, Berlin JA, et al. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002;122(4): 889–96. [30] Wright TL, Combs C, Kim M, et al. Interferon-alpha therapy for hepatitis C virus infection after liver transplantation. Hepatology 1994;20:773–9. [31] Feray C, Samuel D, Gigou M, et al. An open trial of interferon alfa recombinant for hepatitis C after liver transplantation: antiviral effects and risk of rejection. Hepatology 1995;22:1084–9. [32] Vargas V, Charco R, Castells L, et al. Alpha-interferon for acute hepatitis C in liver transplant patients. Transplant Proc 1995;27(1):1222–3. [33] Gane EJ, Lo SK, Riordan SM, et al. A randomized study comparing ribavirin and interferon alfa monotherapy for hepatitis C recurrence after liver transplantation. Hepatology 1998;27(5):1403–7. [34] Bizollon T, Palazzo U, Ducerf C, et al. Pilot study of the combination of interferon alfa and ribavirin as therapy of recurrent hepatitis C after liver transplantation. Hepatology 1997;26(2):500–4.

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[35] Gopal DV, Rabkin JM, Berk BS, et al. Treatment of progressive hepatitis C recurrence after liver transplantation with combination interferon plus ribavirin. Liver Transpl 2001; 7(3):181–90. [36] Ahmad J, Dodson SF, Demetris AJ, et al. Recurrent hepatitis C after liver transplantation: a nonrandomized trial of interferon alfa alone versus interferon alfa and ribavirin. Liver Transpl 2001;7(10):863–9. [37] Alberti AB, Belli LS, Airoldi A, et al. Combined therapy with interferon and low-dose ribavirin in post-transplantation recurrent hepatitis C: a pragmatic study. Liver Transpl 2001;7(10):870–6. [38] De Vera ME, Smallwood GA, Rosado K, et al. Interferon-alpha and ribavirin for the treatment of recurrent hepatitis C after liver transplantation. Transplantation 2001;71(5): 678–86. [39] Firpi RJ, Abdelmalek MF, Soldevila-Pico C, et al. Combination of interferon alfa-2b and ribavirin in liver transplant recipients with histological recurrent hepatitis C. Liver Transpl 2002;8(11):1000–6. [40] Samuel D, Bizollon T, Feray C, et al. Interferon-alpha 2b plus ribavirin in patients with chronic hepatitis C after liver transplantation: a randomized study. Gastroenterology 2003; 124(3):642–50. [41] Rodriguez-Luna H, Khatib M, Sharma P, et al. Treatment of recurrent hepatitis c infection after liver transplantation with combination of PEG-IFN a2b and ribavirin: an open label series. Transplantation 2004;77(2):190–4.

Gastroenterol Clin N Am 33 (2004) 563–579

Management of chronic hepatitis B Marc G. Ghany, MDa,*, Edward C. Doo, MDb a

Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9B-06, 10 Center Drive, MSC 1800, Bethesda, MD 29892-1800, USA b Department of Transplantation, California Pacific Medical Center, 2340 Clay Street, Suite 230, San Francisco, CA 94115, USA

Infection with hepatitis B virus (HBV) is a significant global public health problem. Over one third of the world population has been exposed to the virus, and an estimated 400 million people are chronically infected [1,2]. Up to 40% of chronically infected individuals will be at risk for cirrhosis, decompensated liver disease, and hepatocellular carcinoma (HCC), and each year, an estimated 500,000 deaths occur from these complications. Advances in molecular biology techniques have led to a better understanding of the natural history and pathogenesis of HBV-related liver disease, resulting in the development of potent antiviral agents. Some of these agents can be used safely as maintenance therapy for patients who fail to clear the virus following standard durations of treatment. Overall, the advent of newer therapies has provided a wider range of therapeutic options for chronic hepatitis B (CHB) infection. This article focuses on the natural history of CHB-related liver disease, assessment and selection of patients for therapy, and new therapeutic options. It is meant to provide a succinct update on the management of CHB based on recent advancements in knowledge of the disease. Natural history The natural history of HBV infection is variable and influenced by a complex interplay between the host immune response and the replication fitness of the virus. Other factors impacting the course of HBV infection include age at time of exposure, integrity of the immune system, alcohol consumption, obesity, and concurrent viral infections such as hepatitis C virus (HCV), hepatitis D virus (HDV), and HIV. In addition, viral load, viral variants, and perhaps HBV genotype may affect the clinical course. * Corresponding author. E-mail address: [email protected] (M.G. Ghany). 0889-8553/04/$ - see front matter
2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.04.007

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Ultimately, the outcome of HBV infection is influenced by the robustness of the immune response as highlighted by the different clinical courses of perinatally and adult-acquired infection. Exposure at birth or a young age, when the immune system is thought to be immature, represents the highest risk for developing CHB; 90% to 95% of exposed infants develop chronic infection. When infection occurs during infancy or early childhood, there is typically an absence of liver disease. The clinical course is characterized by a lack of symptoms, mild or no elevation in serum aminotransferase levels, and minimal inflammation on liver biopsy. Nevertheless, HBV DNA levels can be quite high, and hepatitis B e antigen (HBeAg), a surrogate marker of viral replication, is found in serum [3]. This state is believed to be caused by immune tolerance and may persist for 10 to 30 years [3] (Fig. 1A). During this period, there is a low rate of viral clearance. In stark contrast to perinatally acquired infection, 90% to 95% of adult cases of HBV infection resolve spontaneously. In adults who progress onto CHB, however, there is active viral replication and liver injury. This phase is characterized by fluctuating HBV DNA levels, high serum aminotransferase levels, and hepatic necroinflammation. It is thought to be the result of incomplete attempts to control infection by immune-mediated eradication of virally infected hepatocytes [4]. This scenario typifies the immunoactive phase (Fig. 1B). In perinatally acquired infection, the immune tolerant phase may be followed by an immunoactive phase after a variable period of 15 to 30 years. (see Fig. 1A) Clinical manifestations of chronic liver disease may appear during flares of hepatitis, and repeated bouts of these immunemediated flares may accelerate the progression of hepatic fibrosis to cirrhosis [5–7]. During these flares, a small number of patients (10% to 15%) may lose HBeAg spontaneously, followed by the development of antibody to HBeAg (anti-HBe), a so-called HBeAg seroconversion, heralding a period of quiescence in liver disease termed the inactive phase [5–7]. This phase is associated with normal aminotransferase levels and less hepatic inflammation [6]. Some authorities refer to this period as progression from a high to low period of viral replication, because it is associated with undetectable HBV DNA levels by hybridization assays, but HBV DNA may be detectable by polymerase chain reaction (PCR) assays. Hepatitis B surface antigen (HBsAg), however, remains detectable in serum. This phase may last for many years, and in the absence of cirrhosis, there is diminished risk for disease progression or hepatocellular carcinoma [8,9]. Thus HBeAg seroconversion is an important clinical event associated with a period of disease inactivity and improved prognosis, and it often is used as an endpoint of therapy [10]. During the inactive phase, 1% to 2% of individuals per year will clear HBsAg, but as many as 30% of people may relapse to the immunoactive phase. Despite the loss of HBeAg, approximately 5% to 10% of individuals will continue to have detectable HBV DNA, elevated aminotransferase levels, and active inflammation on liver biopsy. These cases are defined as the

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HBeAg+/

A HBeAg+

anti-HBe+

anti-HBe+

HBV DNA

ALT

Immune tolerance phase

Immune clearance phase

HBeAg+

B

Non-replicative phase

Years

anti-HBe+

HBV DNA

ALT

Replicative phase

Non-replicative phase

Years

Fig. 1. Natural history of chronic HBV infection. (dashed lines) Represent typical fluctuations that occur with HBV infection. (straight lines) Represent average trends for both HBV DNA and ALT. (A) Course of perinatally acquired HBV infection. (B) Course of adult-acquired HBV infection.

HBeAg-negative or atypical form of CHB and remain in the immunoactive phase [11]. Based on this knowledge, the natural history of HBV infection can be defined by three clinical, serologic, and virologic patterns:

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1. HBeAg-positive or typical CHB. This is the most common pattern and is defined by the presence of HBeAg and elevated HBV DNA in serum. The prognosis is variable and is in part dependent upon whether the infection is in the immunoactive phase (associated with elevated aminotransaminase levels and chronic hepatitis on liver biopsy) or the immunotolerant phase (associated with normal aminotransaminase levels and minimal to absent inflammation on liver biopsy). 2. HBeAg-negative or atypical CHB. This form of the infection is characterized by the absence of HBeAg but with detectable HBV DNA in serum and elevated aminotransferase levels. Features of chronic hepatitis are seen on liver biopsy, and the disease is immunoactive [12,13]. Molecular analysis has identified the cause of this clinical presentation as caused by mutations in the HBV precore and core gene that result in abrogation of HBeAg synthesis [12,13]. The clinical course can be quite severe, with more frequent episodes of acute hepatitis flares that may accelerate progression to cirrhosis [14]. Patients presenting with this pattern of disease should have other forms of chronic hepatitis excluded, such as hepatitis C and D infections and autoimmune and drug-induced liver disease. 3. The inactive carrier state. This is typified by the presence of anti-HBe in serum, normal alanine aminotransferase (ALT) levels, undetectable HBV DNA by hybridization assays, and minimal changes on liver biopsy. Viral replication is low in these individuals. Patients in this phase of the disease usually have a favorable prognosis and are at low risk for liver disease progression [8,15]. Occasionally, spontaneous reactivation may occur. Assessment and monitoring The primary goals of assessment are to determine the level of disease (active or inactive) and to stage the disease as mild, moderate, or severe. The initial evaluation of the patient should include a complete history and physical examination with particular attention directed toward eliciting signs, symptoms, and risk factors for chronic liver disease. A family history of liver disease should be sought and a detailed alcohol history obtained. Routine blood tests should include standard biochemical and hematological profiles and specific viral serologic assays for HBsAg, HBeAg, antiHBc, anti-HBe, anti-HBs, and quantitation of HBV DNA [16,17]. A still unresolved issue is the type of HBV DNA assay to use in clinical practice. Testing for hepatitis A, C, and D and HIV should be performed routinely, as most of these viruses share similar routes of transmission as HBV, and coinfection with another virus may modify the course of HBV. Other causes of chronic liver disease also should be excluded. A baseline ultrasound examination is recommended to exclude abnormal masses or

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anatomical variants. A liver biopsy provides information on the grade (severity of inflammation) and the stage (severity of fibrosis) of the disease. A biopsy is not an absolute requirement before treatment and should be individualized for each patient. The information gained from a liver biopsy, however, can confirm the diagnosis, provide prognostic information for the patient, and assist in determining the need for therapy. Patients should be informed of other factors that might exacerbate progression of underlying liver disease, notably alcohol consumption and use of hepatotoxic medications. Counseling on reducing the risk of transmission should be undertaken, especially for teenagers, young adults, and injection drug users, populations among whom the risk of sexual and parenteral transmission is high. Close family, household, and sexual contacts should be vaccinated against HBV. Individuals who do not have immunity against hepatitis A virus (HAV) should be offered hepatitis A vaccination. If bridging fibrosis or cirrhosis is found on liver biopsy, or if there is clinical evidence of advanced liver disease, a screening esophagogastroduodenoscopy is advisable to exclude esophageal varices. Attention should be given to initiating a screening program for HCC in patients with established cirrhosis and in males, older individuals, and those with a strong family history of liver cancer. Selection of patients for treatment Identifying patients who require treatment may appear to be straightforward, but it is usually quite complicated in practice. There are many factors to consider in the decision-making process, including the age of the patient, stage of disease, pattern of liver disease, the patient’s willingness to be treated, coinfection with other hepatotrophic viruses (HCV, HDV) and HIV, presence of other comorbid conditions and adverse effects of treatment. CHB often has a fluctuating course; therefore, patients should be monitored for a period of at least 6 months to assess the pattern of disease before initiating therapy (Fig. 2). Patients with inactive CHB are not candidates for therapy. Those with mild disease as evidenced by a fibrosis score of 2 or less on the Ishak and Metavir scales or 1 on the Knodell scale and serum ALT levels persistently less than twice the upper limit of normal can defer therapy safely until more effective treatments or agents with better long-term resistance profiles become available. These patients should continue to be monitored by biochemical and serologic tests every 3 to 6 months. Patients with ALT elevations greater than twice the upper limit of normal, HBV DNA levels greater than 105 copies per mL, or with evidence of moderate-to-severe chronic hepatitis on liver biopsy are candidates for therapy. HBeAg status should be determined, as therapeutic options differ between HBeAg-positive and -negative patients. Patients with decompensated liver disease are managed best at a transplant center by an experienced hepatologist.

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HBsAg + HBeAg

Inactive carrier Anti-HBe+; HBV DNA neg; Normal ALT

No treatment Monitor q 36 months

Pos HBV DNA <105 copies / ml; normal ALT

Decompensated Liver disease Neg HBV DNA >105 copies / ml; elevated ALT for ≥6 months Liver biopsy

Mild hepatitis

Consider antiviral Moderate to severe chronic hepatitis / therapy / compensated cirrhosis refer for OLT Consider antiviral therapy

Fig. 2. Algorithm for selection of patients for therapy.

Role of hepatitis B virus genotypes Traditionally, HBV isolates have been distinguished by serotyping based on three antigenic determinants of the HBsAg. Common to all isolates is the ÔaÕ epitope and two pairs that are mutually exclusive to each other, (d or y) and (r or w), thus giving rise to four major serotypes: adr, adw, ayr, and ayw. With the advent of genetic sequencing, HBV was classified into seven genotypes (A to G) based on a nucleotide divergence in the entire genome of at least 8% [18–20]. Genotypes also can be identified by analysis of the small envelope gene of HBsAg (s-gene), where the inter-genotype divergence is of the order of 4%. The seven genotypes have a characteristic geographical distribution, but most have a worldwide prevalence because of human migration. Of the seven genotypes, types A through D are the most common worldwide. Genotype A is found predominantly in North America, northwest Europe, and central Africa; genotypes B and C prevail in China, Japan, and Southeast Asia. Genotype D is found primarily in the Mediterranean, Middle East, and Indian subcontinent (Table 1). A recent study reported that the predominant United States genotypes were types A and C, suggesting a change in the prevalence of genotypes in the United States population. Over 50% of patients in the study were of Asian ethnicity, however. Additionally, genotype A was more common in American-born patients, whereas genotype C was more common among Asian-born patients. This suggests that the increased prevalence of HBV genotype C in the United States population was caused by immigration from endemic regions of the world [21].

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Table 1 Geographical distribution and clinical relevance of hepatitis B virus genotypes HBV genotype A

B

C

Geographical distribution North America, North western Europe, Central Africa China, Indonesia, Vietnam, Taiwan

D

East Asia, Korea, China, Taiwan, Japan, Polynesia, Vietnam Mediterranean, Middle East, India

E F G

Nigeria, West Africa Alaska, Polynesia North America, France

Clinical relevance

• Lower disease activity • Associated with HCC in noncirrhotic individuals • Improved response to interferon and lamivudine • Associated with more severe liver disease • Associated with precore mutation and HBeAg status Unknown Unknown Unknown

With HCV, genotyping has been found to have an important role in managing infection. It is one of the strongest predictors of response to therapy and influences the therapeutic duration. There have been several recent studies attempting to correlate HBV genotypes with clinical parameters such as the rate of HBeAg seroconversion, development of clinically important mutations, severity of liver disease, and response to treatment. Several studies have suggested that genotype may correlate with disease activity. When compared with genotype B, genotype C was associated with higher ALT levels and a higher prevalence of cirrhosis [22]. HBV genotype B was shown to be associated with an earlier time to HBeAg seroconversion, which may help to explain the lower disease activity reported in Asian patients [22–24], and with a higher rate of hepatocellular carcinoma in younger individuals [25]. A recent study from India found that patients with genotype D have more severe disease and a higher rate of HCC compared with patients with genotype A [26]. Given the heterogeneity of the data, it is clear that the role of HBV genotypes in relation to clinical outcome requires further investigation. A relationship between viral burden and HBV genotype also has been suggested. Analysis of a large cohort of patients enrolled in phase III trials of adefovir showed that in HBeAg-positive CHB patients, HBV DNA levels were significantly higher in genotypes A, B, and D compared with genotype C. In contrast, among HBeAg-negative patients, significantly higher HBV DNA levels were found in those with genotype D. The two predominant mutations that lead to HBeAg-negative CHB appear to be associated with specific HBV genotypes [22,27]. The precore mutation and the basic core promoter mutation are found more commonly with HBV genotypes D and A, respectively.

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Lastly, genotype may affect the response to antiviral treatment. In Asian patients infected with genotypes B or C, interferon (IFN)was shown to be less effective in genotype C compared with genotype B infections [28]. A small European trial suggested that the response to lamivudine was better in patients with serotype ayw (corresponding to genotype D) compared with serotype adw (corresponding to genotype A) [29]. Furthermore, the rate of resistance was higher in patients with serotype adw [29]. A recent analysis suggested that genotype B was associated with a higher sustained loss of HBeAg in lamivudine-treated patients [30]. No association between genotype and response to treatment, however, was found in a larger cohort of adefovir-treated patients [31]. Much of the current data regarding the clinical implications of HBV genotypes should be viewed with some prudence. Many of the studies were small and cross-sectional, comparing two of the major genotypes with each other, either B with C or A with D, and may have been susceptible to referral bias. These issues serve to limit the generalizability of their respective findings and highlight the need for further studies to help define the clinical implications of HBV genotypes. At present, the data are insufficient to merit genotype testing as part of the evaluation of patients with CHB. Screening for hepatocellular carcinoma Hepatocellular carcinoma is a significant cause of morbidity and mortality in patients with CHB. There is no effective therapy for HCC. The rationale for HCC screening is to detect small, solitary lesions that may be more amenable to surgical resection or liver transplantation [32]. The benefit of this approach has not been substantiated. The best data to support a screening program in patients with HBV come from a populationbased screening and surveillance study using periodic alpha fetoprotein (aFP) testing in 1487 HBsAg-positive Alaskan natives [34]. Rates of cancer in the screened group were compared with historical controls from a national cancer registry. During a 16-year period, 100 aFP elevations were detected, and 32 cancers were diagnosed; 22 patients underwent successful resection. The comparison group was comprised of 12 historical controls diagnosed before institution of the screening program. Survival rates were improved significantly in the screened population versus historical controls at 5 years (42% versus 0%) and at 10 years (30% versus 0%) [33]. Thus in this population, screening appeared to be effective in reducing mortality from HCC. There have been no randomized controlled trials of screening for HCC. The two most widely employed modalities for screening are aFP testing and periodic ultrasound exams of the liver [34]. There are several limitations to both options. In the case of aFP, defining a standard cut-off and optimal frequency of testing is a matter of intense debate. Sensitivity of ultrasound is

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poor, ranging from 35% to 84%. It is highly operator-dependent, and like aFP testing, there is no consensus on how frequently the procedure should be performed. HCC has widely variable growth rates, with a doubling time of 1 to 19 months, with a median of 6 months. Thus, most authorities recommend a screening interval of 6 months. Among histologically proven cases of HCC, 30% do not present with serum aFP elevations, and 30% of tumors smaller than 2 cm may not be detected by ultrasound. Thus, in clinical practice, both tests are used, adding to the cost of screening. Specific guidelines for screening are difficult to formulate in part because of the expense of current screening modalities, the absence of a test with suitable sensitivity and specificity, and the lack of effective therapy. Two recent conferences held on the management of CHB recommended that aFP and/or ultrasound should be performed every 6 months in HBV patients with cirrhosis, patients older than 40 years, and those with a family history of HCC [16,17]. Treatment goals The objectives of therapy can be viewed in terms of short- and long-term goals. Short-term objectives are to reduce viral burden, improve serum aminotransferase levels, and reduce hepatic necroinflammation. Improvement of these parameters would be expected to slow the progression of fibrosis. Long-term goals of therapy are to prevent progression to cirrhosis and HCC and ultimately improve survival. Once a decision is made to treat, the dilemmas facing the clinician are choosing which drug to use, deciding upon the optimal duration of treatment, and how to assess response to treatment. There are three approved therapies for CHB: IFN-a, lamivudine, and adefovir dipivoxil. Any of these agents can be used as first-line therapy, and each is discussed in detail in separate articles within this issue. When recommending treatment, the benefits and adverse effects of each drug should be discussed, as well as the situations where one agent is favored over another. The advantages of IFN-a include a finite period of administration, lack of drug resistance and, if attained, a durable response. Patients opting for nucleoside therapy should be informed of the potential need for longterm treatment and the development of drug resistance. Traditionally, the endpoint of therapy was loss of HBeAg and gain of anti-HBe, because seroconversion was associated with a favorable long-term prognosis after successful IFN-a treatment. This endpoint may not be suitable to assess the efficacy of nucleoside/nucleotide analog therapy because of reported relapse rates that range from 30% to 67% 2 to 3 years after therapy cessation [35–37]. At a recent NIH workshop on the management of CHB, the need for standardized definitions of response to antiviral therapy to allow for comparison of responses among different therapies was highlighted. It was recommended that response incorporate biochemical, serological, virological, and histological parameters and

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defined in the context of timing of treatment (ie, at initiation, during, at termination, or after termination of treatment) [16]. The remainder of this article will be devoted to a discussion on new investigative agents, highlighting those that appear to be most promising (Table 2).

Promising new hepatitis B agents Entecavir Entecavir is a cyclopentyl 29-deoxyguanosine nucleoside analog that initially was developed as an antiherpes virus agent and later noted to possess activity against HBV. When studied in animal models of HBV infection, entecavir demonstrated reductions in viral titers in serum and the liver, including the covalently closed circular replicative form of HBV DNA (cccDNA). In chronic HBeAg-positive and -negative patients, entecavir doses ranging from 0.05 to 1 mg daily for 28 days resulted in significant reductions in serum viral titers with no significant treatment-related adverse events [38]. In a phase II study of entecavir compared with lamivudine for 24 weeks, higher doses of entecavir resulted in greater viral reductions. No significant viral resistance genotypes were detected, and few transient moderate adverse events were noted [39]. The study duration and sample sizes were insufficient to adequately assess transaminase and liver histology endpoints. A phase III study of entecavir for CHB infection is in progress. Efficacy of entecavir against classic lamivudine-resistant HBV strains containing polymerase mutations has been tested in in vitro assays. Combinations of lamivudine-resistant mutations with an upstream mutation in the HBV polymerase required 20- to 30-fold increased concentrations of entecavir to inhibit replication [40]. Nonetheless, preliminary studies demonstrate that entecavir has promise as a potentially effective long-term first-line agent for treatment of CHB infection. Tenofovir Tenofovir disoproxil fumarate is the prodrug of tenofovir and is a nucleoside analog approved as an antiretroviral agent. Tenofovir has been shown to exhibit antiviral activity against HBV [41]. In patients coinfected with HIV and HBV where tenofovir was added as a component of antiretroviral therapy, HBV viral load decreased by approximately 4 log after 1 year of therapy [42]. Tenofovir appears to remain effective against the lamivudine HBV polymerase mutant [43,44]. Additionally, in patients with HIV/HBV coinfection who were HBeAg negative, short-term treatment with tenofovir led to a reduction of HBV viral titers [45]. Thus, tenofovir may be a potential adjunctive therapeutic agent against CHB infection in patients coinfected with HIV. Additional studies are needed to evaluate the

Generic name

Molecular structure

Clevudine

Lobucavir

29-fluoro-5-methyl-L-arabinofuranosyl uracil nucleoside analogue 2939dideoxy-59fluoro-39-thiacytidine nucleoside analogue Cyclopentyl 29-deoxyguanosine nucleoside analogue Carbocyclic analogue of oxetanocin

Tenofovir Amdoxovir Beta-L-nucleosides Heteroaryldihydropyrimidines

Adenosine nucleotide analogue D-2,6-diaminopurine dioxolane Beta-L-thymidine Same

Emtricitabine Entecavir

Phase of development

Activity against lamivudine resistant strains

Resistance reported

Phase II

No

Yes

?Phase III

No

?

Phase III

Yes

Yes

Phase I., studies terminated because to toxicity in rodents Phase III Phase I Phase I

Unknown

Unknown

Yes Unclear

No Unknown Unknown Unknown

Unknown

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Table 2 New compounds in development for treatment of chronic hepatitis B infection

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potential of tenofovir as monotherapy for CHB infection. Renal toxicity has been reported with tenofovir. Antiviral agents requiring further investigation Lobucavir Lobucavir is a carbocyclic analog of oxetanocin shown to be an effective antiviral agent against HBV [46]. Further studies were terminated when hepatic and foregut tumors emerged during long-term rodent carcinogenesis studies. Emtricitabine Emtricitabine (FTC, 2939-dideoxy-59fluoro-39-thiacytidine) is a nucleoside analog that is structurally similar to lamivudine. An initial in vitro study demonstrated inhibition of HBV replication by emtricitabine [47]. Significant reductions in woodchuck hepatitis virus (WHV) titers with emtricitabine were observed in chronically infected woodchucks [48]. The antiviral effect also was observed in people in a phase I clinical trial [49]. Given the structural similarity to lamivudine, however, emtricitabine most likely will not be able to overcome the HBV polymerase mutations associated with lamivudine resistance [50]. Clevudine Clevudine (L-FMAU, 29-fluoro-5-methyl-b-L-arabinofuranosyl uracil) is a pyrimidine nucleoside analog that has been demonstrated to have antiviral effects in short-term studies with woodchucks chronically infected with WHV [51]. In chronically infected woodchucks, however, prolonged therapy with L-FMAU resulted in viral rebound cause by the development of resistant WHV polymerase mutants [52]. In a small human pilot study evaluating four doses of clevudine (10 mg, 50 mg, 100 mg, and 200 mg) for 4 weeks, the mean reduction in HBV DNA level was -2.5 to -3.0 log for all doses tested. The reduction in HBV DNA was sustained up to 24 weeks after cessation of treatment and was highest in the 100 mg dose group (-2.7 logs). Of treated patients, 19% had loss of HBeAg, and few adverse effects were reported. No mitochondrial toxicity was observed. Longer-term follow-up is needed before any recommendations regarding clevudine use can be made. Amdoxovir Amdoxovir (DAPD, b-D-2,6-diaminopurine dioxolane) is a prodrug of 1-b-D-dioxolane (DXG), which has antiretroviral activity against HIV-1 [53]. In vitro studies of amdoxovir sensitivity among lamivudine-resistant HBV polymerase mutant strains are inconsistent, and additional studies will be needed to clarify DAPD’s utility in this setting [54].

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Beta-L-nucleosides Beta-L-nucleosides are potential therapeutic antiviral agents against HBV being evaluated in duck hepatitis virus and WHV models. There are three of these analogs under investigation: LdC (beta-L-29-deoxycytidine), LdT (beta-L-thymidine), and LdA (beta-L-29-deoxyadenosine). All have demonstrated specificity for the HBV polymerase, and LdT is being evaluated in clinical trials [55]. Heteroaryldihydropyrimidines Heteroaryldihydropyrimidines (HAPs) are compounds that effectively inhibit HBV replication at the level of viral capsid assembly. Critical molecular events in the life cycle of HBV occur within the milieu of the assembled capsid, including synthesis of the genome [56]. Initial in vitro studies have demonstrated that HAPs disrupt the formation of viral capsids by enhancing proteasome-mediated degradation of capsid monomers [57]. Future studies with these compounds are awaited, as they may represent a novel approach to HBV treatment. Other novel approaches Several novel approaches are being developed for treating hepatitis B. Several immunotherapeutic strategies have been tried in an attempt to modulate the immune response either alone or in combination with antiviral agents [58]. HBsAg vaccination, in combination with lamivudine and a lipopeptide-based T-cell vaccine designed to induce a core-specific cytotoxic T-lymphocyte (CTL) response, has been used in clinical trials, albeit without much success. Another novel approach to inhibit viral replication has been through the development of antisense oligonucleotides and hammerhead ribosomes. Both of these agents form hybridization duplexes with specific target viral mRNA sequences, ultimately leading to viral RNA degradation either through activation of host RNaseH or intrinsic catalytic activity. Several technical issues hinder practical use of this technology in the treatment of HBV infection, such as transport into target cells, absence of target tissue specificity, degradation by host enzymes, and poor bioavailability. Most recently, small interfering RNAs have been shown in cell culture to reduce the level of viral transcripts and proteins and replicative forms [59]. Many technical issues will need to be addressed before these potential therapeutic modalities become feasible. Summary An understanding of the natural history of CHB is critical for the management of the liver disease. Three clinical patterns with different clinical outcomes are recognized: HBeAg-positive CHB, HBeAg-negative

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CHB, and inactive CHB. Patients with elevated aminotransferase levels and HBV DNA greater than 105 viral copies per mL in serum and with features of chronic hepatitis on liver biopsy are candidates for therapy regardless of HBeAg status. Multiple host and viral factors and safety profiles of current therapies need to be considered carefully before recommending therapy. There appears to be no role for HBV genotyping in the management of patients. Three antiviral agents are approved for use against CHB infection: IFN-a, lamivudine, and adefovir. Efficacy is moderate at best and is limited by the poor tolerability of IFN and the development of resistance, coupled with concerns regarding the long-term safety with nucleoside analogs. Several new nucleoside and nucleotide analogs and novel agents are at various stages of development as potential therapies for CHB. The ideal compound would be one that is active against all replicative intermediates of the virus and has a low toxicity profile. Despite current shortcomings, the future of therapy for HBV is promising, as newer therapeutic options are being developed based on an understanding of the HBV life cycle. References [1] World Health Organization Fact Sheet/204. Hepatitis B. Geneva: World Health Organization; 2000. [2] Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337(24):1733–45. [3] Lok AS, Lai CL. A longitudinal follow-up of asymptomatic hepatitis B surface antigenpositive Chinese children. Hepatology 1988;8(5):1130–3. [4] Guidotti LG, Rochford R, Chung J, Shapiro M, Purcell R, Chisari FV. Viral clearance without destruction of infected cells during acute HBV infection. Science 1999;284(5415): 825–9. [5] Hoofnagle JH, Dusheiko GM, Seeff LB, Jones EA, Waggoner JG, Bales ZB. Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis. Ann Intern Med 1981;94(6):744–8. [6] Di Bisceglie AM, Waggoner JG, Hoofnagle JH. Hepatitis B virus deoxyribonucleic acid in liver of chronic carriers. Correlation with serum markers and changes associated with loss of hepatitis B e antigen after antiviral therapy. Gastroenterology 1987;93(6): 1236–41. [7] Realdi G, Alberti A, Rugge M, et al. Seroconversion from hepatitis B e antigen to antiHBe in chronic hepatitis B virus infection. Gastroenterology 1980;79(2):195–9. [8] de Franchis R, Meucci G, Vecchi M, Tatarella M, Colombo M, Del Ninno E, et al. The natural history of asymptomatic hepatitis B surface antigen carriers. Ann Intern Med 1993;118(3):191–4. [9] de Jongh FE, Janssen HL, de Man RA, Hop WC, Schalm SW, van Blankenstein M. Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver. Gastroenterology 1992;103(5):1630–5. [10] Hoofnagle JH, Shafritz DA, Popper H. Chronic type B hepatitis and the healthy HBsAg carrier state. Hepatology 1987;7(4):758–63. [11] Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B. Hepatology 2001;34:617–24. [12] Carman WF, Jacyna MR, Hadziyannis S, Karayiannis P, McGarvey MJ, Makris A, et al. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet 1989;2(8663):588–91.

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Antiviral therapy for treatment-naı¨ ve hepatitis B virus patients Daryl T.-Y. Lau, MD, MSc, MPH, FRCP(C)a,*, Fernando E. Membreno, MD, MScb a

Division of Gastroenterology and Hepatology, Department of Internal Medicine, The University of Texas Medical Branch, 4106 McCullough Building, 301 University Boulevard, Galveston, TX 77555-0764, USA b Gastroenterology and Hepatology Section, Eastern Colorado Health Care System, Denver Veterans Affairs Medical Center, 1055 Clermont Street, MS 111E Denver, CO 80220, USA

Hepatitis B virus (HBV) infection is a major public health problem worldwide, responsible for considerable morbidity and mortality from chronic liver disease [1]. It is estimated that there are 350 million HBV carriers globally. The prevalence of chronic hepatitis B (CHB) infection varies greatly in different regions of the world. In the United States, approximately 1.5 million people are infected and 50,000 to 100,000 new cases are reported annually despite the availability of effective vaccines [2]. Prevalence of CHB among immigrants from high HBV endemic areas was higher than that in the general United States population, but its actual rate was not defined well. In 2001, the authors screened 450 Chinese immigrants in Houston and noted a HBV carrier rate of 8.2% in that population. Chronic hepatitis B infection is defined by the persistence of serum hepatitis B surface antigen (HBsAg) for 6 months or longer [3]. It can be classified into three major forms: HBsAg carriers with inactive disease, hepatitis B e antigen (HBeAg)-positive CHB, and HBeAg-negative CHB. Patients with CHB infection can develop cirrhosis and end-stage liver disease. All HBV carriers, however, including those with inactive or minimal disease activities, have an increased risk for the development of hepatocellular carcinoma (HCC) [4]. HBeAg-negative CHB arises most frequently from a mutation in the precore or precore promoter region of the HBV genome that leads to the loss of ability to secrete HBeAg [5]. Most patients with HBeAg-negative CHB can be differentiated from inactive chronic HBsAg carrier state with elevated aminotransferases and detectable HBV * Corresponding author. E-mail address: [email protected] (D.T.-Y. Lau). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.04.008

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DNA in serum. Patients with HBeAg-negative CHB, however, could have heterogeneity of the disease activities characterized by markedly different patterns of serum aminotransferases elevations. Three patterns of the HBeAg-negative CHB include continuous alanine aminotransferase (ALT) elevated in approximately 24% of patients, fluctuating ALT levels in 48% of patients, and intermittent or relapsing activities in 28% of patients [6]. Patients with intermittent ALT elevations could be misdiagnosed as inactive HBV carriers between flares of hepatitis. These observations underscore the importance of regular assessments of HBsAg-positive patients over time to confirm the diagnosis of HBeAg-negative CHB versus inactive HBV carrier. The frequency of the HBV variants differs significantly in various regions of the world as a result of the geographic distribution of the HBV genotypes. HBeAg-negative CHB is common in Asia and the Middle East, accounting for about 70% to 80% of the chronic HBV in those regions [7]. In contrast, an overall low prevalence of HBeAg-negative chronic HBV infection (24%) was reported in the United States in 1996 [8]. The rate of these HBV variants, however, may have increased preferentially in different ethnic groups, especially among immigrant populations from endemic areas. In a recent cross-sectional study conducted in 17 liver centers in the United States, Chu et al reported that 63% of the 530 study patients had HBeAgnegative CHB. Among them, 38% had precore variants; 51% had core promoter variants, and 19% had both HBV variants [9]. HBeAg-positive and HBeAg-negative CHB with persistent or intermittent elevation of aminotransferases and HBV DNA levels and histological evidence of active hepatitis should be considered for antiviral therapy. Therapy for chronic hepatitis B There are three antiviral agents approved by the US Food and Drug Administration (FDA) for treating CHB. They are interferon-alfa (IFN-a), lamivudine, and adefovir dipivoxil. This article focuses on the application of these compounds for HBeAg-positive and HBeAg-negative CHB. Goals of therapy Goals of antiviral therapy for CHB include sustained suppression of the viral replication, delayed or arrest the progression of liver injury, and development of hepatic complications such as HCC. Complete eradication of the HBV is difficult because of its tendency to integrate into the host genome. It is recognized that small amounts of replicating HBV are detectable even in patients with long-term disease remission [10]. Definitions of responses to antiviral therapy Based on the summary of the National Institutes of Health (NIH)sponsored workshop on the management of HBV in 2000 [11], treatment

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responses can be classified as (1) biochemical (normal aminotransferase levels), (2) virologic (decrease of HBV DNA to less than 105 copies/mL and loss of HBeAg in those who initially were positive), or (3) histologic (decrease in degree of inflammation and necrosis). Responses also should be designated as initial (occurring within the first 6 months), end-of-treatment (at the time of stopping therapy), maintained (at the time of last evaluation during long-term therapy), and sustained (6 to 12 months after stopping therapy). A combined response should meet the criteria of biochemical, virologic, and (if available) histologic responses. A complete response should be defined by sustained loss of HBsAg.

Interferon-alfa Interferon-alfa was approved as therapy of chronic hepatitis B in the United States in 1992. The therapeutic effects of IFN-a are secondary to its antiviral, antiproliferative, and immunomodulatory properties. The immunomodulatory effects of IFN-a can be recognized clinically as flares of hepatitis with increased levels of aminotransferases. The flare of hepatitis often precedes a virologic response [12]. The general recommended dosage regimen for IFN-a in adults is 5 million units daily or 10 million units three times weekly for 16 weeks in HBeAg-positive patients and for 12 months in HBeAg-negative patients. Furthermore, there is evidence that continuing therapy for an additional 16 weeks for the HBeAg-positive patients is beneficial if they achieve a significant fall in HBV DNA (less than 10 pg/mL) but remained HBeAg-positive during the first 16 weeks of treatment [13]. Hepatitis B e antigen-positive patients Traditionally, one of the most important treatment endpoint for patients with HBeAg-positive CHB has been the loss of HBeAg. The efficacy of IFNa for HBeAg-positive CHB was evaluated in a well-designed meta-analysis in 1993 [14]. Wong et al reviewed over 25 randomized controlled studies involving a total of 837 adult patients who received interferon in doses of 5 to 10 million units given daily to three times weekly for 4 to 6 months. Loss of HBeAg was significantly higher among treated patients (33%) compared with controls (12%). Importantly, loss of HBsAg occurred in 7.8% of IFNtreated patients, but in only 1.8% of control patients. Most controlled trials of IFN therapy of hepatitis B, however, have included only a 1-year followup. The question arises whether the loss of HBeAg will result in long-term disease remission. Several long-term follow-up studies of IFN-a therapy for HBeAgpositive hepatitis were conducted in Asia, North America, and Europe. Most of these studies compared long-term clinical outcomes in treated patients with historical controls or treatment responders with nonresponders. Because of the differences in study designs and definition of responses,

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direct comparisons of the study outcomes are not possible. Several trends, however, emerge in the follow-up studies from the different geographical regions [15–17]. Long-term studies from North America and Europe reported encouraging results that 95% to 100% of treatment responders (loss of HBeAg, HBV DNA, and biochemical remission) continued to be HBeAg-negative after 5 to 10 years of follow-up, and 30% to 86% of them eventually lost HBsAg [15–17]. Liver-related complications and mortality were greater in nonresponders compared with responders, especially among those with pre-existing cirrhosis [15]. These studies demonstrated that the loss of HBeAg is a reliable treatment endpoint that is associated with longterm disease remission and that IFN therapy is beneficial in preventing the progression to end-stage liver disease. In contrast, long-term follow-up of patients in Asian studies generally showed a lower rate of durable responses to IFN-a and inconsistent rates of HBeAg and HBsAg clearance [18–20]. Despite the lower response, the study by Lin et al in Taiwan suggested that IFN therapy might prevent the development of HCC [18]. These differences in long-term IFN-a treatment outcomes noted in the Eastern and Western countries could reflect the differences in viral factors such as genotypes and in the natural history of the disease in high versus low endemic areas [21]. Several factors predict the likelihood of a favorable response to IFN-a treatment in patients with chronic HBV infection, the most important of these being high baseline ALT and low serum HBV DNA levels [22]. A flare in liver aminotransferase during treatment with IFN-a also was found to be a predictor of good response. Lau et al observed that 39% of patients experienced a hepatitis flare on treatment [23]. Flare was defined as an increase in ALT level to at least twice the baseline during therapy. In 52% of the cases, the hepatitis flare was associated with a good virologic response. The flares with favorable treatment outcomes typically occurred within the first month of therapy and were associated with a significant decrease in HBV DNA to less than 105 copies/mL at the peak of ALT elevation. Another recent study demonstrated that the degree of aminotransferase elevation during treatment had strong predictive value for response, especially for those patients with high serum HBV DNA levels [24]. Although a flare in aminotransferases predicts favorable response, the IFN-a-induced flare also could precipitate decompensation in patients with cirrhosis. For this reason, IFN-a is contraindicated for patients with reduced hepatic reserve. Hepatitis B e antigen-negative patients Hepatitis B antigen-negative CHB is a heterogeneous group in terms of disease activity and patient characteristics. Because sequencing of the HBV DNA to determine the different variants of the HBV is not readily available or routinely performed in clinical trials, the heterogeneous patient population could explain, at least in part, the discrepancies in study results.

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Different patterns of disease activities and study designs further complicate comparisons of study results. There are approximately 20 published studies using IFN for HBeAgnegative CHB. The endpoint of most of these studies has been loss of HBV DNA detectable by molecular hybridization (HBV DNA less than 106 copies/mL) and normalization of serum ALT within 1 year after therapy. Similar to HBeAg-positive CHB, both end-of-treatment and sustained responses are superior in treated subjects [25]. Among the controlled trials, the end-of-treatment response was reported to range between 38% and 90% in treated patients versus a range of 0% and 37% in untreated controls. The sustained response rate was 10% to 47% in treated subjects compared with 0% in the controls. In view of the high relapse rate (greater than 50%) with HBeAg-negative CHB, an important issue is to improve the durability of response. Of note, relapses can occur months to even years after therapy [25]. In a long-term follow-up study on HBeAg-negative CHB, Manesis and Hadziyannis performed a retrospective analysis of the clinical outcomes of 216 patients treated with 3 million units of IFN-a2b three times weekly for 5 or 12 months [26]. After a median follow-up of 7 years, 18% of the patients remained in biochemical and virologic remission after a single course of therapy. Longer treatment duration (12 months) and a biochemical response within the first 4 months of therapy were identified as predictors of longterm sustained response. Encouragingly, patients with a sustained response also had significant improvement of liver histology, and 32% of them ultimately lost HBsAg. This study suggests that patients with HBeAgnegative CHB require a longer course of IFN therapy to achieve complete response. Lamivudine (3TC, Epivir) Lamivudine is a synthetic nucleoside analog that was approved for the treatment of chronic hepatitis B in the United States in December 1998. Lamivudine is the (-) enantiomer of 29-39 dideoxy-39-thia-cytidine. The phosphorylated form (3TC-TP) exerts its therapeutic action by competing with dCTP for incorporation into the growing viral DNA chains, causing chain termination. By inhibiting the RNA- and DNA-dependant DNA polymerase activities, the synthesis of the first second strands of HBV DNA is interrupted [27]. Lamivudine is an oral medication, and its dose for CHB is 100 mg daily. This dose was chosen based on a preliminary trial published by Dienstag et al, who randomly assigned 32 patients to receive 25, 100 or 300 mg of lamivudine daily for 12 weeks. Lamivudine therapy was tolerated well, and the daily dose of 100 mg was more effective than 25 mg and was similar to 300 mg in reducing HBV DNA levels [28]. The loss of HBV DNA, however, was measured by molecular hybridization (HBV DNA less than 106 copies/mL) in the study, so it remains uncertain whether

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300 mg would cause a greater decline in HBV DNA levels compared with the 100 mg dose. Hepatitis B e antigen-positive chronic hepatitis B There were two large placebo-controlled trials on treatment-naı¨ ve patients performed in North America and Asia [29,30]. In both studies, 1-year therapy with lamivudine was associated with significantly better HBeAg seroconversion (defined as loss of HBeAg, development of antibody to HBeAg, and undetectable HBV DNA) in 16% and 17% of the patients, compared with 4% and 6% of patients receiving placebo. Fall in serum HBV DNA level occurred in virtually all patients who received lamivudine. A rapid decline in HBV DNA, with a median reduction of 97% (compared with baseline value) after 2 weeks and 98% throughout the study was observed. Among the treated patients, sustained normalization of ALT levels occurred in 41% of patients in the North American study and 72% of patients in the Asian study. Only 70% of the Asian patients had elevated ALT levels at baseline, whereas all patients in the North American study had abnormal ALT levels. Furthermore, both studies demonstrated an improvement in hepatic necroinflammatory activity, defined as improvement of at least 2 points in the Knodell score. In contrast, worsening of inflammation occurred in 30% of patients receiving placebo. The loss of HBsAg was generally low. No patient in the Asian study lost HBsAg during the study, and only 2% of patients in the North American study had undetectable HBsAg at the end of 52 weeks. In the Asian long-term lamivudine treatment study, an incremental HBeAg seroconversion from 17% at 1 year to 27% at 2 years was observed [31]. Continuous treatment with lamivudine for 3 and 4 years was associated with HBeAg seroconversion rates of 40% and 47%, respectively [32,33]. HBeAg seroconversion increased linearly with increasing pretherapy ALT levels. Liaw et al showed that patients with normal ALT levels did not have HBeAg seroconversion, while seroconversion occurred in 23% and 80% of patients with ALT levels two to five times and greater than five times the upper limit of normal, respectively [31]. This finding was confirmed in at least two other studies showing 1 year HBeAg seroconversion rates occurring in 4%, 15%, 26% to 28%, and 56% to 64% of patients with pretreatment ALT levels within normal, one to two times normal, two to five times normal, and more than five times normal, respectively [34,35]. Asians and Caucasians have similar rates of HBeAg seroconversion at comparable ALT levels [36]. In addition to pretreatment ALT level, histologic activity index (HAI) score and body mass index (BMI) have been identified as important predictors of HBeAg seroconversion during lamivudine therapy [34,35]. Relapse rates are conflicting in patients who achieved HBeAg seroconversion after stopping lamivudine. Schiff et al observed a relapse of HBeAg

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in 19% of patients (8 of 42 patients) with a response to lamivudine [36]. In a recent study, Dienstag et al followed 40 subjects with lamivudine-induced HBeAg seroconversion for a median duration of 36.6 months (range of 4.8 to 45.6 months). HBeAg seroconversion was demonstrated at the last visit in 77% of patients (30 of 39 patients). Nine of 40 patients (23%) became HBsAg negative at the last assessment. Seventy-four percent of patients (17 of 23 patients) had sustained virologic and biochemical responses at the last visit. No safety issues of concern emerged [37]. In contrast, in a retrospective Korean study with 98 patients treated with lamivudine at 150 mg daily for a mean duration of 9.3 months, plus or minus 3 months, the cumulative relapse rates at 1 year and 2 years post-treatment were 37.5% and 49.2%, respectively [38]. Van Nunen et al combined data from 24 centers in 14 countries with a total of 59 patients who responded to lamivudine therapy and showed a 3-year cumulative HBeAg relapse rate of 54% for the lamivudine-treated patients, compared with 32% for IFN and 23% for IFN–lamivudine combination therapy [39]. Similarly, a Taiwanese study reported high cumulative relapse rates of 45% and 56% at 48 and 72 weeks post-treatment, respectively [40]. By multivariate analysis, pretreatment serum HBV DNA levels, pretreatment ALT levels, duration of additional lamivudine therapy after HBeAg seroconversion, and age (greater than 25 years) have been identified as important independent predictors of posttreatment relapse [38–40]. Hepatitis B e antigen-negative chronic hepatitis B The efficacy and safety of lamivudine were evaluated in several studies [41–44]. In a placebo-controlled, double-blind study, 60 patients receiving lamivudine for 52 weeks were compared with 65 patients receiving placebo. Among patients in the lamivudine group, 65% had both virologic and biochemical responses (HBV DNA less than 2.5 pg/mL and normal ALT) that were significantly higher compared with 6% in the placebo group (P less than 0.001). At week 52, 60% of the lamivudine-treated patients also had a histological improvement (at least a 2-point reduction in the Knodell necroinflammatory score) [41]. An Italian study had similar end biochemical and virologic responses in 13 of 15 (87%) patients at the end of 52 weeks of lamivudine therapy. However, all the patients relapsed within 1 to 12 months after stopping therapy, however, so sustained responses were rare [42]. Hadziyannis et al assessed the long-term efficacy of lamivudine at 150 mg daily for 24 months in 25 patients [43]. Biochemical response was 96% at 12 months, but this dropped to 59.5% by 24 months. Similarly, virologic response was 68% and 59.2% at 12 months and 24 months, respectively. The decrease in rates of response over time was secondary to biochemical and virologic breakthrough [44]. ALT increased to higher than the baseline levels in 70% of patients, with a biochemical breakthrough reaching acute hepatitis levels in over 50% of patients.

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Lamivudine resistance In general lamivudine is tolerated well and safe even with long-term therapy in both HBeAg-positive and HBeAg-negative CHB. The long-term effectiveness of lamivudine and durability of response have been shadowed, however, by the emergence of mutations in the HBV DNA polymerase, which confers to the variant virus a selective resistance to the drug [45]. Two main mutations have been associated with such resistance: a methionine-tovaline or -isoleucine substitution in the YMDD motif of the catalytic C domain of HBV polymerase at position 204 (M204V/I, formerly M552V/I) and a leucine-to-methionine substitution at position 180 (L180M formerly L528M) upstream of the YMDD motif [46–48] (Fig. 1). Clinically, lamivudine resistance is defined as the presence of biochemical breakthrough (increase in ALT or AST activity greater than 1.5 times the upper limit of normal after an initial biochemical response) and virologic breakthrough (reappearance of detectable serum HBV DNA by polymerase chain reaction [PCR] after an initial virologic response). Typically, virologic breakthrough precedes biochemical breakthrough by a median of 4 months. Studies have shown that the emergence of the YMDD variant can be detected as early as 49 days after taking lamivudine, but clinically important virologic and biochemical breakthrough does not occur before 6 months [49,50]. Withdrawal of lamivudine typically has led to reappearance of the wild-type species, and subsequent repeat treatment with lamivudine has been associated with a more rapid reappearance of the HBV variant [49]. In a study by Liaw et el, acute exacerbation of hepatitis B with significant elevation of the aminotransferases (defined as five times the upper limit of normal or to a level greater than 300 U/L) was observed in about 30% of patients 4 to 94 weeks (median, 24 weeks) after emergence of the YMDD mutation [51]. There was no significant difference in baseline ALT or HBV DNA levels between those who did or did not experience exacerbations.

Terminal Protein

Spacer

HBV Polymerase

RNase H

Lam Resistance Variants in YMDD motif of C Domain M

0 18

1

L

F G

A

B

C

V 04

or

I

M2

344

D E

N236T ADV Resistance Variant in D Domain Fig. 1. Mutations in hepatitis B virus polymerase related to lamivudine and adefovir dipivoxil resistance.

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Serum HBV DNA levels were, however, significantly higher in patients who experienced exacerbations. Acute hepatitis B exacerbation with high HBV DNA and ALT levels also has been described with the withdrawal of lamivudine therapy, and a proportion of those patients developed hepatic decompensation [52]. In HBeAg-positive CHB, YMDD variants were reported to occur in approximately14% of patients after 1 year of therapy [30]. With continuous treatment, the rates increased to 38% after 2 years, 53% after 3 years, and 67% after 4 years of therapy [32,53,54]. A long-term study by Leung et al assessed the clinical outcomes of continuous lamivudine therapy in the presence of YMDD variants in 33 patients [32]. Fifteen of the patients who developed YMDD variants at week 104 and who continued to receive lamivudine experienced ALT flares of more than two times the upper limit of normal. Nine of the patients with lamivudine resistance had liver biopsies at baseline, week 52, and week 156. Worsening of the HAI by 2 to 9 points was observed in six patients between the week 52 and week 156 biopsies. On the other hand, approximately 25% of the patients eventually achieved HBeAg seroconversion with continuous therapy despite the presence of the YMDD variants. Dienstag et al evaluated the histological outcome during long-term lamivudine therapy [55]. They found that after 3 years of continuous lamivudine treatment, 35 of 63 patients (56%) patients showed improvement; 21 of 63 patients (33%) had no change, and 7 of 63 patients (11%) had worsening. Those without YMDD variants were more likely to improve compared with those with YMDD variants (77% versus 44%) and less likely to deteriorate (5% versus 15%). Furthermore, patients with YMDD variants for more than 2 years were least likely to improve. Lau et al observed similar histological response in patients with lamivudine resistance on continuous therapy. The eight HBeAg-positive patients who developed lamivudine resistance before month 12 had no improvement in HAI score. The pretreatment mean HAI score was 12 compared with 11.3 at 1 year [49]. These data suggest that continued therapy with lamivudine (up to 156 weeks) results in increased HBeAg seroconversion and improved histology. The studies, however, also show that continued treatment after the emergence of the YMDD variant HBV could result in exacerbation of hepatitis, reversion of initial histological benefits, and, in some cases, progression of liver disease. In HBeAg-negative CHB, reported rates of lamivudine resistance are variable. In a small United States study, Lau et al reported a low resistance rate of only 10% after 2 to 4 years of continuous therapy [49]. In contrast, YMDD variants developed in approximately two thirds of patients within 3 years of therapy in the Mediterranean [44]. The differences could be related to the heterogeneity of HBV. For example, most patients in the United States study had HBV genotypes B and C, whereas most study subjects in the Mediterranean had HBV genotype D. It is important to note that when the genotype D precore variant becomes YMDD-resistant, its replicative

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efficacy increases [56]. This observation may explain the frequent occurrence of severe virologic and biochemical breakthroughs in patients with HBeAgnegative CHB under lamivudine treatment that have been reported in studies from Greece, where there is a 95% predominance of HBV genotype D. Papatheodoridis et al studied the course of virologic breakthroughs in 32 patients under long-term lamivudine monotherapy [44]. After the onset of virologic breakthrough, the biochemical remission rate reduced from 44% at 6 months to 21% at 12 months, and 0% by 24 months. Follow-up liver histologic lesions in patients with biochemical breakthroughs did not differ from baseline findings. This study concludes that the emergence of viral resistance under long-term lamivudine monotherapy is usually a result of an increased HBV DNA level that culminates in the development of biochemical breakthroughs in most cases. Predictive factors of the emergence of lamivudine resistance by multivariate analysis include high baseline HBV DNA, high baseline ALT, and high HAI score [57]. Because lamivudine therapy can be associated with exacerbations of hepatitis, either during therapy because of the development of drug resistance, or after discontinuation of lamivudine therapy because of relapse of wild-type HBV, patients should be monitored closely. They should have at least serum aminotransferases and preferably also HBV DNA and evaluations every 2 to 3 months during treatment and for at least 1 year after discontinuation of therapy to allow early detection of hepatitis flares.

Adefovir dipivoxil Adefovir dipivoxil is an oral diester prodrug of adefovir, a nucleotide analog that, in its active form (adefovir diphosphate), inhibits HBV DNA polymerase. Because the acyclic nucleoside phosphonate already contains a phosphate-mimetic group, it needs only two, instead of three, phosphorylation steps to reach the active metabolite stage. Hence, it does not depend on the virus-induced kinase to exert its antiviral action [58]. Adefovir dipivoxil acts against several DNA viruses in addition to HBV and retroviruses (eg, HIV). Adefovir dipivoxil has in vitro and in vivo activity against wild-type, precore HBV and lamivudine-resistant HBV variants. Adefovir dipivoxil received approval by the FDA for treatment of CHB in September 2002. Hepatitis B e antigen-positive chronic hepatitis B With the encouraging preclinical and early clinical results, a large phase III study involving 515 HBeAg-positive patients with CHB from 78 centers in North America, Europe, Australia, and Southeast Asia was conducted [59]. The patients were randomized to receive 10 mg of adefovir dipivoxil, 30 mg of adefovir dipivoxil, or placebo daily for 48 weeks. Patients who

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received the 30 mg of adefovir dipivoxil had the most significant fall in serum HBV DNA levels: 4.76 log copies/mL compared with 3.52 log copies/ mL (P less than 0.001) in the 10 mg dose group and 0.55 log copies/mL in the placebo group. As a result, undetectable HBV DNA by PCR (less than 400 copies/mL) was achieved in 39% of those who received 30 mg per day, 21% of those who received 10 mg per day, and in none of the placebotreated patients. Similarly, normalization of ALT levels was higher in the treatment groups, 55% (30 mg) and 48% (10 mg) compared with 16% in the control group. HBeAg seroconversion occurred in 14% and 12% of the treated patients on 30 mg and 10 mg, respectively and was infrequent, at 6%, in the placebo group. Improvement in necroinflammatory and fibrosis scores on liver biopsy at the end of therapy was observed in 53% and 59% of the treated patients, respectively, compared with 25% of patients taking placebo. The safety profile of the 10 mg dose of adefovir dipivoxil was similar to that of placebo; however, there was a higher frequency of adverse events caused by renal laboratory abnormalities in the group given 30 mg of adefovir dipivoxil per day. The major nephrotoxicity to adefovir dipivoxil is a Fanconi-like syndrome with phosphaturia and proteinuria. The cause of the renal toxicity is related to renal tubular damage, but the exact mechanisms are not understood well. This toxicity appears to be dependent on the daily and accumulative dose of the medication and is generally reversible. It is, therefore, important to monitor renal function regularly during therapy. In the authors’ experience, 24-hour urine creatinine clearance is the best method to detect early renal toxicity. Because the 10 mg dose has a favorable risk-benefit profile for long-term treatment, it is the recommended dose for CHB. Hepatitis B e antigen-negative chronic hepatitis B A multi-center phase III clinical trial involving 185 patients with HBeAgnegative CHB was conducted at 32 international sites [60]. Patients were randomized to receive either 10 mg of adefovir dipivoxil or placebo once daily for 48 weeks in a 2:1 ratio and a double-blind manner. The primary endpoint was histologic improvement at the end of therapy. Similar to the HBeAg positive patients, the treated patients had significant histologic improvement compared with the placebo-treated group (64% versus 33%, P less than 0.001). The median decrease in log-transformed HBV DNA levels was greater with adefovir dipivoxil treatment than with placebo (3.91 versus 1.35 log copies/mL, P less than 0.001) and the magnitude of the HBV DNA reduction was comparable with the HBeAg-positive CHB trial. Serum HBV DNA levels were reduced to fewer than 400 copies/mL in 51% of patients in the adefovir dipivoxil group and in 0% of those in the placebo group. ALT levels had normalized at week 48 in 72% of treated patients, compared with 29% of those on placebo (P less than 0.001). The safety profile of adefovir dipivoxil was similar to that of placebo.

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Because CHB is a heterogeneous disease, and genotypes may influence disease progression and antiviral response, a recent study was performed to analyze the antiviral efficacy of adefovir dipivoxil at 10 mg with respect to HBV genotype, HBeAg serostatus, and race in patients from the two multinational phase III studies [61]. Regardless of geographical location, Asian patients were infected predominantly with genotypes B or C, whereas Caucasian patients were infected predominantly with genotypes A or D. Adefovir dipivoxil at 10 mg for 48 weeks resulted in significant reductions in serum HBV DNA levels independent of genotype, HBeAg status, or race. Similarly, there was no statistical difference in HBeAg seroconversion rates between genotypes in these patients. Adefovir dipivoxil resistance During the initial 48-week of therapy in the HBeAg-positive and HBeAgnegative CHB clinical trials, there was no clinically important drug resistance noted [59,60,62]. Four substitutions (rtS119A, rtH133L, rtV214A, and rtH234Q) developed once each at conserved sites in HBV polymerase in four treated patients. Seven conserved site substitutions developed in six placebo-treated patients. HBV variants encoding the four substitutions that emerged in treated patients remained fully susceptible to adefovir in vitro. In an ongoing program to monitor for the emergence of resistance in 124 patients who received continuous adefovir dipivoxil for 2 years, drug resistance developed in two patients (1.6%) [63]. Locarnini et al recently reported the clinical course of a patient who developed clinical breakthrough with elevation of HBV DNA and aminotransferase levels and who was confirmed to have a new HBV variant by week 80 on therapy [64]. Comparison of pretreatment and post-treatment HBV DNA by PCR sequencing identified a novel asparagine to threonine mutation at residue rt236 in domain D of the HBV polymerase (see Fig. 1). In vitro testing of a laboratory strain encoding the rtN236T mutation and testing of patient-derived virus confirmed that the rtN236T substitution caused a marked reduction in susceptibility to adefovir dipivoxil. The patient responded to subsequent lamivudine therapy, with normalization of aminotransferase and a significant decrease in HBV DNA level. Long-term resistance surveillance in different patient populations is necessary to evaluate and characterize the frequency and clinical consequences of adefovir dipivoxil-induced HBV variants.

Combination therapy After evaluating the efficacy and limitations of each agent for the therapy of chronic hepatitis B, it is logical to examine a combination of the drugs with different mechanisms of action to optimize the suppression of the HBV and to improve short- and long-term responses. Mathematical modeling of the HBV kinetics with nucleotide analog therapy showed a biphasic decline of the

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HBV levels. The initial, faster phase of viral load decline reflects the clearance of HBV particles from plasma. The second, slower phase of viral load decline closely mirrors the rate-limiting process of infected cell loss [65]. Because the second phase of viral decline is likely to be induced by an immune-mediated process, immune clearance of the virus should be upregulated by immunomodulators such as IFNs. This suggests a theoretical advantage to use of nucleoside/nucleotide analogues and IFN in combination. Nucleoside analogues and immunomodulators There are several published multi-center clinical trials using a combination of lamivudine and IFN-a [66–68]. In two of the studies, patients were treated initially with lamivudine monotherapy for 8 weeks followed by a combination of lamivudine and IFN-a for an additional 16 weeks [66,67]. These studies failed to show a significant difference in response between combination therapy and monotherapy with either agent alone. In contrast, Barbaro et al [68] showed an increased sustained response rate with combination therapy. They randomized 150 patients to receive IFN-a2b at 9 million units three times a week and lamivudine 100 mg daily concurrently for 24 weeks or to lamivudine at 100 mg daily as monotherapy for 52 weeks. The rate of HBeAg seroconversion was 35% with combination therapy, compared with 19% with monotherapy. Repeat liver biopsy at the end of therapy showed also a higher rate of improvement in fibrosis among the patients on combination therapy (42%) than among those on monotherapy (24%). It is conceivable that concurrent treatment with both agents is more effective than the sequential treatment approach. Further studies are needed, however, to confirm the benefits of a combined therapy with nucleoside analogs and IFN, especially with a pegylated IFN (PEG IFN). Preliminary results showed that the PEG IFN-a caused a greater reduction in HBV DNA and HBeAg levels compared with standard IFN-a. Thymosin -a, a bovine thymus extract, is another immunomodulator that potentially can exert additive or synergistic effects in combination with nucleoside or nucleotide analogs. As a monotherapy for CHB, there are heterogeneous reports on its efficacy. In a meta-analysis of five trials with a total of 353 patients [69], Chan et al showed that thymosin is effective in suppressing viral replication in CHB virus infection, but the effect is delayed until 12 months after the cessation of treatment. The virologic responses of thymosin over placebo at the end of treatment, 6 months post-treatment, and 12 months post-treatment were 0.56 (95% confidence interval [CI], 0.2 to 1.52), 1.67 (0.83 to 3.37), and 2.67 (1.25 to 5.68), respectively. Combined nucleoside/nucleotide analogues There have been limited data on the efficacy of combining nucleoside/ nucleotide analogs. Lau GK et al evaluated combination therapy with lamivudine and famciclovir in 21 HBeAg-positive Chinese patients [70].

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Table 1 Recommendations for treatment of chronic hepatitis B HBeAg

HBV DNA1

ALT

Treatment strategy

þ

þ

\2
normal

þ

þ

>2
normal



þ

>2
normal





\2
normal

þ/

þ

Cirrhosis

þ/



Cirrhosis

If liver biopsy shows moderate inflammation and fibrosis, treat with either lamivudine or adefovir dipivoxil. IFN has limited efficacy for low ALT, þþ adverse effects. If liver biopsy shows no or mild fibrosis, observe. Regular monitoring including HCC surveillance. IFN-a or lamivudine or adefovir dipivoxil therapy. In patients with contraindications to IFN-a or renal dysfunction, lamivudine is preferred. IFN-a or lamivudine or adefovir dipivoxil therapy. Long-term treatment beyond 1 year usually is required. If persistent normal ALT and undetectable HBV DNA, likely inactive carrier. No treatment required but monitor regularly for HBV reactivation and HCC surveillance. If intermittent or mild ALT elevations, assess HBV severity by liver biopsy. If liver biopsy shows moderate inflammation and fibrosis, treat with either lamivudine or adefovir dipivoxil. IFN has limited efficacy for low ALT, þþ adverse effects. If liver biopsy shows no or mild fibrosis, observe. Compensated: IFN-a (close monitoring required), lamivudine or adefovir Decompensated, normal renal function: lamivudine or adefovir dipivoxil. liver transplantation referral Compensated: observe Decompensated liver transplantation

1 HBV DNA >105 copies/mL. This value is arbitrarily chosen and may be lower for patients with HBeAg-negative chronic hepatitis B and those with decompensated cirrhosis.

They found that patients who received lamivudine at 150 mg daily and famciclovir at 500 mg three times daily had more rapid fall in HBV DNA levels and a higher rate of HBeAg loss compared with those on lamivudine monotherapy. There are ongoing clinical studies examining the efficacy of combination therapy with lamivudine and adefovir dipivoxil. Current treatment recommendations As stated previously, the goals of therapy for CHB are to achieve sustained viral suppression and improve clinical outcome, thus decreasing

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the risk of cirrhosis, liver failure, and HCC. Therefore, patients with evidence of chronic hepatitis especially on liver biopsy should be considered for therapy. Because a proportion of patients with HBeAg CHB have fluctuating ALT levels and intermittent or relapsing activities, liver biopsy is a very valuable tool to evaluate the extent of hepatic inflammatory and fibrosis in these patients. Furthermore, patients with normal or low levels of aminotransferases do not respond well to the current medications, so liver biopsy can be very useful to assist in their treatment decisions. In 2001, Lok and McMahon published AASLD Practice Guidelines for the treatment of chronic hepatitis B [47]. Since then, adefovir dipivoxil was approved and is available in the United States. The authors modified the AASLD guidelines according to their experience in the treatment of CHB (Table 1). It must be kept in mind, however, that treatment needs to be tailored to the individual patient, because HBV is a heterogeneous disease with variable manifestations. The severity of liver disease and efficacy and potential complications of the therapeutic agents need to be considered before initiating a course of therapy. A comparison of the efficacy and safety of these three FDAapproved agents is shown in Table 2. There are advantages and disadvantages of all three agents, namely, IFN-a, lamivudine, and adefovir dipivoxil as monotherapy. There are inadequate data to make recommendations for combined therapy with two or more of these medications. The major advantages of IFN-a are its finite duration of treatment and lack of resistant HBV variants. The disadvantages of IFN-a are the adverse effects. Lamivudine is tolerated well and has an excellent safety profile; however, its major limitation as a monotherapy is the emergence of resistant HBV variants. Adefovir dipivoxil at a dose of 10 mg daily appears to be tolerated well; however, nephrotoxicity with cumulative dose remains an uncertainty. Its advantage is the relatively low resistance rate at 2 years of continuous therapy. Longer treatment studies Table 2 Comparison of the efficacy and safety of interferon, lamivudine and adefovir dipivoxil Interferon

Lamivudine

Adefovir dipivoxil

30% (eAg-ve) 60% to 70%

15% to 20% (eAg-ve) 60% to 70%

12% (eAg-ve) 50%

80% to 95% 10% to 47% þþþ

50% to 80% approximately 10% Negligible

Drug resistance

None

approximately 20% y 1 approximately 70% y 5

? ? Potential Nephrotoxicity None y 1 approximately 2% y 2

Duration of therapy HBeAg þve HBeAg ve

4–6 mos 12 mos

>1 y Indefinite

Likely >1 y Likely >1 y

Initial Response (yr1) HBeAg þve HBeAg ve Sustained response HBeAg þve HBeAg ve Adverse effects

596

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will be able to elucidate its long-term efficacy and safety profiles. Future therapy likely will consist of combination therapy with multiple agents that have different specific mechanisms of action. References [1] Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337:1733–45. [2] McQuillan GM, Coleman PJ, Kruszon-Moran D, Moyer LA, Lambert SB, Margolis HS. Prevalence of hepatitis B virus infection in the United States: the National Health and Nutrition Examination Surveys, 1976 through 1994. Am J Public Health 1999;89:14–8. [3] Mast EE, Mahoney FJ, Alter MJ, Margolis HS. Progress toward elimination of hepatitis B virus transmission in the United States. Vaccine 1998;16:S48–51. [4] McMahon BJ. Hepatocellular carcinoma and viral hepatitis. In: Wilson RA, editor. Viral hepatitis. New York: Marcel Dekker; 1997. p. 315–30. [5] Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B. Hepatology 2001;34:617–24. [6] Brunetto MR, Oliveri F, Coco B, Leandro G, Colombatto P, Gorin JM, et al. Outcome of anti-HBe positive chronic hepatitis B in alfa-interferon treated and untreated patients: a long-term cohort study. J Hepatol 2002;36:263–70. [7] Schalm SW, Thomas HC, Hadziyannis SJ. Chronic hepatitis B. In: Popper H, Schaffner F, editors. Progress in liver disease. New York: WB Saunders; 1990. p. 443–62. [8] Margolis HS, Alter MJ, Hadler SC. Hepatitis B: evolving epidemiology and implications for control. Semin Liver Dis 1991;11:84–92. [9] Chu CJ, Keeffe EB, Han SH, Perrillo RP, Min AD, Soldevila-Pico C, et al. Prevalence of HBV precore/core promoter variants in the United States. Hepatology 2003;38(3):619–28. [10] Lau DT, Everhart J, Kleiner DE, Park Y, Vergalla J, Schmid P, et al. Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa. Gastroenterology 1997; 113(5):1660–7. [11] Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000—summary of a workshop. Gastroenterology 2001;120:1828–53. [12] Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology 1995;109:908–16. [13] Janssen H, Gerken G, Carreno V, Marcellin P, Naoumov NV, Craxi A, et al. Interferon alfa for chronic hepatitis B infection: increased efficacy of prolonged treatment. Hepatology 1999;30:238–43. [14] Wong D, Cheung A, O’Rourke K, Naylor CD, Detsky AS, Heathcoate J, et al. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. Ann Intern Med 1993;119:312–23. [15] Lau D, Everhart J, Kleiner D, Park Y, Vergalla J, Schmid P, et al. Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa. Gastroenterology 1997; 113:1660–7. [16] Fattovich G, Giustina G, Realdi G, Corrocher R, Schalm S, the European Concerted Action on Viral Hepatitis. (EUROHEP). Long-term outcome of hepatitis B e antigenpositive patients with compensated cirrhosis treated with interferon alfa. Hepatology 1997;26:1338–42. [17] Niederau C, Heintges T, Lange S, Goldman G, Niderau CM, Mohr L, et al. Long-term follow-up of HBeAg positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med 1996;334:1422–7. [18] Lin S, Sheen I, Chien R, Chu C, Liaw YF. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology 1999;23:971–5. [19] Yuen M, Hui C, Cheng C, Wu CH, Lai YP, Lai CL, et al. Long-term follow up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: the effect

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[58] De Clercq E. Clinical potential of the acyclic nucleoside phosphonates cidofovir, adefovir, and tenofovir in treatment of DNA virus and retrovirus infections. Clin Microbiol Rev 2003;16(4):569–96. [59] Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, et al. Adefovir Dipivoxil 437 Study Group. Adefovir dipivoxil for the treatment of hepatitis B e antigenpositive chronic hepatitis B. N Engl J Med 2003;348(9):808–16. [60] Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Adefovir Dipivoxil 438 Study Group. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003;348(9):800–7. [61] Westland C, Delaney W 4th, Yang H, Chen SS, Marcellin P, Hadziyannis S, et al. Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil. Gastroenterology 2003;125(1):107–16. [62] Westland CE, Yang H, Delaney WE 4th, Gibbs CS, Miller MD, Wulfsohn M, et al. Week 48 resistance surveillance in two phase 3 clinical studies of adefovir dipivoxil for chronic hepatitis B. Hepatology 2003;38(1):96–103. [63] Gibbs CS, Xiong S, Yang H, Westland CE, Delaney WE IV, Colledge D, et al. Resistance surveillance in HBeAg chronic hepatitis B patients treated with adefovir dipivoxil for two years [abstract]. ICAR 2003. [64] Angus P, Vaughan R, Xiong S, Yang H, Delaney W, Gibbs C, et al. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology 2003;125(2):292–7. [65] Tsiang M, Rooney JF, Toole JJ, Gibbs CS. Biphasic clearance kinetics of hepatitis B virus from patients during adefovir dipivoxil therapy. Hepatology 1999;29(6):1863–9. [66] Schalm S, Heathcote J, Cianciara J, Farrell G, Sherman M, Willems B, et al. Lamivudine and alfa interferon combination treatment of patients with chronic hepatitis B infection: a randomized trial. Gut 2000;46:562–8. [67] Schiff ER, Dienstag JL, Karayalcin S, Grimm IS, Perrillo RP, Husa P, et al. Lamivudine and 24 weeks of lamivudine/interferon combination therapy for hepatitis B e antigenpositive chronic hepatitis B in interferon nonresponders. J Hepatol 2003;38(6):818–26. [68] Barbaro G, Zechini F, Pellicelli A, Francavilla R, Scotto G, Bacca D, et al. Long-term efficacy of interferon alfa-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An Italian multi-center, randomized trial. J Hepatol 2001;35:406–11. [69] Chan HL, Tang JL, Tam W, Sung JJ. The efficacy of thymosin in the treatment of chronic hepatitis B virus infection: a meta-analysis. Aliment Pharmacol Ther 2001;15(12): 1899–905. [70] Lau GK, Tsiang M, Hou J, Yuen S, Carman WF, Zhang L, et al. Combination therapy with lamivudine and famciclovir for chronic hepatitis B-infected Chinese patients: a viral dynamics study. Hepatology 2000;32(2):394–9.

Gastroenterol Clin N Am 33 (2004) 601–616

Management of chronic hepatitis B in treatment-experienced patients Chee-kin Hui, MD, MBBS, MRCP, Hai-ying Zhang, PhD, George K.K. Lau, MD, MBBS, MRCP* Division of Gastroenterology and Hepatology, University Department of Medicine, Queen Mary Hospital, 103 Pokfulam Road, Hong Kong SAR, China

Hepatitis B virus (HBV) infection is one of the most common viral infections in people. Approximately 2 billion people have been infected with HBV, and 350 million are chronically infected. Among them, approximately 25% to 40% will die of liver disease (cirrhosis with or without hepatocellular carcinoma). The death rate is 50% for males and 15% for females [1]. Only interferon (IFN), lamivudine, and adefovir monotherapy have been approved for the treatment of chronic HBV infection. Not all patients with chronic hepatitis B infection respond to these treatments, however. This article focuses on patients with chronic hepatitis B infection and prior exposure to IFN, lamivudine, and adefovir. With the future introduction of new antiviral agents such as such as entacavir, clevudine, L-Fd4C, tenofovir [2], pegylated IFN (PEG IFN) [3] and others, one would anticipate more clinical trials be conducted to investigate the effectiveness of these agents, either as monotherapy or combination therapy with approved agents [4,5] in drug-experienced chronic hepatitis B patients who fail to respond to previous treatment. Defining nonresponders In hepatitis B, surrogate markers such as types (virologic, biochemical, histologic, and composite) and time points (early, end-of-therapy, maintained during long-term therapy, and sustained after therapy) of response Grant support: This project was supported with a grant from the Cheng Si-yuan (ChinaInternational) Hepatitis Research Foundation (to the University of Hong Kong), China National 973 research grant (G 1999 054105 to G.K.K. Lau). * Corresponding author. E-mail address: [email protected] (G.K.K. Lau). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.04.009

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have been adopted to assess response to treatment [6]. In hepatitis B e antigen (HBeAg)-positive cases, stable hepatitis B e antibody (anti-HBe) seroconversion with HBV DNA suppression and normal alanine transaminase (ALT) levels after the withdrawal of therapy are considered endpoints of treatment. In HBeAg-negative cases and in those without anti-HBe seroconversion, the extent of HBV DNA suppression with normal ALT levels without breakthrough or development of resistance are considered as the endpoints of treatment. The use of virologic endpoints, (such as a HBV DNA level less than 105 copies/mL cutoff recommended by the National Institute of Health HBV Workshop [7]) may not correlate with an improvement in clinical outcomes, because viral eradication of HBV rarely is achieved. In fact, most patients require prolonged therapy to suppress disease activity and progression. Interferon Interferon-a2b was the first drug to be approved by the US Food and Drug Administration for treatment of chronic HBV infection, followed by lamivudine and most recently adefovir dipivoxil. The efficacy of IFN, defined as sustained loss of HBeAg and HBV DNA, is limited, however. In a meta-analysis of 15 randomized, controlled trials, loss of HBeAg and HBV DNA in HBeAg-positive patients was seen in 33% and 37% of IFN-treated patients, compared with 12% and 17% of untreated patients, respectively [8]. In Caucasians, the long-term durability of HBeAg is as high as 90% [9], while approximately 20% to 70% of patients with anti-HBe seroconversion eventually will lose HBsAg [9,10]. In those with detectable HBV DNA after HBeAg seroconversion, the HBV DNA will be undetectable in 60% to 100% of those who lose HBsAg. Although most clinical studies have used IFN-a, a small study using IFN-b at 3 MU weekly for 24 weeks showed a 50% seroconversion rate from HBeAg to anti-HBe, a rate similar to that achieved with IFN-a [11]. In HBeAg-negative variants (precore mutants and others), prolonged IFN at a dose of 3 to 5 mU three times weekly for at least 12 months results in a sustained biochemical remission in 15% to 25% of patients [12,13]. Factors that predict a favorable response to IFN include low pretreatment level of HBV DNA (less than 200 pg/mL), high levels of serum transaminase (less than 100 U/L), and evidence of necroinflammatory activity on liver biopsy [14]. In contrast, male gender, duration of infection, Asian origin, precore mutants, and HIV coinfection are factors associated with poor response to IFN [15]. In a recent study from Taiwan, patients with genotype B were more likely to respond to IFN than those with genotype C [16]. Recent data, however, suggest that spontaneous seroconversion is also greater with genotype B [17]. The rate of achieving HBeAg seroconversion in Asian patients has been low [18]. This difference between Asian and Caucasian patients is thought to

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603

be related to the duration of the chronic state. HBV is acquired by Asians perinatally, but Caucasians acquire HBV predominantly in their adolescence or adulthood. In perinatally acquired infection, infection is followed by a lengthy period of immune tolerance, during which the HBV DNA is high, while the serum ALT levels are normal or near normal, and liver necroinflammation is minimal [18–20]. In HBV infection acquired at an older age, there is a more robust host immune response directed towards clearance of the infection, with elevated ALT levels and necroinflammatory activity common on liver histology [21]. Lamivudine Lamivudine, the (-) enantiomer of the deoxycytidine analog 29-deoxy-39thiacytidine, competitively inhibits viral reverse transcriptase and terminates proviral chain DNA viral extension [22,23]. Because of its mode of action, lamivudine is equally effective in Asians and Caucasians. Lamivudine can induce a rapid 2 to 3 log decrease in serum HBV DNA levels in patients with chronic HBV [24]. Several randomized trials in HBeAg-positive patients demonstrated that a 1-year course of lamivudine can induce HBeAg seroconversion in 16% to 18% of patients [25–27]. It was able to decrease the serum HBV DNA levels to undetectable levels in about 93% to 100% of patients. After discontinuation of therapy, however, HBV DNA reappeared in most patients. The most important predictor of a favorable response following lamivudine treatment is a high pretreatment ALT level, with the rate of HBeAg seroconversion being 2% in those with normal ALT as compared with 47% in those with ALT levels five times the upper limit of normal (ULN) [28]. The sustained seroconversion rate of HBeAg to anti-HBe increased during the second year of treatment, from 17% to 27% [29]. The durability of HBeAg seroconversion in patients receiving 3 to 4 years of lamivudine ranges from 38% and 73% [30,31]. On the other hand, with a mean duration of treatment of 9.3 months, the cumulative relapse rates were 37.5% at 1 year and 49.2% at 2 years [32]. Unlike IFN, lamivudine can suppress HBV replication effectively in patients with precore mutants [36]. The initial response in these patients to lamivudine is similar to those reported in HBeAg-positive patients. Biochemical and virological response was seen in 60% to 70% of patients after 52 weeks of treatment, but 90% of these patients relapsed after lamivudine was discontinued. A sustained virological and biochemical response was maintained in 11% to 20%, with a relapse rate of 48% after 6 months of follow-up, rising to 74% by 12 months [33–35]. One major drawback of lamivudine treatment is the development of drug-resistant HBV after 6 to 9 months of treatment. The lamivudineresistant viruses have a characteristic amino acid substitution in the tyrosine-methionine-aspartate-aspartate (YMDD)-motif of the

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RNA-dependent DNA polymerase [37,38]. The methionine at codon 204 is replaced by an isoleucine (rtM204I) or by a valine (rtM204V). In addition, the rtM204V mutation frequently is accompanied by a leucine-180-tomethionine (rtL180M) substitution (Fig. 1). The mutation at the YMDD motif of the polymerase gene is noted after 6 months of treatment, and the rate of mutation is related to the duration of treatment. At the end of the first, second, third, and fourth years of treatment, the incidences of resistance are 15% to 32%, 38%, 56%, and 67%, respectively [39]. Although lamivudine-resistant mutants have less viral replication competence compared with the wild-type virus, rtL180M mutation in combination with the rtM204V change may restore its replication fitness partially [40,41]. The emergence of these mutants results in phenotypic resistance or viral breakthrough 3 to 4 months after the development of genotypic resistance [42]. Despite the development of breakthrough viremia caused by mutants, many patients have serum HBV DNA and ALT levels that remain lower than pretreatment values, suggesting that there may be a continued suppressive effect on the wild-type virus and a lower virulence of the mutant virus [25,26]. A hepatitis flare, however, defined by an increase in serum ALT levels five times greater than the ULN, occurred in 40% of HBeAgpositive patients [42,43] and in 50% of HBeAg-negative patients during continued lamivudine therapy after the emergence of YMDD mutations [30,42]. Although HBeAg seroconversion has been reported in 48% of the patients at the end of 5 years of treatment despite the development of lamivudine-resistant mutants, severe hepatitis with hepatic decompensation, especially in patients with advanced liver disease, has been known to occur [43]. Recently, mortality related to the development of lamivudine resistance in immunocompetent patients has been described [44]. Compared with the hepatitis flare during the natural course of chronic hepatitis B infection, a hepatitis flare in association with YMDD mutants during continued lamivudine treatment is more severe in terms of the incidence of hepatic decompensation (Table 1) [43,44].

Codon Wild-type

S

P

F

L

rtM204I

S

P

F

L

rtM204V

S

P

F

L

rtL180M

S

P

F

L

rtL180M/rtM20 4V

S

P

F

L

180 ttg L ttg L ttg L atg M atg M

A

Q

F

T..

..A

F

S

Y

A

Q

F

T..

..A

F

S

Y

A

Q

F

T..

..A

F

S

Y

A

Q

F

T..

..A

F

S

Y

A

Q

F

T..

..A

F

S

Y

204 atg M ata I gtg V atg M gtg V

D

D

V

V

D

D

V

V

D

D

V

V

D

D

V

V

D

D

V

V

Fig. 1. Amino acid mutations in the rt domain of the viral polymerase associated with lamivudine resistance.

605

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Table 1 Acute exacerbation of chronic hepatitis after the development of tyrosine methionine aspartate aspartate mutants during lamivudine therapy compared with natural history of chronic hepatitis B infection Patients

Annual incidence

ALT > 1000 U/L

Bil > 2 mg/dL

PT > 3s

32

27%

23%

30%

23%

358 279

27% 11%

27% 27%

11% 21%

3% 0%

Number

YMDD mutants Natural course: HBeAg (þ) HBeAg (
)

Adefovir dipivoxil Adefovir dipivoxil is the third drug to be approved for treatment of chronic hepatitis B infection. It is an acyclic nucleotide analog and is a potent inhibitor of HBV replication. It has been shown to be effective for HBeAg-positive and -negative patients. Forty-eight weeks of treatment can result in HBeAg seroconversion in 12% and undetectable (less than 400 copies/mL) serum HBV DNA in 21% of those receiving 10 mg daily [45]. In HBeAg-negative patients treated with 10 mg daily adefovir, 51% had undetectable serum HBV DNA after 48 weeks of treatment [46]. Even though adefovir-resistant mutant (rtN236T) (Fig. 2) has been detected in those treated for 96 weeks, the occurrence is low, at only 1.6%. Therapy for nonresponders Retreatment with interferon The retreatment of IFN nonresponders with IFN has been performed in three studies [47–49] (Table 2). These studies show that retreatment with IFN can induce HBeAg seroconversion and loss of HBV DNA in previous nonresponders. Retreatment with IFN also can lead to suppression of HBV DNA in 22% of HBeAg-negative patients [47]. Younger age, higher pretreatment ALT levels, and lower HBV DNA are predictive factors for response to IFN retreatment [48]. Combination interferon and ribavirin Ribavirin is a purine analog that can interfere with viral messenger RNA synthesis and inhibit the replication of RNA and DNA viruses in vitro and Codon

230

Wild-type

S

L

G

I

H

RtN236T

S

L

G

I

H

236

238

241

L

N

P

D

K

T

K

L

T

P

D

K

T

K

Fig. 2. Amino acid mutation in the rt domain of the viral polymerase associated with adefovir resistance.

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Table 2 Repeated treatment with interferon in prior interferon nonresponders

Treatment regimen Janssen et al [47]

Carreno et al [48] Munoz et al [49]

IFN 1.5 MU daily for 4 weeks followed by 3 MU daily for 8 weeks and then 5 MU daily for 4 weeks IFN 9 MU three times weekly for 24 weeks Control group IFN 6 MU five times weekly for 24 weeks IFN 6 MU five times weekly for 24 weeks

Pretreatment HBeAg

Sustained loss of HBV DNA

HBeAg seroconversion to anti-HBe

HBeAg þ (n = 18)

17%

11%

HBeAg þ (n = 27)

44%

22%

HBeAg þ (n = 30) HBeAg þ (n = 11)

33% 18%

10% 18%

HBeAg – (n = 18)

22%

-

in vivo. Only one uncontrolled study has examined the role of combination IFN and ribavirin for treating chronic hepatitis B patients who did not respond to IFN monotherapy [50]. Sustained virological response was achieved in 21% of patients, and a biochemical response (normalization of ALT) was achieved in 21% of patients. This study also showed an improvement in necroinflammatory activity and fibrosis score in 50% of those with sustained virological response but in none of the nonresponders. Treatment was discontinued in 20.8% of patients. Discontinuation because of ribavirin intolerance occurred in 16.7% of patients; discontinuation because of exacerbation of disease occurred in 4.2% of patients. Combination lamivudine and interferon In general, studies on the concomitant administration of IFN and lamivudine have failed to show an increased sustained suppression of serum HBV DNA or an increase in HBV-specific T-cell responsiveness in HBeAgpositive IFN monotherapy nonresponders when compared with lamivudine monotherapy [51–56] (Table 3). One small study, however, showed more impressive results [57]. In this study, 14 IFN nonresponders were treated with sequential lamivudine and IFN. The treatment schedule was comprised of three successive phases: lamivudine at 100 mg daily for 20 weeks followed by a combination of lamivudine at 100 mg per day and IFN at 5 MU three times per week for 4 weeks and ending with IFN at 5 MU three times per week for 24 weeks. With this regimen, 8 of 14 patients achieved sustained suppression of serum HBV DNA 6 months after the completion of treatment, while HBeAg to anti-HBe seroconversion was achieved in 5 of 11 patients without the occurrence of lamivudine-resistant mutants (see Table 3). The high response rates observed in this study may be related to

Table 3 Combination lamivudine and interferon for interferon nonresponders Treatment Regimen

Santantonio et al [53]

Jaboli et al [54]

Tatulli et al [55] Schiff et al [56]

Serfaty et al [57]

LAM 12 weeks þ IFN 10 MU three times weekly for 16 weeks LAM 16 weeks þ IFN 10 MU three times weekly for 16 weeks LAM for 52 weeks LAM þ IFN 5 MU three times weekly for 52 weeks LAM for 4 weeks followed by LAM þ IFN 6 MU three times weekly for 52 weeks followed by LAM for 52 weeks LAM for 52 weeks LAM þ IFN 6 MU three times weekly for 52 weeks LAM for 52 weeks Placebo for 52 weeks LAM 8 weeks followed by LAM þ IFN 10 MU three times weekly for 16 weeks LAM for 20 weeks followed by LAM þ IFN for 4 weeks followed by IFN for 24 weeks LAM for 20 weeks followed by LAM þ IFN for 4 weeks followed by IFN for 24 weeks

HBeAg þ (n = 6)

100%

0%

HBeAg þ (n = 14)

100%

25%

HBeAg – (n = 26) HBeAg – (n = 24)

17% 19%

– –

HBeAg – (n = 34)

44%

–

HBeAg – (n = 24) HBeAg – (n = 29)

33% 14%

– –

HBeAg þ (n = 116) HBeAg þ (n = 54) HBeAg þ (n = 63)

55% 17% 23%

24% 14% 9%

HBeAg þ (n = 11)

45%

45%

HBeAg – (n = 4)

100%

HBeAg seroconversion to anti-HBe

–

607

Abbreviation: LAM, lamivudine.

Sustained loss of HBV DNA

C.-K. Hui et al / Gastroenterol Clin N Am 33 (2004) 601–616

Mutimer et al [51]

Pretreatment HBeAg

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two factors. First, the duration of IFN treatment was longer, 28 weeks versus 16 weeks in other studies. Second, sequential rather than concurrent administration may be more effective because of the moderate increase in viral levels observed after the withdrawal of lamivudine. The latter results in a situation in which IFN is typically more effective [13]. Studies conducted in HBeAg populations, also have failed to show that concomitant combination of lamivudine and IFN is superior to lamivudine monotherapy in inducing sustained suppression of HBV [54,55] (see Table 3). Combination of hepatitis B surface antigen vaccination and interferon-a Therapeutic vaccines have been developed as monotherapy or in combination therapy with IFN or lamivudine. Vaccines can improve the inefficient response of T helper cells and cytotoxic T lymphocytes and correct the Th1/Th2 imbalance in chronic hepatitis B patients. One such vaccine is the Gen H-B –Vax (Pasteur-Merieux, MSD-Behringwerke, Munich, Germany). The use of this vaccine in combination with IFN was evaluated in 18 IFN nonresponders [58]. In this uncontrolled study, 18 patients received subcutaneous IFN at 5 MU three times weekly for 6 months in combination with Gen H-B-Vax administered intramuscularly at the beginning of IFN treatment and at weeks 4 and 12. At the end of 24 weeks of treatment, serum HBV DNA was not detectable in 50% of patients, and 39% achieved HBeAg seroconversion. Lamivudine and adefovir Lamivudine monotherapy also has been shown to be effective for HBeAg-positive and -negative IFN nonresponders (see Table 3) [53,56]. Seventeen patients who previously failed interferon therapy were included by Dienstag et al [25] into their study on lamivudine. Three patients (17.6%) achieved HBeAg seroconversion, while five patients (29.4%) had undetectable serum HBV DNA. In a study involving 20 pediatric patients who were IFN nonresponders, 52 weeks of lamivudine therapy led to a sustained undetectable HBV DNA in 44%; one patient (5.0%) had HBeAg seroconversion [47]. The clinical trials using adefovir dipivoxil included 123 HBeAgpositive and 48 HBeAg-negative patients who previously failed IFN therapy [45,46]. The HBeAg seroconversion rates in those with prior IFN treatment were similar to those in treatment-naıı¨ ve patients. These studies offer evidence that both lamivudine and adefovir can be a treatment option for patients who have not responded to IFN treatment. Therapy for patients with lamivudine-resistant mutants Several nucleoside/nucleotide analogs, such as adefovir dipivoxil [59], entecavir [60], tenofovir [61], L-Fd4C [62], and MCC-478 [63], recently have been shown to be effective against lamivudine-resistant HBV mutants in

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609

vitro. Other nucleoside analogs with in vitro activity against lamivudineresistant HBV include amdoxovir (DAPD) and lobucavir. There are case reports of IFN being used to treat patients with lamivudine-resistant HBV also. Adefovir dipivoxil In addition to inhibiting the replication of wild-type HBV, adefovir can be used to treat patients who have developed lamivudine-resistant HBV mutants. Adefovir dipivoxil has been shown to inhibit the replication of HBV variants with the rtM204V, rtM204I, and rtL180M/rtM204V mutations in the DNA polymerase in vitro [64,65] (see Fig. 1). In a randomized study of 90 patients with lamivudine-resistant HBV, 20% of those randomized to receive adefovir had undetectable HBV DNA at week 52 of treatment, while in the placebo group, no patient had undetectable HBV DNA at week 52 [66]. Eight percent of those on adefovir achieved HBeAg seroconversion, while in the placebo group, the rate of HBeAg seroconversion was 2% [66]. The safety and efficacy of adefovir in the treatment of lamivudineresistant HBV mutants in chronic hepatitis B patients coinfected the HIV were assessed in 35 patients [67]. These patients were treated for a median of 48 weeks, and a mean decrease in serum HBV DNA by 3.40 log10 copies/mL at week 24 and a decrease by 4.01 log10 copies/mL at week 48 were observed. Therefore, adefovir dipivoxil can be considered in lamivudine-resistant HBV patients, with and without HIV coinfection, who develop an acute reactivation of hepatitis or fulminant hepatic failure. Tenofovir disoproxil fumarate Tenofovir disoproxil fumarate is another acyclic nucleotide analog that is closely related to adefovir. It can be incorporated directly into a DNA chain causing premature termination of the viral DNA chain. Tenofovir has been shown to exert antiviral activity against lamivudine-resistant HBV, with a median drop in serum HBV DNA of 2.3 to 4.3 log10 copies/mL after 4 to 30 weeks (median 24 weeks) of treatment [61,62,64,68–71] (Table 4). The results of these small series indicate that tenofovir at 300 mg daily can reduce serum HBV DNA levels in those with lamivudine-resistant HBV and can be considered as a therapeutic option in this patient population. Interferon Someya et al [72] were the first to report on the use of IFN in patients with lamivudine-resistant HBV mutants. This was followed-up by a report [73] of six patients with lamivudine-resistant HBV mutants treated with IFN at 6 mU daily for 4 weeks followed by IFN two or three times a week until virological and biochemical relapse was controlled. Four patients (66.7%)

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Table 4 Results of tenofovir 300 mg daily on HIV/hepatitis revirus coinfected patients with lamivudineresistant HBV variants

Van Bommel [61] Nunez et al [68] Benhamou et al [69] Bruno et al [70] Ristig et al [71]

Patients

Duration of Treatment

Median Decrease in HBV DNA

5 12 12 5 6

24–30 weeks 24 weeks 24 weeks 4 weeks 24 weeks

4.3 log10 copies/mL 3.78 log10 copies/mL 2.6 to 2.3 log10 copies/mL 2.42 log10 copies/mL 4.3 log10 copies/mL

had undetectable HBV DNA levels within 4 weeks of IFN therapy, and two patients (33.3%) achieved HBeAg seroconversion. This report, however, did not state the median duration of IFN therapy or whether there is a recurrence of activity after the therapy has been stopped. Therefore, until more data are available, the use of IFN in lamivudine-resistant HBV is not recommended. Therapy for adefovir-resistant mutants Adefovir-resistant HBV has been described and is associated with an increase in serum HBV DNA with increased serum ALT levels. It also may lead to impairment in hepatic synthetic function [74]. Resistance to adefovir, however, is much less common than resistance to lamivudine. In vitro crossresistance testing of this mutant shows that it has retained antiviral susceptibility to lamivudine. Therefore, for patients with adefovir-resistant HBV mutants, lamivudine would appear to be the treatment of choice. One must recognize, however, that the clinical experience with this newly described mutants is limited. Potential future treatments for drug-experienced patients Entecavir Entecavir is a deoxyguanosine analog with potent and selective inhibition of HBV replication. It has an in vitro potency that is 100- to 1000- fold greater than that of lamivudine, and it has a selectivity index (concentration of drug that reduces the viable cell number by 50%/concentration of drug that reduced viral replication by 50%) of 8000 [75]. In an in vitro study, inhibition of wild-type and lamivudine-resistant HBV by entecavir triphosphate was measured by using recombinant HBV nucleocapsids and compared with that of lamivudine triphosphate. This study showed that entecavir triphosphate is a potent inhibitor of wild-type virus and is also 100- to 300- fold more potent than lamivudine triphosphate against lamivudine-resistant HBV. A 20- to 30-fold higher concentration of entecavir is required to inhibit lamivudine-resistant HBV, however [76].

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611

Entecavir is also effective in IFN pretreated patients. In a study of 181 patients with persistent viremia or YMDD, mutants after 24 weeks on lamivudine, 24 weeks of entecavir resulted in undetectable HBV DNA in 19% treated with 0.1 mg of entecavir daily, 53% with 0.5 mg of entecavir daily, and 79% with 1 mg of entecavir daily [60]. Emtricitabine Emtricitabine has similar molecular structure, antiviral potency, and selectivity to lamivudine in a woodchuck model. It has not been shown to be effective in suppressing lamivudine-resistant HBV [77]. Clevudine Clevudine, a pyrimidine analog with potent anti-HBV activity, is not effective against lamivudine-resistant virus [77,78], particularly in the presence of concomitant rtL180M mutation [78]. Amdoxovir Amdoxovir, a prodrug of dioxalane guanosine, is effective against lamivudine-resistant HBV in vitro [77,78]. Beta-L-nucleoside Beta-L-29-deoxycytidine (LdC), beta-L-thymidine (LdT), and beta-L-29deoxyadenosine (LdA) are potent inhibitors of HBV. The activity of these three drugs against lamivudine-resistant virus is unknown. Preliminary data on the antiviral efficacy of LDT (telbivudine) in HBeAg-positive patients without prior lamivudine exposure was reported recently [79]. After 48 weeks treatment, 64% of patients had undetectable HBV DNA levels (less than 1000 copies/mL) in the telbivudine groups (400 and 600 mg daily) versus 32% in the lamivudine monotherapy arm. The drug was tolerated well. Summary Interferon is one of the best studied drugs for the treatment of chronic HBV. Despite achievement of favorable outcomes such as normalization of serum ALT levels, decrease in viral replication, HBeAg seroconversion, and improved histology, this agent has its limitations. The availability of lamivudine as an alternative agent for treatment of chronic HBV represents a great advancement. Lamivudine is effective in patients with precore mutants and can be used in patients who have failed to respond to IFN or those who relapsed after IFN. Its major disadvantage is the increased likelihood of developing lamivudine-resistant mutants with prolonged therapy. Lamivudine-resistant HBV can be treated effectively with newer nucleoside analogs

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such as adefovir or tenofovir or with a combination of nucleoside analogs. Adefovir-resistant HBV, although delayed and infrequent, may create be a problem in the future, especially in those who require long-term antiviral therapy. Fortunately, adefovir-resistant HBV is susceptible to lamivudine. Because of the emergence of drug-resistant mutants with monotherapy (lamivudine and adefovir), there exists a rationale for the use of combination therapy. A combination of agents, each acting on different sites of the HBV replication cycle, may have additive or even synergistic effects. With the appropriate combination of drugs, the doses required to produce viral suppression may be less than that required in monotherapy, and so reducing the adverse effects of individual agents. As lamivudine-resistant HBV mutants are susceptible to adefovir and tenofovir, it is possible that combination therapy using lamivudine and adefovir or tenofovir may prevent the emergence of lamivudine- and adefovir-resistant HBV.

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[70] Bruno R, Sacchi P, Zochetti C, Ciappina V, Puoti M, Filice G. Rapid hepatitis B virusDNA decay in coinfected HIV-hepatitis B virus e-minus patients with YMDD mutations after 4 weeks of tenofovir therapy. AIDS 2003;17:783–4. [71] Ristig MB, Crippin J, Aberg JA, Powderly WG, Lisker-Melman M, Kessels L, et al. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus coinfected individuals for whom interferon-a and lamivudine therapy have failed. I Infect Dis 2002;186:1844–7. [72] Someya T, Suzuki Y, Arase Y, Kobayashi M, Suzuki F, Tsubota A, et al. Interferon therapy for flare up of hepatitis B virus infection after emergence of lamivudine-induced YMDD motif mutant. J Gastroenterol 2000;32:1078–88. [73] Suzuki F, Tsubota A, Akuta N, Someya T, Kobayashi M, Suzuki Y, et al. Interferon for treatment of breakthrough infection with hepatitis B virus mutants developing during long-term lamivudine therapy. J Gastroenterol 2002;37:922–7. [74] Angus P, Vaughan R, Xiong S, Yang HL, Delaney W, Gibbs C, et al. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology 2003;125:292–7. [75] De Man RA, Wolters LM, Nevens F, Chua D, Sherman M, Lai CL, et al. Safety and efficacy of oral entecavir given for 28 days in patients with chronic hepatitis B virus infection. Hepatology 2001;34:578–82. [76] Levine S, Hernandez G, Yamanaka S, Zhang S, Rose R, Weinheimer S, et al. Efficacies of entecavir against lamivudine-resistant hepatitis B virus replication and recombinant polymerases in vitro. Antimicrob Agents Chemother 2002;46:2525–32. [77] Seigneres B, Pichoud C, Martin P, Furman P, Trepo C, Zoulim F. Inhibitory activity of dioxane purine analogs on wild-type and lamivudine-resistant mutants of hepadnaviruses. Hepatology 2002;36:710–22. [78] Chin R, Shaw T, Torresi J, Sozzi V, Trautwein C, Bock T, et al. In vitro susceptibility of wild-type or drug-resistant hepatitis B virus to (-)-b-D-2, 6-diaminopurine dioxolane and 29-fluoro-5-methyl-b-L-arabinofuranosyluracil. Antimicrob Agents Chemo 2001;45: 2495–501. [79] Lai CL, Teo EK, Tong M, Wong F, Hann HW, Han S, et al. Results of a one-year international phase IIB comparative trial of telbivudine, lamivudine, and the combination, in patients with chronic hepatitis B. Hepatology 2003;38:262A.

Gastroenterol Clin N Am 33 (2004) 617–627

Treatment of hepatitis B virus infection in patients coinfected with HIV Yves Benhamou, MD, PhD, Luminita Bonyhay, MD Service d ÕHe´pato-Gastroente´rologie, Hoˆpital Pitie´-Salpeˆtrie`re, 27 Boulevard de lÕHoˆpital, 75013 Paris, France

Chronic infection with hepatitis B virus (HBV) affects about 5% of the world population [1]. In Western Europe, Australia, and the United States, the prevalence of chronic carriers of hepatitis B surface antigen (HBsAg) is less than 1% of the population. Among people with HIV, this prevalence is approximately 10-fold higher [2]. Until recently, there have been relatively few studies on the impact of HBV infection in HIV seropositive patients. The natural history of chronic HBV infection is modified by coinfection with HIV. After initial HBV infection, both the development and persistence of chronic HBV (CHB) infection are greater in patients with prior HIV infection [3,4]. Among chronic HBsAg carriers, a high level of HBV replication, or the presence of hepatitis B e antigen (HBeAg) is common in people with HIV/HBV coinfection [3,4]. These two conditions may be predictive of poor survival. Studies performed in deeply immunosuppressed patients before the era of highly active antiretroviral therapy (HAART), however, found mild necroinflammatory liver lesions associated with low serum transaminase levels [5–7]. More recent studies conducted in the HAART era have reported a higher incidence of liver-related cirrhosis and mortality in HIV/HBV coinfected patients compared with HIV monoinfected persons [8–10]. Factors affecting progression to cirrhosis in patients with HIV/HBV coinfection remain unknown. HAART-related immune restoration may have switched the immune reaction to HBV from a tolerance to an intolerance phase, leading, in a few cases, to the complete control of HBV replication or, in most patients, to an exacerbation of chronic hepatitis. HAART-related hepatotoxicity also could have contributed to the worsening of liver damage. On the other hand, improvement of liver lesions may be observed in patients receiving antiretroviral regimens containing lamivudine E-mail address: [email protected] (Y Benhamou). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.04.010

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(LAM). Finally, the effect of HIV infection on the natural history of CHB also could be modified by a longer life expectancy, which may allow more time for cirrhosis to develop. Therefore, because of the complex and potent interactions between these two viruses, and with the immune system and antiretroviral therapy, the strategy and management of anti-HBV therapy in people with HIV must take both viral infections into consideration. Therapy of CHB in patients with HIV has been studied insufficiently. Most of the reported trials were nonrandomized, included a small sample size of patients, and were performed in the pre-HAART period. In addition, these studies did not consider liver histology as an endpoint. Interferon alfa 2 (IFN-a2) was the first drug used for the treatment of HBV in patients with HIV. LAM has been the most studied drug in this area; recently, adefovir dipivoxil has been tested for the treatment of LAM-resistant HBV. Additionally, anti-HBV activity of tenofovir disoproxil fumarate has been reported recently in patients with HIV.

Interferon alfa Almost all of the studies conducted in HIV/HBV coinfected patients concluded that there is a reduced response to IFN-a2 compared with HBV mono-infected patients [11–16]. Endpoints were heterogeneous, however, and the number of studied patients was small. Furthermore, these studies were performed in immunosuppressed patients not receiving potent antiHIV therapy. Only two of the reported trials with IFN-a2 were randomized [11,12]. In a dose ranging study of IFN-a2a, 41 patients (14 with HIV) with documented chronic wild-type HBV infection were treated with either 2.5 mU/m2 (three HIV-positive, six HIV-negative), 5 mU/m2 (five HIV-positive, four HIV-negative) or 10 mU/m2 (five HIV-positive, four HIV-negative) three times weekly for 3 (six patients) or 6 months (26 patients) [16]. Nine patients were not treated. None of the HIV-positive patients treated with IFN-a2 became HBV DNA negative (measured by molecular hybridization) or became HBeAg negative. This finding was confirmed later in another randomized, controlled study using IFN-a2a (5 MU/m2 then increased to 10 MU/m2 three times per week for 1 and 12 weeks, respectively) in 50 chronically infected patients [13]. Twenty-five of the patients were HIVpositive without AIDS or AIDS-related complex. Only one of the 12 (8.3%) HIV-positive treated patients and none of the 13 HIV-positive controls seroconverted to anti-HBe with negative serum HBV DNA. In comparison, 5 of the 13 (38.5%) HIV-negative treated patients responded compared with 1 of 12 (8.3%) HIV-negative control patients. IFN-a2 in HIV/HBV coinfected patients untreated for HIV appears to have the same tolerance profile as reported in non-HIV patients, although one trial showed a higher

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rate of adverse effects and treatment discontinuation in the HIV-positive treatment group compared with the HIV-negative treatment group [16]. No information regarding IFN-a2 activity in HIV-positive patients with precore mutant HBV is available. In summary, it is impossible with the limited amount of published data to propose strong recommendations for the treatment of HBV with IFN-a2 monotherapy in HIV coinfected patients. Although putting altogether these results suggests that IFN-a2 was inadequately effective for the treatment of wild-type HBV in HIV-infected patients. HIV/HBV coinfected individuals treated after 1996 are most likely immunologically different from patients included in these early published trials, with the major difference being significant use of HAART therapy in industrialized countries. HAARTtreated patients have improved immunity. Large trials in patients receiving HAART are needed to assess safety and efficacy of IFN-a2 (or pegylated IFN [PEG IFN]) in coinfected patients. Serological, virological, and histological endpoints should be considered in these studies.

Lamivudine Lamivudine is effective against both HIV and HBV replication. Among HIV/HBV coinfected patients, LAM (150 mg twice daily) given for HIV infection as monotherapy or as part of an antiretroviral regimen promptly inhibits HBV replication [17,18]. Anti-HBV LAM activity first as assessed in a prospective open-label study in 40 patients with advanced HIV infection [17]. After 1 year of treatment, 96.3% of patients had an undetectable serum level of HBV DNA (less than 5 pg/mL, by molecular hybridization). AntiHBe seroconversion and HBeAg seronegativity were observed in 11% and 18.5% of cases, respectively. In patients with detectable serum HBV DNA at baseline (greater than 5 pg/mL), increases in serum alanine aminotransferase (ALT) were observed 2 to 8 weeks after LAM initiation. Subsequently, at week 52 of treatment, ALT significantly decreased compared with baseline. A retrospective analysis of HIV/HBV coinfected patients prospectively enrolled within the CAESAR trial has been reported [18]. This was a randomized, double-blind, placebo-controlled trial of LAM (150 mg twice daily) or LAM plus loviride added to zidovudine-containing regimens for patients with advanced HIV infection [19]. Among patients included in the CAESAR study, 122 were coinfected with HBV (97 in the LAM arm and 25 in the placebo arm). Approximately 60% of the patients were HBeAg carriers in the two groups. Although randomization was not based on HBV infection, there was no difference between LAM arm and placebo-treated patients with respect to baseline demographic characteristics, HIV disease, serum ALT, and HBV virological status. Main virological and biological results are summarized in Fig. 1. At week 52, the median serum HBV DNA reduction was 2.7 log10 copies/mL measured by polymerase chain reaction

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60%

52% 50%

40% 40%

30%

21,80%

19%

20%

10% 10%

0% 0% HBV DNA<400 copies/mL*

HBeAg negativation

LAM

ALT normalization

Placebo

Fig. 1. HBV responses after 1 year of lamivudine therapy (150 mg twice daily) in 122 HIV/HBV coinfected patients enrolled in the CAESAR trial (Data from Dore GJ, Cooper DA, Barrett C, Goh LE, Thakrar B, Atkins M. Dual efficacy of lamivudine treatment in human immunodeficiency virus/hepatitis B virus-coinfected persons in a randomized, controlled study (CAESAR). The CAESAR Coordinating Committee. J Infect Dis 1999;180:607–13.) 1 LAM (n ¼ 79) versus placebo (n ¼ 19). p ¼ 0.018.

(PCR) (Monitor Roche, Nutley, New Jersey, quantification range 2.6 to 7.6 log10 copies/mL) in the LAM-treatment arm compared with no reduction in placebo-treated patients. Using this sensitive method, serum HBV DNA was undetectable in 40% of LAM-treated patients at week 52. Finally, LAM (150 mg twice daily) showed an excellent tolerance profile in HIV infected patients and in HIV/HBV coinfected patients. No information regarding the underlying liver disease was available in either of these two studies, however. Resistance to LAM is recognized in HIV strains, and it is encoded within the YMDD motif near the catalytic site of the reverse transcriptase (RT) [20]. The key mutation, M184V, occurs in almost all treated individuals. M184V also confers a fitness deficit on the virus, at least in part because of reduced processivity of the RT [21]. This may explain observations that the presence of M184V may not compromise HIV viral load reduction by LAM-containing regimens [22]. HBV polymerase contains a homologous YMDD motif, also around the catalytic site. Mutations in the YMDD motif of the DNA polymerase confer resistance to LAM. Two major types of mutation have been identified, namely M550V together with L526M, and M550I alone (methionine at codon 550 is homologous to codon 184 within the HIV RT) [23,24]. An incidence of 50% and 90% of HBV resistance to LAM after 2 and 4 years of therapy, respectively, was reported in a retrospective cohort study of HIV/HBV coinfected persons (Fig. 2) [25,26]. CD4 cell count decrease, body mass index, and duration of LAM

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Proportion of patients with sustained HBV DNA suppression

1,00

0,75

0,50

0,25

0,00 0

368

735

1103

1470

Days of Lamivudine Therapy* Number of patients under observation

57

32

13

6

3

Fig. 2. Cumulative risk for development of HBV resistance to lamivudine in patients HIVinfected patients (since the clearance of serum HBV DNA [ie, after 60 days of lamivudine at 300 mg per day]). (From Benhamou, Y, Bochet M, Thibault V, Caumes E, Bricaire F, et al. Longterm incidence of hepatitis B virus resistance to lamivudine in HIV-infected patients. Hepatology 1999;30:1302–6; with permission.)

therapy have been associated with an increased risk of the emergence of HBV resistance [27]. Emergence of resistance is characterized by a rise in serum HBV DNA and a moderate increase in serum ALT levels [25,27]. At breakthrough, serum HBV DNA levels are lower than the pre-LAM level. Serum HBV DNA returns to pretreatment levels within 6 to 12 months, however [25]. The clinical consequences of HBV resistance in patients with HIV are unknown. As observed in HBV mono-infected patients, however, cases of CHB exacerbation and liver failure have been reported in HIV/ LAM-resistant HBV coinfected individuals [28,29]. Thus, progression of liver damage related to chronic LAM-resistant HBV is expected in patients who remain untreated. Lamivudine used as an anti-HIV drug at 150 mg twice daily is effective and tolerated well for the control of HBV replication in HIV coinfected individuals, although there is no documented improvement of liver lesions in patients with HBV suppression, and the anti-HBe seroconversion rate is low. Rebound in serum HBV DNA and ALT occur rapidly after LAM discontinuation and is associated with CHB exacerbation [25,30]. Therefore, the duration of LAM therapy in patients who do not seroconvert to antiHBe is unknown. On the other hand, durability of the response to LAM therapy is limited by the emergence of HBV-resistant strains, with an approximate incidence of 15% to 20% per year.

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Adefovir dipivoxil The efficacy of adefovir dipivoxil (ADV) in HBV-infected/HIV-negative patients has been demonstrated in vitro and in vivo using wild-type and precore HBV replication assays [31–34]. Among HIV/HBV coinfected patients, ADV has been investigated for the treatment of LAM-resistant HBV [28]. In an ongoing, open-label pilot study conducted in 35 HIV/HBV coinfected subjects with LAM-resistant HBV and controlled HIV infection, ADV (10 mg) was administered once daily concurrently with lamivudine (150 mg twice daily) [35]. Mean decreases in serum HBV DNA concentrations from baseline (8.64
0.08 log10 copies/mL) were -3.40 log10 copies/ mL at week 24 (n ¼ 31) and -4.01 log10 copies/mL at week 48 (n ¼ 29; P less than 0.0001). Two patients underwent hepatitis anti-HBe seroconversion, at weeks 32 and 36, respectively. ADV interruption was followed by a rebound in serum HBV DNA. A transient increase in serum ALT concentrations was observed in 15 patients by week 8 to week 24. By week 60, serum ALT levels were significantly lower than baseline levels [36]. During 48 weeks of ADV therapy, there was no rebound in serum HBV DNA levels and no mutations in the genes encoding HBV DNA polymerase and HIV RNA RT were identified. A significant decrease in necroinflammatory lesions was observed in the 15 patients who had baseline and week 48 liver biopsies [36]. No significant changes in either HIV RNA or CD4 cell counts were observed. ADV generally was tolerated well; there was no change in renal function throughout the study. Additional data presented recently at the European Association for the Study of the Liver 2002 meeting in Madrid, Spain, showed that serum HBV DNA continue to decline with a mean decrease of 5.13
0.24 log10 copies/mL at week 92 with no viral rebound in any patient on ADV (Fig. 3) [36]. In summary, ADV (10 mg once daily) is the only extensively studied therapeutic alternative for LAM-resistant HBV infection in HIV coinfected patients. ADV therapy in HIV/HBV co-infected patients can be associated with a transient increase in serum ALT, but this is not related to drug toxicity. The impact of LAM discontinuation in HIV/HBV coinfected patients treated with ADV is unknown. It is anticipated, however, that HBV replication would remain controlled with continued ADV therapy even if LAM administration is discontinued [37].

Tenofovir disoproxil fumarate Tenofovir disoproxil fumarate (TDF) has been shown to have significant activity against HIV and HBV. TDF is a nucleotide RT inhibitor and has been shown to have potent in vitro activity against wild-type and LAMresistant HBV [38]. TDF is approved for treatment of HIV-1 infection as a once daily 300 mg tablet. In short-term pilot studies, TDF demonstrated

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HBV DNA (log10 copies/mL)

0

-1 -2 Week 92 : ±.24 log10 copies/mL -5.13±

-3

P<0.0001 -4

-5

-6 Bas.

12

24

36

48

60

72

84 92

31

31

29 13

Weeks of ADV Number of patients 35

33

31

31

31

Fig. 3. Mean changes from baseline (8.64
0.08 log10 copies/mL) in serum HBV DNA measured by PCR during adefovir dipivoxil therapy. (From Benhamou Y, Bochet M, Thibault V, Calvez V, Fievet MH, Vig P, et al. Safety and efficacy of long-term adefovir dipivoxil [ADV] for lamivudine-resistant [LAM-R] HBV in HIV-infected patients [abstract]. J Hepatol 2002;36(Suppl 1):138; with permission.)

anti-HBV activity in HIV/HBV coinfected patients (Table 1) [39–42]. In one of these studies, HBe Ag seroconversion was observed in 25% of the cases after 52 weeks of treatment [41]. A larger patient population and a longer treatment period, however, are necessary to assess the extent and durability of HBV suppression, and its long-term tolerance profile, the potential emergence of resistance to TDF, and HBeAg seroconversion rates. Anti-HBV therapy is indicated in HIV/HBV coinfected patients with evidence of liver disease (ie, necroinflammatory lesions and fibrosis at liver biopsy). LAM, TDF, and ADV have demonstrated anti-HBV activity in coinfected patients. Because LAM and TDF also have anti-HIV activity, however, anti-HBV strategies must consider both viruses. In HIV-infected patients who do not require anti-HIV therapy, monotherapy with LAM (150 mg twice daily) has demonstrated both efficacy and safety. TDF monotherapy has never been evaluated in HIV/HBV coinfected patients untreated for HIV infection. In absence of published data, it is impossible to recommend LAM or TDF monotherapy in HIV/HBV coinfected patients who are not receiving antiretroviral combination therapy. A high risk of emergence of HIV resistance to these drugs is likely. ADV monotherapy may be an alternative in these patients, since ADV shows efficacy against HBV wild-type and precore mutant HBV.

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Table 1 Anti hepatitis B virus activity of tenofovir disoproxil fumarate in HIV/hepatitis B virus coinfected patients

Benhamou Y et al [39] Cooper D et al [40] Nelson M et al [41] Ristig MB et al [42] 1 2

Number of patients

HBV wildtype/ lamirudine resistant

Duration of tenofovindisoproxil fumarate therapy (weeks)

Change from baseline in serum HBV DNA (log10 copies/mL)

12 12 20 6

0/12 5/7 9/11 0/6

24 24 52 24

-3.83
0.381 -5
0.71 -42 -4.32

Mean. Median.

In addition, after at least 2 years of ADV monotherapy, there has been no emergence of HIV or HBV resistance in patients with controlled HIV replication. In HIV/HBV coinfected patients who require anti-HIV therapy, LAM should be considered in the antiretroviral regimen. In early results, TDF showed efficacy against HBV wild-type or precore mutant HBV. Inclusion of LAM or TDF in antiretroviral regimen may prevent CHB exacerbation related to immune restoration. In patients with LAM-resistant HBV, ADV 10 at mg per day should be added to pre-existing antiretroviral regimens, although early TDF reports show that short-term treatment also has strong activity against LAM-resistant HBV. Finally, trials of combination anti-HBV therapies with PEG IFN, LAM, ADV, or TDF must be assessed in coinfected patients to improve anti-HBe seroconversion rates and to prevent long-term resistance. Summary The prevalence of HBV infection in patients with HIV is high. HIV/HBV coinfected patients have an increased risk of cirrhosis and liver-related death. Both HIV and HBV infections must be taken into account when treatment is considered because of the dual antiviral activity of LAM and TDF. LAM, when used as part of an antiretroviral regimen, has been shown to be effective and safe for the control of HBV replication in coinfected patients. HBV resistance, however, may occur at an incidence of 15% to 20% per year. Preliminary reports of anti-HBV activity by TDF-containing HAART regimens showed encouraging results for the treatment of wildtype and LAM-resistant HBV. The long-term efficacy and safety of ADV have been demonstrated in patients infected with LAM-resistant HBV. Further research is needed to improve the anti-HBe seroconversion rate in this population.

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[18] Dore GJ, Cooper DA, Barrett C, Goh LE, Thakrar B, Atkins M. Dual efficacy of lamivudine treatment in human immunodeficiency virus/hepatitis B virus-coinfected persons in a randomized, controlled study (CAESAR). The CAESAR Coordinating Committee. J Infect Dis 1999;180:607–13. [19] CAESAR Coordinating Committee. Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovudine containing regimens for patients with HIV-1 infection: the CAESAR trial. Lancet 1997;349:1413–21. [20] Schuurman R, Nijhuis M, van Leeuwen R, Schipper P, de Jong D, Collis P, et al. Rapid changes in human immunodeficiency virus type 1 RNA load and appearance of drugresistant virus populations in persons treated with lamivudine (3TC). J Infect Dis 1995;171: 1411–9. [21] Back NK, Nijhuis M, Keulen W, Boucher CA, Oude Essink BO, van Kuilenburg AB, et al. Reduced replication of 3TC-resistant HIV-1 variants in primary cells due to a processivity defect of the reverse transcriptase enzyme. EMBO J 1996;15:4040–9. [22] Miller V, Stark T, Loeliger AE, Lange JM. The impact of the M184V substitution in HIV1 reverse transcriptase on treatment response. HIV Med 2002;3:135–45. [23] Bartholomew MM, Jansen RW, Lennox JJ, Jeffers J, Reddy KR, Johnson LC, et al. Hepatitis B virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation. Lancet 1997;349:20–2. [24] Ling R, Mutimer D, Ahmed M, Boxall EH, Elias E, Dusheiko GM, et al. Selection of mutations in the hepatitis B virus polymerase during therapy of transplant recipients with lamivudine. Hepatology 1996;24:3711–3. [25] Benhamou Y, Bochet M, Thibault V, Di Martino V, Caumes E, Bricaire F, et al. Longterm incidence of hepatitis B virus resistance to lamivudine in HIV-infected patients. Hepatology 1999;30:1302–6. [26] Thibault V, Benhamou Y, Seguret C, Bochet M, Katlama C, Bricaire F, et al. Hepatitis B virus (HBV) mutations associated with resistance to lamivudine in patients coinfected with HBV and human immunodeficiency virus. J Clin Microbiol 1999;37:3013–6. [27] Pillay D, Cane PA, Ratcliffe D, Atkins M, Cooper D. Evolution of lamivudine-resistant hepatitis B virus and HIV-1 in coinfected individuals: an analysis of the CAESAR study. CAESAR Coordinating Committee. AIDS 2000;14:1111–6. [28] Bruno R, Sacchi P, Malfitano A, Filice G. YMDD-mutant HBV strain as a cause of liver failure in an HIV-infected patient. Gastroenterology 2001;121:1027–8. [29] Bonacini M, Kurz A, Locarnini S, Ayres A, Gibbs C. Fulminant hepatitis B due to a lamivudine-resistant mutant of HBV in a patient coinfected with HIV. Gastroenterology 2002;122:244–5. [30] Bessesen M, Ives D, Condreay L, Sherman KE. Chronic active hepatitis B exacerbations in human immunodeficiency virus-infected patients following development of resistance to or withdrawal of lamivudine. Clin Infect Dis 1999;28:1032–5. [31] Xiong X, Flores C, Fuller M, Mendel D, Mulato A, Moon K, et al. In vitro characterization of the antihuman cytomegalovirus activity of PMEA (adefovir). Antiviral Res 1997;36:131–7. [32] Xiong X, Flores C, Yang H, Toole J, Gibbs C. Mutations in hepatitis B DNA polymerase associated with resistance to lamivudine do not confer resistance to adefovir in vitro. Hepatology 1998;28:1669–73. [33] Marcellin P, Chang TT, Lim SG, Tong M, Sievert W, Shiffman M, et al. Adefovir dipivoxil for the treatment of hepatitis B antigen-positive chronic hepatitis B. N Engl J Med 2003; 348:808–16. [34] Hadziyannis SJ, Tassopoulos NC, Heathcote E, Chang TT, Kitis G, Rizzetto T, et al. Adefovir dipivoxil for the treatment of hepatitis B antigen-negative chronic hepatitis B. N Engl J Med 2003;348:800–7.

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[35] Benhamou Y, Bochet M, Thibault V, Calvez V, Fievet MH, Vig P, et al. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus. Lancet 2001;358(Supp 1):718–23. [36] Benhamou Y, Bochet M, Thibault V, Calvez V, Fievet MH, Vig P, et al. Safety and efficacy of long-term adefovir dipivoxil (ADV) for lamivudine-resistant (LAM-R) HBV in HIV infected patients [abstract]. J Hepatol 2002;36(Supp 1):138. [37] Peters M, Hann HW, Martin P, Heathcote E, Buggisch P, Moorat AE, et al. Adefovir dipivoxil (ADV) alone and in combination with lamivudine (LAM) suppresses LAMresistant hepatitis B virus (HBV) replication: 16 week interim analysis [abstract]. J Hepatol 2002;36(Suppl 1):6. [38] Ying C, De Clercq E, Nicholson W, Furman P, Neyts J. Inhibition of the replication of the DNA polymerase M550V mutation variant of human hepatitis B virus by adefovir, tenofovir, L-FMAU, DAPD, penciclovir, and lobucavir. J Viral Hepat 2000;7:161–5. [39] Benhamou Y, Bochet M, Tubiana R, Thibault V, Suffisseau L, Sullivan M, et al. Tenofovir disoproxil fumarate suppresses lamivudine resistant HBV replication in patients coinfected with HIV/HBV. N Engl J Med 2003;348:177–8. [40] Dore GJ, Cooper DA, Pozniac AL, DeJesus E, Zhong L, Miller MD, et al. Efficacy of tenofovir disoproxil fomarate in anti-retroviral therapy naive and experienced patients coinfected with HIV-1 and hepatitis B virus. J Infect Dis 2004;189:1185–92. [41] Nelson M, Portsmouth S, Stebbing J, Atkins M, Barr A, Matthews G, et al. An open-label study of tenofovir in HIV-1 and Hepatitis B virus coinfected individuals. AIDS 2003;17: F7–10. [42] Ristig MB, Crippin J, Aberg JA, Powderly WG, Lisker-Melman M, Kessels L, et al. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alfa and lamivudine therapy have failed. J Infect Dis 2002;186:1844–7.

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Antiviral therapy in patients with chronic hepatitis B and cirrhosis Cindy J. Lai, MDa, Norah A. Terrault, MD, MPHb,* a

Division of General Internal Medicine, University of California, San Francisco, S357, 513 Parnassus Avenue, San Francisco, CA 94143-0538, USA b Division of Gastroenterology, University of California, San Francisco, S357, 513 Parnassus Avenue, San Francisco, CA 94143, USA

More than 350 million people worldwide are chronic carriers of hepatitis B virus (HBV), accounting for 5% of the world’s population [1]. Chronic carriers of HBV are at risk for cirrhosis, which ultimately develops in approximately 25% of cases. Deaths related to chronic HBV and its complications, including hepatocellular carcinoma (HCC), account for approximately 1 million deaths per year [3]. Patient characteristics that are associated with risk of progression to cirrhosis include older age, presence of bridging hepatic necrosis, and persistence of quantifiable HBV DNA in serum [4–7]. Once cirrhosis develops, mortality is high in untreated patients. Compensated patients have a 5-year mortality rate of 16%, and decompensated patients have a 5-year mortality rate of 86% [8]. The presence of older age, parameters related to decreased hepatic function (abnormal albumin and bilirubin), and portal hypertension (thrombocytopenia, splenomegaly, and ascites) independently have a negative impact on survival [8,9]. The presence of hepatitis B e antigen (HBeAg) in the serum is an additional poor prognostic factor in patients with compensated cirrhosis [8]. Given the reduced survival of patients with decompensated liver disease and/or HCC, the optimal means of preventing complications is by preventing infection. The positive impact of vaccination on the serious complications of chronic HBV infection has been demonstrated in Taiwan, where the incidence of childhood HCC has declined significantly since universal vaccination of infants was introduced [10]. For those with chronic infection, however, the emphasis must be on secondary prevention. The goals of antiviral therapy are to prevent or delay progression of cirrhosis and its associated including decompensated liver disease and HCC. * Corresponding author. E-mail address: [email protected] (N.A. Terrault). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.05.002

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Rationale for antiviral therapy in cirrhotic patients The mechanism of liver injury caused by HBV is not understood fully. The virus itself is not cytopathic; rather, hepatocyte injury is primarily caused by a host immune response that is not vigorous enough to eradicate virally infected cells, but sufficient to cause ongoing liver injury [11]. In individuals with cirrhosis, ongoing liver inflammation in the setting of reduced functioning hepatocyte mass may lead to liver decompensation. Thus, therapy of HBV-associated chronic hepatitis is directed at the sustained eradication of viral replication and reduction in liver inflammation and necrosis, to prevent or delay progression to end-stage liver disease. Additionally, because patients with decompensated cirrhosis frequently require liver transplantation (LT) as treatment, antiviral therapy has an important role in stabilizing patients before LT or, in some instances, delaying the need for LT. Finally, control of viral replication before LT is an important factor in the success of LT in patients with HBV infection. Patients with low or undetectable levels of HBV DNA before LT have a higher rate of survival than patients with high levels of viral replication prior to transplantation. A sustained reduction in circulating HBV DNA (undetectable by hybridization assays) and, in patients with HBeAg-positive cirrhosis, the clearance of HBeAg with or without development of hepatitis B e antibody (anti-HBe), are associated with a decrease in the HBV DNA found in hepatic tissue [12,13], reduced necroinflammatory activity on liver biopsy, and significantly improved clinical outcomes and survival [5,14,15]. Thus, in clinical trials, one of the primary endpoints is a reduction in necroinflammatory activity and fibrosis on liver biopsy (histological response). Other endpoints of importance include virological response (VR), loss of HBV DNA by non-PCR-based assays, normalization of serum alanine aminotransferase (ALT) (biochemical response [BR]), and if present, clearance of HBeAg with or without development of anti-HBe. Therapy should be considered in patients with HBV-induced cirrhosis if there is evidence of viral replication (usually levels [10e4 copies/mL and higher). The goals of therapy depend on the patient’s clinical status and the severity of liver disease. Antiviral therapy has been associated with: (1) delayed progression of cirrhosis in early, compensated cirrhotics; (2) clinical stabilization and even improvement in decompensated cirrhotics; (3) delayed need for LT in some transplant candidates; (4) reduced post-LT recurrence of HBV infection if initiated before and continued after LT; and (5) decreased recurrence of HCC after resection.

Interferon-alfa Interferon-alfa (IFN-a) is a cytokine with antiviral, immunomodulatory, and antiproliferative effects. In 1992, IFN-a was approved as therapy for chronic HBV in the United States, and it has been proven to be an effective

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treatment. Predictors of a favorable response include high pretreatment alanine transferase (ALT) level, low pretreatment serum HBV DNA level, active liver histology, adult-acquired HBV infection, absence of HBV precore mutants (HBeAg-positive), absence of hepatic decompensation, and HBV genotype B (as compared with genotype C) [16–20]. In a cirrhotic population, the benefits of IFN-a have to be weighed carefully against the risks of treatment. Approximately 30% to 50% of patients experience a flare of aminotransferase activity during treatment with increased ALT values at least twofold over their baseline values [17], and patients with decompensated cirrhosis appear to be particularly prone to flares, with a 50% occurrence rate in one series [21]. This flare is thought to be caused by an immune-mediated lysis of infected hepatocytes triggered by IFN-a and has been associated with an increased likelihood of sustained response to treatment in some studies [22]. Other adverse effects include flulike symptoms that usually resolve after 1 week, psychiatric manifestations including depression and anxiety, exacerbation of autoimmune disorders, and serious bacterial infections [21]. The increased risk of infections is likely caused by bone marrow suppression induced by IFN-a and to the underlying immunologic abnormalities that predispose cirrhotics to infections [23,24]. Interferon-alfa for hepatitis B e antigen-positive compensated cirrhosis Interferon-alfa has been proven to be effective and safe in certain subsets of patients with HBV-related liver disease, including those with HBeAgpositive compensated cirrhosis. Randomized trials of IFN-a treatment that included compensated cirrhotics have shown that the response rate of these patients is similar to that of noncirrhotics [14,17]. Not surprisingly, however, the risks of death and hepatocellular carcinoma were higher in patients with pre-existing cirrhosis than in those without cirrhosis [25]. The short-term outcome is favorable in patients with chronic HBV infection treated with IFN-a, including those with compensated cirrhosis. A meta-analysis of 15 randomized controlled trials evaluated 837 HBeAgpositive chronic HBV patients. A total of 730 patients were biopsied before therapy, and 12.7% were found to have cirrhosis. The meta-analysis revealed that IFN-a, at optimal doses of 5 to 10 MU three times per week for 4 to 6 months, led to clearance of HBeAg in 33% of IFN-treated patients, compared to only 12% of controls [26]. IFN-a also led to a significant loss of hepatitis B surface antigen (HBsAg) (7.8% versus 1.8% in controls) and detectable HBV DNA (37% versus 17%). In another study by Perrillo et al, 31% of cirrhotic patients who received IFN-a experienced seroconversion to anti-HBe and sustained loss of HBV DNA, similar to the 30% of noncirrhotics who achieved this goal [17]. Interferon-a therapy also has been shown to improve liver histology and long-term clinical outcomes in patients with HBV-related chronic hepatitis, especially in those who have a clearance of HBeAg with normalization of

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ALT levels. The degree of necroinflammatory activity and fibrosis is reduced after IFN-a therapy, particularly in those who have a sustained antiviral response [16,27]. In a small study of patients from Hong Kong that included 10 cirrhotics, 79 patients were treated with IFN-a with or without prednisone, and 36 remained untreated [16]. A significant reduction in lobular activity, periportal piecemeal necrosis, portal inflammation, and total histological score was seen in the responders. Although the difference was not statistically different between the groups, there was a trend toward reduced fibrosis on the post-treatment biopsy in those who responded to treatment, with 2 of 14 responders (14%) having a reduction in fibrosis, compared with 3 of 47 nonresponders (6%) and 1 of 29 controls (1%). Long-term follow-up of treated patients suggests significant clinical benefits. In a retrospective review from the National Institutes of Health, patients with cirrhosis who lost HBeAg with IFN-a had a significant improvement in 10-year survival when compared to nonresponders [15]. A long-term prospective study following 103 patients who were treated with various doses and schedules of IFN-a, found that liver-related complications were limited almost entirely to nonresponders [14]. Regardless of base line histology, survival was significantly longer and liver-related complications were very rare in patients who cleared HBeAg after IFN-a therapy. Six of 103 treated patients (all persistently HBeAg-positive) died of liver failure, and two needed LT. Overall, patients with compensated cirrhosis appear to derive significant benefits from treatment with IFN-a. Rates of HBeAg seroconversion and sustained suppression of HBV DNA are similar between cirrhotic and noncirrhotic patients. Patients who respond to treatment have improved histology and reduced rates of liver-related complications [28]. Interferon-alfa for hepatitis B e antigen-negative, hepatitis B virus DNA-positive (precore mutant) compensated cirrhosis Interferon-alfa is associated with suboptimal virological and histological responses in patients with HBeAg-negative variant infection because of high rates of relapse after treatment discontinuation. The most common HBeAgnegative variants have mutations in the pre-C/C (precore) gene that prevent formation of HBeAg; such precore mutants are characterized by the presence of high levels of circulating HBV DNA despite the absence of HBeAg and anti-HBe. Patients with the HBeAg-negative variant form of chronic HBV infection typically have recurrent fluctuations of serum HBV DNA and ALT levels. HBeAg-negative chronic HBV patients are plagued by a particularly aggressive clinical course, putting them at higher risk for complications related to liver disease, including hepatic decompensation and HCC [29,30]. Although the end-of-treatment VR and BR rates range from 60% to 90% in all-comers with HBeAg-negative liver disease who receive up to 6 months

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HBeAg-positive or negative, HBV DNA-positive cirrhosis

Child’s Class B/C (Decompensated)

Child’s Class A (Compensated)

IFN-α or Lamivudine or Adefovir dipivoxil

Sustained virological response

Post - LT

Long-term Lamivudine or Adefovir Lamivudine-resistant HBV strains Improved liver disease

Monitor

Clinical deterioration

Lamivudine or Adefovir dipivoxil + HBIg prophylaxis

Sustained virological response

Longterm lamivudine

Continue Add/Change Lamivudine or to add/change to Adefovir Adefovir dipivoxil dipivoxil

Lamivudineresistance

Add Adefovir dipivoxil

Adefovir dipivoxilresistance

Add Lamivudine

+/- HBIg

Improvement No improvement

LT

Continue Adefovir dipivoxil

HBIg = hepatitis B immunoglobulin LT = liver transplant

Fig. 1. Management of HBeAg-positive or negative, HBV DNA positive cirrhosis. The HBV DNA levels are typically 100,000 copies/mL or higher. For HBeAg-positive cirrhosis, IFN, lamivudine or adefovin are options if Child’s class A cirrhosis but IFN is not recommended Child’s Class B or C cirrhosis. For HBeAg-negative cirrhosis, lamivudine or adefovir are favored for treatment as longer duration therapy is generally required.

of IFN-a (as measured by hybridization assays), most patients relapse within 12 months of ending therapy, thus leading to a sustained response rate of only 10% to 15% in most studies [29,31–33]. Subsequent studies have shown that longer courses of IFN-a can increase sustained response (SR) rates to 20% to 25% [34]. In an Italian pilot study using a 24-month course of IFN-a2b therapy (6 MU, three times per week), sustained suppression of HBV DNA (as measured by hydridization assay) occurred in 38% of 21 treated patients compared with 10% of untreated controls, but adverse effects were common, leading to early discontinuation of therapy in 25% of patients [35]. In a subsequent, uncontrolled study of 101 HBeAg-negative Italian patients, 60% of whom had bridging fibrosis or cirrhosis (F4 to F6

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on Ishak scoring system [36]), a 24-month course of IFN-a2b (6 MU, three times a week) similarly resulted in a sustained VR and BR in 30% of patients [37]. Sustained BR and VR rates were similar in patients with cirrhosis (34%) and without cirrhosis (27%). Despite the high relapse rates, an IFN-induced sustained remission may lead to improved clinical outcomes in patients with HBeAg-negative cirrhosis. Several studies have shown that progression of chronic hepatitis to cirrhosis is slower in patients who respond to IFN-a and that complications related to cirrhosis are reduced [7,37,38]. In a cohort study of 164 HBeAg-negative patients who were followed for a mean of 6 years, IFN-treated patients were found to have a 2.5-fold reduction in development of cirrhosis-related complications compared with untreated patients [7]. In another study, none of the 30 sustained responders had progression of liver disease (ie, chronic hepatitis progressing to cirrhosis and decompensation of cirrhosis), compared with 11 of 41 (27%) nonresponders or relapsers during 4.5 years of follow-up [37]. The rate of development of HCC was the same in responders and nonresponders (7%). Predictors of liver-related complications were failure to respond to IFN-a (hazard ratio, 7.8; 95% confidence interval [CI], 1.8 to 34.0, P = 0.006) and high baseline scores for fibrosis (hazard ratio, 1.71, 95% CI, 1.17 to 2.50, P = 0.05). The improved clinical outcomes seen in those who responded to IFN-a must be tempered by the observation that although IFN-treated cirrhotic patients fared better than untreated patients, the survival in patients with cirrhosis remained worse compared with those without. With only an overall 20% to 25% sustained response with any IFN-a regimen because of high rates of post-treatment relapse, IFN-a therapy for patients with HBeAg-negative variant infection is far from satisfactory [30,39,40]. Response to IFN-a treatment, however, is associated with improved clinical outcomes in these patients. If IFN-a is selected for treatment, HBeAg-negative patients should be treated for at least 12 months, and perhaps up to 24 months, using a dose of 6 MU three times per week. Given the need for prolonged therapy, orally administered antiviral drugs with low rates of adverse effects, such as lamivudine and adefovir dipivoxil, may be better treatment options for these patients.

Impact of interferon-alfa on preventing hepatocellular carcinoma The effect of IFN-a on the development of HCC in patients with HBVrelated liver disease remains uncertain. Individual studies suggest a benefit (Table 1), but a meta-analysis of seven nonrandomized controlled trials, suggested that IFN-a did not decrease the risk of HCC in this population [43]. The potential mechanisms by which IFN-a may induce HCC include viral eradication, reduction in necroinflammation, or direct activity that has been demonstrated in vitro and in vivo in human hepatoma cell lines [41,42].

Table 1 Interferon-alfa and hepatocellular carcinoma in hepatitis B virus-related cirrhotics Mean (range) follow-up (mo)

3 MU daily
10 days/mo every 3 mo 10 MU three times weekly
6 mo [300 MU total in 60% of patients 6 MU twice weekly
[6 mo (for 69% of patients) 3 MU weekly
3 mo

518 (86%)

4–6 MU/m2 daily
3 mo 6–10 MU three times weekly
20–26 wks total 655 MU

Study/authors

Treatment dose and duration

Oon, 1992 [112]

NRCT

Mazzella, 1996 [113] Fattovich, 1997 [114] Ikeda, 1998 [44]

NRCT

HHC Study Group, 1998 [115] Lin, 1999 [25] Benvegnu, 1998 [116] Di Marco, 1999 [117] Papatheodoridis, 2001 [38]

Lampertico, 2003 [37]

NRCT NRCT

NRCT

RCT NRCT NRCT

N (%) HCC in treated

N (%) HCC untreated

P Value

12 (12–60)

0/600 (0%)

10/180 (6%)

P \ 0.001

34 (100%)

49 (12–119)

2/34 (6%)

4/28 (14%)

NS

40 (100%)

86 (80–92)

3/40 (8%)

4/50 (8%)

NS

94 (100%)

84 (6–168)

10/94 (11%)

51/219 (23%)

P = 0.012

49 (100%)

NA

8/49 (16%)

18/97 (19%)

NS

7 (10%)

89 (54–124)

1/67 (1.5%)

4/34 (12%)

P = 0.043

10 (100%)

72 (48–95)

0/10 (0%)

4/18 (22%)

NS

26 (of 109, 24%)

93 (6-180)

2/26 (8%)

6/60 (10%)

NS

26/209 (12%) includes deaths caused by HCC 7/101 (7%)

20/195 (10%)

NS

NA

NA

NRCT

Median 3 MU three times weekly
24–48 wks

57 (of 209, 27%) HBeAg-negative

72 (12–162)

NRCT

6 MU three times weekly
24 mo

61 (60%) HBeAg-negative

68 (5–136)

635

Abbreviations: NS, not statistically significant; NA, not available; NRCT, nonrandomized controlled trial; RCT, randomized controlled trial.

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Number with cirrhosis in treated cohort (%)

Study design

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Although the HCC preventive effect of IFN-a has been suggested in some studies, most studies have methodological issues that limit interpretation of the results. In a study of 313 patients from Japan, HBV-related cirrhotic patients treated with long-term IFN-a for at least 6 months had a 5-year and 10-year hepatocarcinogenesis rate of 7% and 17%, respectively, compared with 19.6% and 30.8% in the untreated cohort (P = 0.0124) [44]. Although the study did not evaluate the effect of therapy on viral replication, IFN-a therapy itself was found to be a variable independently associated with a rate reduction in carcinogenesis compared with no therapy (risk ratio 0.39, 95% CI, 0.17 to 0.92, P = 0.03). A large retrospective cohort study of 209 IFNtreated and 195 untreated patients with HBeAg-negative liver disease, including 27% cirrhotics in the IFN-treated group, showed that patients who had a sustained BR to IFN-a had significantly better survival and a lower rate of development of HCC than patients without a sustained BR or untreated patients (1.8% versus 10.5% versus 8.1%) over a mean followup of 6 years [38]. Data in patients with chronic hepatitis C virus (HCV) infection show that IFN-a therapy given after resection of HCC reduces the rate of HCC recurrence [45–47]. Preliminary results of a randomized controlled trial of patients with HBV-related HCC after curative resection show that longterm IFN-a treatment improves disease-free survival that is not associated with HBeAg seroconversion [46]. Although promising, the effect of IFN-a on the postresection recurrence rate of HCC in HBV-related cirrhosis requires further study. Interferon-alfa in patients with chronic hepatitis B virus and decompensated liver disease Patients with decompensated HBV-related liver disease are difficult to treat and carry a poor prognosis, with a 5-year survival rate of 14% to 35% [4,8]. IFN-a therapy is contraindicated in patients with severely decompensated liver disease, because the risks of worsening hepatic failure or bacterial sepsis outweigh the potential benefits of virological or biochemical remission [2,21,48]. Although successful treatment of patients with mildly decompensated liver disease (Child-Pugh Class A) has been demonstrated using IFN-a, this is not recommended routinely because of the potential risk of adverse events and the availability of safer antiviral agents. Treatment of cirrhotic patients with mild or early decompensation using very low doses (less than 1 MU) and careful titration may result in the loss of HBV DNA and normalization of serum aminotransferase levels often leading to clinical stabilization and improvement in liver function [2,21,48,49] (Table 2). In the first study known to include decompensated cirrhotics, six of seven patients with decompensated cirrhosis experienced loss of HBV DNA during low-dose IFN-a therapy (1 to 2.5 MU three times per week, titrated up to 5 MU in some patients), and 50% of responders

Table 2 Treatment of Decompensated HBV-Related Cirrhosis with Interferon-a Number treated and severity of disease

% Virologic response* (number/cases)

Outcomes

(IFN) 2b 1 MU three times weekly titrated up to 5 MU three times weekly as tolerated (for 1 mo after SVR) (IFN) 2–5 MU three times weekly (16 wks)

7

71% (5/7); loss of HBeAg in 4/7

Improved clinical function: 3/5 responders

33% (6/18)

Improved clinical function in responders

38% (10/26); seroconversion HBeAg to anti-HBe in 77% (10/13)

Combination of loss of HBV DNA, biochemical improvement, and clinical stabilization: 5/5 (100%) Child’s A, 5/15 (33%) Child’s B, 0/6 (0%) Child’s C Combination of sustained loss of HBV DNA and HBeAg (if present) and biochemical improvement: 10/15 (66%). Improved clinical function: 7/10 (70%)

Study design

Nevens, 1993 [48]

UC

Hoofnagle, 1993 [21]

UC

Perrillo, 1995 [2]

UC

(IFN) low-dose, titratable (range 0.5–3 MU every other day, with further advance as tolerated)

Marcellin, 1997 [53]

UC

(IFN) low-dose (3 MU), three times weekly, titratable (3–48 mo)

1 11 6 5 15 6

Child’s Child’s Child’s Child’s Child’s Child’s

A B C A B C

4 Child’s A 8 Child’s B 3 Child’s C

67% (10/15)

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Treatment (dose and duration)

Author, Year

Abbreviations: UC, uncontrolled study; MU, million units; SVR, sustaine virologic response. * Defined as loss of HBV DNA by hybridization assay. 637

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achieved a sustained virologic, biochemical, and clinical response up to 16 months after treatment [48]. In another study of decompensated patients, 12 of 18 patients with clinically apparent cirrhosis had an end-of-treatment response to IFN-a [50]. Six (33%) of the responders, five of whom had Child’s Class A or B cirrhosis, had a sustained loss of HBV DNA and HBeAg, normalization of liver function tests, and improvement of clinical symptoms during treatment and at 1 year post-treatment. The remaining six responders relapsed in the year of follow-up. These apparent benefits of low-dose IFN-a therapy in decompensated cirrhosis are outweighed largely by the risk of serious adverse effects and poor tolerability, particularly when standard doses of IFN-a are used [51]. Acute flares of hepatitis have been reported in 50% to 86% of patients, and the risk of IFN-induced worsening of hepatic decompensation is higher in those with advanced cirrhosis compared with those with early wellcompensated cirrhosis [2,21]. Serious infections, including spontaneous bacterial peritonitis and septicemia, were seen in nearly 30% to 50% of patients [21,52]. Overall, tolerance of therapy is poor; in one study, 50% of cirrhotic patients had to discontinue therapy early because of such adverse effects [21]. Regimens of IFN-a that start with very low doses and titrate to tolerability may increase the number of patients who can complete a course of therapy. In a multicenter study of 26 patients with HBV-related cirrhosis treated with low-dose IFN-a-2b beginning at 0.5 MU on alternate days with titration according to patient’s tolerance, a sustained loss of HBV DNA was obtained in 38% and a transient loss of HBV DNA in 15% [2]. The median peak dose achieved by Child’s Class A patients was 3 MU every other day (range 3 MU on alternate days to 3 MU every day) and the median peak dose achieved by patients with Child’s Class B was 5 MU on alternate days (range 0.5 MU on alternate days to 5 MU daily). Both groups required frequent dose modifications but few discontinued treatment. Patients with Child’s Class C required frequent dose modification, and 75% discontinued therapy because of adverse effects. Patients with Child’s Class A cirrhosis were most likely to achieve a sustained loss of HBV DNA, reduction in ALT levels, and clinical stabilization. Patients with more advanced decompensation responded poorly; only five patients (33%) with Child’s B Class and no patients with Child’s Class C had a sustained response to IFN-a. Over 75% of the HBeAg-positive patients who cleared HBV DNA from their serum during therapy eventually seroconverted to anti-HBe. Compared with standard doses of IFN-a used in the other studies described, the frequency of adverse effects with low-dose IFN-a was lower. Still, serious bacterial infections occurred in 12% of patients, and acute hepatitis flares occurred in 12% of patients. In another study by Marcellin et al, 15 decompensated cirrhotics (four Child’s Class A, eight Class B, three Class C) were treated with prolonged (3 to 48 months) of IFN-a at low doses (3 MU) [53]. Ten patients (66%) cleared HBV DNA and HBeAg and experienced

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normalization of ALT levels, and 7 of 10 of these responders had marked clinical improvement with few complications. In summary, IFN-a can lead to sustained virological and biochemical responses in some patients with decompensated cirrhosis, but no longer is recommended routinely, because alternative agents that are tolerated better in patients with decompensated cirrhosis are available. Thus, lamivudine and adefovir dipivoxil are the agents of choice in patients with cirrhosis with any degree of liver decompensation. There may be a limited role for IFN-a in the treatment of multi-drug-resistant HBV, as treatment options for this subgroup of patients are limited. If IFN-a therapy is undertaken in a patient with decompensated cirrhosis, only patients with Child’s class A cirrhosis should be treated, and IFN-a should be initiated at low doses (no more than 1 MU) and titrated up slowly to tolerability. Gradual escalation of IFN-a is essential to minimize the frequency of adverse events and treatment discontinuation. Interferon-alfa and hepatitis B immunoglobulin prophylaxis for liver transplant candidates Patients with decompensated HBV-related liver disease are candidates for LT, but most transplanted patients have recurrence of HBV infection of allografts and reduced survival if there is evidence of replicating virus before transplant. Passive immunoprophylaxis with HBV immunoglobulin (HBIg) reduces the rates of recurrent HBV infection, but a proportion of patients fail this therapy. Those with active replication before transplantation are at highest risk of recurrent HBV infection [54–57]. Thus, pretransplant antiviral therapy with agents such as IFN-a, lamivudine, and adefovir, has been combined with post-transplant HBIg in an effort to reduce the risk of HBV recurrence. Results vary with the antiviral agent used. There is a lack of uniform efficacy of IFN-a in preventing recurrence of HBV infection after LT [58,59]. This, coupled with the risk of adverse events related to IFN-a treatment, has led to an abandonment of IFN-a as a component of HBV prophylaxis in favor of newer antiviral agents.

Lamivudine Lamivudine, an oral nucleoside analog that acts by inhibiting HBVRNA-dependent DNA polymerase, was the first oral agent approved for the treatment of chronic HBV infection. Lamivudine has been shown to be a safe and effective therapy in patients with compensated and decompensated cirrhosis and in LT recipients [60–64]. Treatment efficacy is limited by the development of lamivudine resistance with extended periods of drug administration. This is a particularly important issue for patients with decompensated cirrhosis, as long-term use frequently is required.

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After one year of lamivudine therapy, 14% to 32% of patients have resistant HBV infection, and the incidence of resistance is more than 50% after 3 years in HBeAg-positive and HBeAg-negative patients [65–67]. The emergence of lamivudine resistant virus is indicated by the reappearance of HBV DNA and rise in ALT levels, but levels are often lower than seen with the initial wild-type virus [68,69]. In some reports, clinical deterioration and worsening of histology occurred [38,70], but in other reports, histological improvement was maintained even after the emergence of viral resistance [71]. The clinical significance of breakthrough HBV infection varies with the underlying histological stage of disease. Patients with cirrhosis are at risk for liver decompensation when lamivudine resistance develops [72,73]. Both compensated and decompensated cirrhotic patients on lamivudine require close monitoring for the development of resistance, as the clinical consequences can be more severe. Lamivudine for compensated hepatitis b virus-related cirrhosis The available data suggest that patients with HBV-related compensated cirrhosis respond to lamivudine similar to patients without cirrhosis, regardless of HBeAg status [60,68,74]. Three randomized controlled trials of 731 treatment-naive patients, 7% to 13% of whom had advanced fibrosis or cirrhosis, have shown that a 12-month course of lamivudine at a daily dose of 100 mg led to HBeAg seroconversion (defined as loss of HBeAg, detection of anti-HBe, and loss of HBV DNA measured by non-PCR assays), occurred in 16% to 18% of treated patients compared with 4% to 6% of untreated patients [60,68,74], and rates of sustained suppression of HBV DNA were 44% in treated patients compared with 16% in controls [60]. The rate of HBeAg seroconversion improved with increasing duration of therapy, high pretreatment ALT levels, and low pretreatment HBV DNA levels [75,76]. Lamivudine is also effective for patients with HBeAgnegative liver disease, including cirrhotics, with approximately two-thirds of treated patients achieving loss of detectable HBV DNA, as measured by non-PCR-based assays, and improvement of biochemical markers after a 12-month course of lamivudine. However, only approximately 10% sustain these effects after stopping treatment [67,71,77,78]. Detailed information on the histological benefits of lamivudine treatment is available. Lamivudine improves the degree of necroinflammation and fibrosis, regardless of HBeAg status [61,71,79]. In the large randomized controlled trials mentioned previously, lamivudine-treated patients had a higher rate of histologic response than controls (52% to 56% versus 23% to 25%, P \ 0.001) and were less likely to have worsening of fibrosis (P = 0.01). In an open-label Japanese study, 7 of 20 patients (35%) had regression of fibrosis [79]. In another study of 63 lamivudine-treated HBeAgpositive patients who underwent three liver biopsies over a period of 3 years, 36 of 63 patients (57%) showed an improvement in necroinflammatory

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activity, defined as a 2-point reduction in the histologic activity index (HAI), after 1 year of therapy [61]. Furthermore, bridging fibrosis and cirrhosis improved by at least one fibrosis level (on a 4-point HAI scale) in 12 of 19 patients (63%) and 8 of 11 patients (73%) respectively. Only 2% showed progression to cirrhosis and 9% to bridging fibrosis, all of whom had developed lamivudine-resistant mutations. Lamivudine also improves fibrosis in HBeAg-negative patients. In the randomized controlled trial by Tassopoulos et al, analysis of ranked assessment of pretreatment and posttreatment biopsy pairs revealed that 11% of patients had regression of fibrosis; 86% were stable, and only 2% had worsening of fibrosis [71]. In summary, lamivudine is effective in inducing a sustained suppression of HBV DNA and normalization of liver enzymes in patients with HBVrelated cirrhosis, but the risk of virological breakthrough increases with duration of therapy. Reversal of fibrosis or lack of histological progression is seen in most treated patients, but maintenance of the virological response appears to be important in obtaining these histological results. Lamivudine in decompensated cirrhosis and impact on need for liver transplantation Lamivudine has been shown to effectively inhibit circulating HBV DNA and to significantly improve liver function and clinical status in patients with end-stage HBV-related liver disease, irrespective of HBeAg status [80–84] (Table 3). In addition to reversing liver decompensation, lamivudine may delay and reduce the need for LT [80–82,85]. Nearly all patients achieve a reduction in HBV DNA levels after starting lamivudine [63]. Among 35 patients with actively replicating HBV infection and decompensated cirrhosis with Child-Pugh-Turcotte (CPT) scores of at least 8 (10 with Child’s Class B, 25 Child’s Class C) who were treated with 100 or 150 mg of lamivudine, liver function and clinical status improved significantly (defined by CPT reduction of at least 2 points) in 22 of 23 patients treated for at least 6 months (mean follow-up period 19 months) [81]. Of the remaining patients, seven (20%) required transplantation, and five (14%) died within the first 6 months of lamivudine treatment. In another smaller uncontrolled study, 13 consecutive HBV DNA-positive patients with CPT score greater than or equal to 10 (Class C) were treated with prolonged lamivudine at 150 mg daily for a mean 17.5 months without LT (range 3 to 39 months) [80]. Treatment led to a sustained suppression of HBV DNA in 11 of 12 patients, and a significant improvement of liver function (defined as a decrease in CPT score of at least 3) in 9 of 13 (69%) patients. Improvement in clinical status among these more severely decompensated cirrhotics occurred gradually and was most apparent after 6 to 9 months of treatment. Five of 13 patients (38%) improved sufficiently so as to be placed on the inactive list for transplantation. To address the potential selection bias associated with earlier uncontrolled studies, Yao et al evaluated the effect of lamivudine on 23

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Author, Year

Study design (number in sample)

Treatment (duration)

Number treated and severity of disease

Villeneuve, 2000 [81]

UC (35)

Lamivudine 100 or 150 mg daily (mean duration 19 mo)

10 Child’s A 25 Child’s C

Kapoor, 2000 [82]

UC (18)

Lamivudine 150 mg daily (mean duration 17.9 mo)

18 Child’s B

Sponseller, 2000 [118]

UC (5)

Lamivudine 100 mg daily (mean duration 36–77 wks)

1 Child’s A 2 Child’s B 2 Child’s C

Yao, 2000 [80]

UC (13)

Lamivudine 150 mg daily (mean duration 17.5 mo)

13 CPT  10 (median score = 11)

% Virologic response* (number/cases) 100% after 6 mo of treatment; 6/13 HBeAgþ seroconversion 100% after 2 mo of treatment; 3/18 HBeAgþ seroconversion 100%

100%; 3/7 HBeAg þ loss of HBeAg

Outcomes Improved clinical function (decrease in CPT  2): 96% (8/8 Child’s A, 14/15 Child’s C). Mean CPT decreased from 8.3 to 6.7, decreased morbidity and hospitalization for liver complications Improved clinical function (decrease in CPT 4-5): 60%. Improved liver function tests: 60%. OLT in 1 patient. Improved clinical function (decrease CPT  3, symptoms): 9/13 (69%). OLT in 2/13. Break through infection in 1 patient (clinically stable)

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Table 3 Treatment of decompensated hepatitis B virus-related cirrhosis with lamivudine or adefovir dipivoxil

Cohort with historical controls (23)

Lamivudine 150 mg daily (mean duration 13 mo)

23 CPT 11 (range 10–13)

100%; 4/16 (25%) loss of HBeAg

Andreone, 2002 [119]

UC (25)

Lamivudine 100 mg daily (mean duration 12 mo)

25 CPT 9 (range 7–13), all HBeAg negative

92% at 3 mo (by hydridization assay)

Schiff, 2003 [101]

UC (128)

Adefovir 10 mg daily (mean duration 18.7 weeks, max 72)

25 Child’s A 26 Child’s B 16 Child’s C

81% at 48 wks of treatment

Abbreviations: UC, Uncontrolled; CPT, Child-Pugh-Turcotte score. * Loss of HBV DNA by hybridization assay.

Improved clinical function (decrease CPT 3): 61% treated versus 0% controls, possible improved time to death or OLT. OLT: 35% treated versus 74% controls (P = 0.04). Improved time to death or OLT (P \ 0.001). Breakthrough infection: 10% (clinically stable) Improved clinical function (decrease CPT = 1) and biochemical tests. Improved time to OLT: 13/25 (52%) Improved or stable clinical function: 92% at 24 weeks. Improved survival: 84% at 1 year. No adefovir-resistant mutations detected after 1 year of treatment.

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Yao, 2001 [85]

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consecutive patients with CPT of at least 10 and detectable HBV DNA in sera (measured by bDNA or Digene assays) compared with a matched, historical control cohort [85]. Improved liver function (defined as decrease in CPT of at least 3) again was observed in most treated patients (61%) versus none of the controls (P \ 0.001), and time to death or LT was significantly longer in treated patients than in controls (P \ 0.001). Specifically, at 14 months after initial presentation, 65% of treated patients were alive without LT (95% CI, 43% to 87%), compared with the outcomes of historical controls, all of whom had died or required LT. Although these smaller studies suggest that the need for LT may be reduced with lamivudine therapy, not all studies have confirmed this survival benefit [64]. In a recent large retrospective, multi-center analysis of 162 lamivudinetreated and 147 untreated HBsAg-positive patients awaiting transplantation, lamivudine treatment was not associated with improved pre-LT or LT-free survival [64]. Subanalysis, however, showed that patients with less advanced liver failure derived clinical benefit from lamivudine, with a delay in the need for transplantation. This suggests that the benefit of lamivudine, in delaying the need for transplantation may depend on the severity of disease at the time of treatment initiation and on the total treatment duration. Because clinical improvement tends to lag behind virological response, patients with severely decompensated liver disease may die before the clinical benefits of lamivudine therapy can be realized. The development of lamivudine resistance caused by YMDD mutations can occur in decompensated cirrhotics as in any other patient group on lamivudine therapy. Approximately 10% to 27% of decompensated HBVrelated cirrhotic patients treated with lamivudine developed breakthrough infection after 8 to 12 months of treatment [64,81,83,85]. The clinical consequences of lamivudine resistance in a cirrhotic population are variable [50,72]. Short-term outcomes of patients who develop YMDD mutations are generally favorable [64,83,85,86]. In a study by Villeneuve et al, only 3 out of the 23 patients treated for at least 6 months with lamivudine developed YMDD mutations, and these patients continued to have stable liver function during follow-up of mean 19 [81]. In the study by Yao et al, 2 of 20 patients (10%) with quantitative HBV DNA at baseline had reappearance of HBV DNA after a median follow-up of 13 months, but they maintained stable liver function in the short-term [85]. Clinical deterioration in cirrhotic patients who have developed resistance to lamivudine has been reported, however [72,85]. In the large North American study by Fontana et al, breakthrough infection was reported in 11% of patients awaiting transplant after a median of 12 months of lamivudine treatment [64]. Of 18 patients who developed breakthrough infection, one patient died of worsening hepatic failure, and one was removed from the transplant list because of clinical deterioration. Lamivudine is very well-tolerated in patients with decompensated cirrhosis [82,85,86]. A few patients have shown liver function deterioration

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with an increase in bilirubin or CPT score while on lamivudine, but this decline appears to be related to decompensation due to lack of response to lamivudine, rather than to the drug therapy itself [85]. Lamivudine monotherapy as prophylaxis in liver transplant patients Lamivudine monotherapy is moderately effective in reducing the rate of reinfection of the allograft [70,86,87]. In a large United States–Canadian multi-center trial, 77 transplant candidates with HBsAg-positive liver disease were treated with lamivudine while waiting for LT and continued on therapy post-transplantation [70]. Of the 47 patients who eventually underwent LT, 51% and 55% were positive for HBeAg and HBV DNA in the serum, respectively, before lamivudine therapy. The presence of serum HBV DNA at baseline was an important determinant of post-transplant recurrence. The reinfection rate (presence of HBsAg) was 60% at treatment week 156 in patients who were positive for HBV DNA by quantitative assay (lower limit of quantitation approximately 105 to 106 copies/mL) at baseline, compared with 0% who were negative for HBV DNA at baseline. The efficacy of lamivudine monoprophylaxis is limited by the emergence of lamivudine-resistant YMDD mutants with prolonged therapy. The emergence of lamivudine resistance in patients awaiting transplantation may affect clinical status adversely and increase the risk of recurrent HBV infection post-transplantation. Among LT recipients on lamivudine monotherapy, the reported incidence of HBV polymerase mutants varies from 10% to as high as 27% after 8 to 12 months of therapy [64,70,86,88–91]. In the United States–Canadian study of lamivudine monotherapy pre- and post-transplantation, two deaths occurred in transplant recipients had developed YMDD mutants, but these were attributed to myocardial infarction and recurrent HCC [70]. Others have reported significant clinical deterioration and even death caused by recurrent HBV in LT recipients developing lamivudine resistance [83,92]. Thus, while the short-term outcome of patients with lamivudine resistance is favorable in most patients, there is a risk of clinical deterioration in a proportion in others. Lamivudine as part of combination prophylaxis in liver transplant recipients The combination of lamivudine and HBIg prophylaxis is more efficacious than lamivudine monotherapy in preventing recurrent HBV infection in LT recipients, especially those with detectable HBV DNA or HBeAg pre-LT [62,93–95]. A retrospective review of 166 LT recipients at a single center also noted improved recurrence-free survival in patients receiving combination therapy (lamivudine 150 mg daily and HBIg) with 1- and 3-year recurrencefree survival rates being 94% and 83%, respectively, compared with 75% and 65% in patients receiving lamivudine monotherapy [62]. Using fixed-dose or targeted levels of anti-HBs to determine HBIg dose, combination HBIg and lamivudine is highly effective in preventing reinfection, with a graft survival

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rate of approximately 90% at 2 years. By multivariate analysis, urgent United Network for Organ Sharing (UNOS) status and presence of HCC adversely affected patient and graft survival rates, whereas combination prophylactic therapy had a strong positive association with patient and graft survival rates and recurrence-free survival rates [62]. Thus, combination prophylactic therapy with lamivudine and HBIg is an effective strategy to prevent recurrence of HBV after transplant, although the minimum dose of HBIg required still is debated. Also unclear is the optimal timing of initiation of lamivudine therapy pre-transplantation, because there is a risk of breakthrough infection increases with duration of lamivudine and treatment breakthrough before transplantation may increase the risk of prophylaxis failure with combination lamivudine and HBIg.

Adefovir dipivoxil Adefovir dipivoxil, an oral nucleotide analog of adenosine monophosphate, inhibits HBV replication by inhibiting reverse transcriptase and DNA polymerase activity levels [96,97]. It has in vitro and in vivo activity against lamivudine-resistant HBV and wild-type HBV [97,98]. Adefovir dipivoxil is associated with histologic, virologic, and biochemical improvements in diverse patient groups, including treatment-naıı¨ ve, lamivudine-resistant, and pre- and post-LT groups, irrespective of HBeAg status [99–102]. The recommended treatment dose of adefovir is 10 mg daily for 48 weeks. Approximately 25% of patients who discontinue adefovir dipivoxil may have reversible aminotransferase elevations that usually occur within 3 months of drug discontinuation [98,103]. The acute hepatitis flare generally is not associated with symptoms or hepatic decompensation [98]. The drug is tolerated very well. Renal toxicity is rare at the HBV-approved dose of 10 mg daily, but dose modifications are needed for patients with renal insufficiency. Adefovir dipivoxil in hepatitis B virus-related liver disease Adefovir dipivoxil treatment is associated with histologic improvements, suppression of HBV DNA, and normalization of ALT levels in most patients. In an international trial of 515 patients with HBeAg-positive liver disease, including patients who had failed IFN-a, patients were randomized to placebo, 10 mg of adefovir, or to 30 mg of adefovir for 48 weeks [100]. The proportion of patients with cirrhosis was not given, but the median fibrosis score was low (1 on a 4-point HAI scale). Compared with placebo, 10 mg of adefovir led to histologic improvement in necroinflammation (53% versus 25%) and fibrosis (41% versus 26%). Flares of amniotransferases (above 10 times the upper limit of normal) occurred in 10% of patients on the 10 mg dose but generally were tolerated well, and overall discontinuation due to adverse effects occurred in only 2% of patients.

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Adefovir dipivoxil also has been shown to be effective in patients with chronic HBeAg-negative liver disease [29]. In a multi-center trial of 185 patients treated with 10% and 11% of adefovir-treated and untreated patients having cirrhosis at baseline, and treated adefovir with 10 mg for 48 weeks, significant improvement in histology (64% versus 33%), clearance of HBV DNA (51% versus 0%), and biochemical normalization (72% versus 29%) respectively were seen [100]. The relapse rate following discontinuation of adefovir dipivoxil is not known but is predicted to be similar in this difficult-to-treat patient group. Adefovir dipivoxil for lamivudine-resistant chronic hepatitis B virus liver disease Adefovir dipivoxil has been associated with significant clinical improvement in several groups with lamivudine-resistant chronic HBV, including patients with compensated liver disease, and in the pre- and post-transplant settings. In an international, open-label study of 324 patients, 128 patients who were awaiting LT (all of whom had decompensated liver disease as evident by Child’s Class B or C) and 196 who had received LT were treated with adefovir dipivoxil for a mean duration of 18.7 weeks [101] (see Table 3). For those who received 48 weeks of treatment, 81% of the pre-LT and 34% of the post-LT cohort attained undetectable serum HBV DNA to less than 400 copies/mL (by Roche Amplicor PCR). Impressively, the CPT score stabilized or improved in over 90% of patients in both cohorts, and 1-year survival was 84% for pre-LT and 93% for post-LT patients. When compared to historical controls, all patients who received adefovir dipivoxil had improved survival, and post-LT patients had a reduction in rate of recurrent HBV infection. No adefovir-resistant mutants were identified during 1 year of therapy. Resistance to adefovir dipivoxil Emergence of adefovir resistance has been reported recently [104]. The incidence of drug resistance is estimated to be 1.6% after 2 years of treatment. The signature mutation occurs in domain D of the polymerase (N236T) and is associated with rebound in HBV DNA levels and in vitro resistance to adefovir. Interestingly, the adefovir-resistant HBV has in vivo sensitivity to lamivudine. Other mutations have been identified, but their clinical significance is not known.

New antiviral agents In addition to IFN-a, lamivudine, and adefovir dipivoxil, several other antiviral agents are under investigation for treatment of chronic HBV liver disease, including additional agents with activity against lamivudine-resistant

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HBV. Data on the safety and efficacy of these drugs in a cirrhotic population are not available. Entecavir Entecavir, an oral nucleoside analog, has been shown to have in vitro and in vivo efficacy in patients with chronic hepatitis B, including those with lamivudine-resistant mutants [105]. In a controlled trial of 169 patients, a 24-week course of entecavir monotherapy led to greater suppression of HBV DNA than lamivudine [105]. In a randomized controlled trial of 181 patients who had failed lamivudine, in which patients were assigned to three different doses of entecavir or continued on lamivudine, a 48 week course of entecavir at any dose was more effective than lamivudine in reducing and suppressing HBV DNA levels, and no virologic breakthroughs were detected at the 1 mg dose at end of treatment [106]. Entecavir is being evaluated for treatment of HBeAg-positive and HBeAg-negative liver disease in phase III clinical trials. Emtricitabine Emtricitabine, the 5-fluorinated derivative of lamivudine, appears to have higher potenay and a lower rate of drug resistance than lamivudine. However, cross-resistance with lamivudine exists. In one study, a 48-week course of emtricitabine at three different doses led to a reduction of HBV DNA levels in all groups [107]. Study results showed that serum HBV DNA was undetectable in 61% of patients receiving the 200 mg dose. Loss of HBeAg occurred in 40% of patients, which increased to 51% of patients who continued on emtricitabine for another 48 weeks [108]. At the end of 2 years of treatment, the rate of HBeAg seroconversion was 29%. Phase III studies are ongoing. Tenofovir disoproxil fumarate Tenofovir disoproxil fumarate is a nucleotide reverse transcriptase inhibitor that has proven efficacy and safety against HIV, and most recently against lamivudine-resistant HBV [109–111]. In a small study of LT recipients with lamivudine-resistant HBV, tenofovir (300 mg daily) for 2 to 12 months resulted in a significant decline in HBV DNA levels [112]. In patients coinfected with HIV and lamivudine-resistant HBV, tenofovir resulted in a significant decrease in HBV DNA viral load in all and HBeAg seroconversion in up to 25% of patients [110,111]. The drug was tolerated well in transplant recipients and coinfected patients.

Summary The goals of therapy in HBV-related cirrhosis depend on the patient’s clinical status and treatment history (see Fig. 1). In patients with compensated cirrhosis and normal liver synthetic function, initiation of

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antiviral therapy is the same as in patients without cirrhosis. Lamivudine and adefovir dipivoxil, are the preferred therapies over IFN-a. Treatment of compensated cirrhotic patients with active disease can be expected to not only result in improvement in liver enzymes, but treatment, also may reduce the risk of future liver decompensation. In patients with decompensated cirrhosis (Class B or C), LT should be considered the definitive therapy. Patients with evidence of active disease (elevated liver enzymes and quantifiable levels of HBV DNA) should be treated with lamivudine or adefovir dipivoxil while awaiting LT with the goal of stabilizing clinical status and inhibiting viral replication before transplantation. The emergence of drug-resistant mutants during prolonged therapy with resultant clinical deterioration is a concern, and thus close monitoring for virologic breakthrough is recommended. Inhibition of viral replication before OLT reduces the risk of reinfection of the graft after surgery. Moreover, clinical improvements while on the waiting list may occur that result in a delay in need for LT. The most effective method of preventing HBV recurrence post-transplantation is with a combination of nucleoside analogs (eg, lamivudine or adefovir) and HBIg immunoprophylaxis. Transplant candidates and transplant recipients who have developed resistance to lamivudine have improved clinical function and survival when treated with adefovir dipivoxil. The drug is well-tolerated, and the rate of resistance appears to be low (at least in the first 2 years of treatment). References [1] Lok AS. Chronic hepatitis B. N Engl J Med 2002;346(22):1682–3. [2] Perrillo R, et al. Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus. Gastroenterology 1995;109(3):908–16. [3] Merican I. Treatment of chronic hepatitis B virus infection in special groups of patients: decompensated cirrhosis, immunosuppressed and paediatric patients. J Gastroenterol Hepatol 2000;15:E71–8. [4] Fattovich G, et al. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis. Hepatology 1995;21(1):77–82. [5] Liaw YF, et al. The development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Hepatology 1988;8(3):493–6. [6] Moreno-Otero R, et al. Development of cirrhosis after chronic type B hepatitis: a clinicopathologic and follow-up study of 46 HBeAg-positive asymptomatic patients. Am J Gastroenterol 1991;86(5):560–4. [7] Brunetto MR, et al. Outcome of anti-HBe-positive chronic hepatitis B in alfa-interferon treated and untreated patients: a long-term cohort study. J Hepatol 2002;36(2):263–70. [8] de Jongh FE, et al. Survival and prognostic indicators in hepatitis B surface antigenpositive cirrhosis of the liver. Gastroenterology 1992;103(5):1630–5. [9] Fattovich G. Natural history and prognosis of hepatitis B. Semin Liver Dis 2003;23(1): 47–58. [10] Chang MH, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med 1997;336(26):1855–9.

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Treatment of chronic viral hepatitis in patients with renal disease Fabrizio Fabrizi, MDa,b, Paul Martin, MDa,*, Suphamai Bunnapradist, MDa a

Center for Liver and Kidney Diseases and Transplantation, Cedars-Sinai Medical Center, University of California-Los Angeles School of Medicine, 8635 West Third Street, Suite 590W, Los Angeles, CA 90048, USA b Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS, Pace 9, Milano 20122, Italy

Although several largely successful measures mandated by Centers for Disease Control and Prevention (CDC) reduced the spread of hepatitis B virus (HBV) in the dialysis setting by the late 1970s, chronic viral hepatitis, especially hepatitis C, remains common in patients with end-stage renal disease (ESRD) and is an important cause of morbidity and mortality in this population. In the last several years, numerous studies on the natural history and outcomes of viral hepatitis in dialysis and transplantation have been reported. Despite these, the management of hepatitis C virus (HCV)- or HBV-related liver disease in ESRD continues to be an area of controversy. This article aims to address the current therapeutic options for patients with renal disease and chronic viral hepatitis.

Epidemiology and outcomes of viral hepatitis in end-stage renal disease Hepatitis B In a recent report by Tokars using CDC hemodialysis surveillance, the prevalence of HBV infection in dialysis patients in the United States had decreased from 7.8% in 1976 to 0.9% in 2000, with the incidence decreasing from 3% to 0.05% [1]. Incidence and prevalence rates for HBV in hemodialysis patients had fallen even before the introduction of HBV vaccination, as a result of several measures mandated by CDC, including * Corresponding author. E-mail address: [email protected] (P. Martin). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.04.011

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regular serological surveillance for HBV infection and isolation of infected patients with the use of dedicated machines. Outbreaks of HBV infection continue to be investigated by CDC, however, reflecting the lack of adherence to these precautions established to prevent HBV transmission within hemodialysis units. Acute HBV infection in hemodialysis (HD) patients is often subclinical but is highly likely to become chronic. This has been attributed in part to depressed cell-mediated immunity despite increased CD4/CD8 ratio [2]. The impact of HBV infection on dialysis patient survival remains controversial. Most reports have revealed no significant differences in morbidity and mortality between dialysis patients according to hepatitis B surface antigen (HBsAg) status, and less than 5% of HBV infected dialysis patients die from liver disease. The most frequent causes of death among patients on maintenance dialysis remain cardiovascular disease and sepsis. Cirrhosis is not recognized as frequently as a comorbid condition in Western dialysis populations, but the death rate for dialysis patients with cirrhosis is 35% higher than those without it. The mean delay in the development of HBVrelated complications (liver cirrhosis and hepatocellular carcinoma) probably exceeds the mean life expectancy of many dialysis patients. Many HBsAg positive dialysis patients likely will die with the infection rather than of it. Nonetheless, the proportion of dialysis patients with serious liver disease is expected to grow as their life expectancy increases, because of the improvement in dialysis technology. Aminotransferase levels in patients with chronic renal failure undergoing maintenance dialysis or in the predialysis stage typically are depressed, making it more difficult to assess liver disease by biochemical activity alone. Indeed aminotransferase levels in the normal range for the general population do not exclude hepatic inflammatory activity in the dialysis setting, and an increase of baseline levels does not need to reach the abnormal range to indicate the presence of HBV-related liver disease. Guh et al have suggested that the best cutoff point for evaluating viral hepatitis should be set at lower levels (less than 20 IU/L for aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) to enhance the diagnostic yield of AST and ALT in the dialysis population [3]. The course of HBV infection is generally more aggressive in patients after renal transplantation (RT) compared with those remaining on maintenance dialysis. HBV infection is associated with significant hepatic dysfunction after RT, and HBV-related liver disease is a major long-term risk of morbidity and mortality in RT recipients. HBsAg positive patients with ESRD may have an accelerated course of liver disease after RT at least in part because of enhanced replication associated with immunosuppressive therapy after RT. The HBV genome contains a glucocorticoidresponsive element that, when activated, may increase the transcription of HBV genes. Importantly, even RT recipients with a serological profile indicating remote resolved HBV with negative HBsAg may have reactivation of HBV with reappearance of HBsAg. In a transgenic mouse

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model of HBV, in which HBsAg is incorporated into the host genome, HBsAg production is regulated by glucocorticoids. Cyclosporin also may enhance HBV replication. Before the advent of nucleoside analogues, the adverse impact of HBV infection was even worse in renal allograft recipients, especially in those who had more severe hepatitis on biopsy. Ten-year graft and patient survivals are lower in HBsAg-positive compared with HBsAg-negative RT recipients. HBV-related glomerulonephritis occurring after RT may decrease graft survival further. Decisions about RT in patients with HBV should be based on the severity of histology and the results of testing for markers of replication in serum, including HBV DNA and hepatitis B e antigen (HBeAg). Liver biopsy is recommended before kidney transplantation and when antiviral treatment is being considered to ascertain the activity of hepatitis and the degree of fibrosis. Studies in North America have shown that patients with severe chronic active hepatitis or established cirrhosis on liver biopsy are at particular risk for hepatic decompensation following RT, and in these individuals RT should be avoided, especially if markers of active viral replication are also present. Cirrhosis is considered a contraindication to renal transplantation. Given the generally favorable outcome of many HBV-infected ESRD patients with less histologically severe liver disease, however, RT should not be precluded in this setting. All patients with HBV must be cautioned, however, that even histologically mild disease has the potential to deteriorate under the influence of immunosuppression. The role and optimal timing of liver biopsy in otherwise asymptomatic patients without clinical or biochemical abnormalities remain uncertain, but candidacy for RT should prompt its consideration. Hepatitis C Shortly after the development of serological testing for HCV, it became apparent that HD patients had a high prevalence of HCV infection. The first-generation HCV serological tests were relatively insensitive in the HD population, with false negative results up to 10% of viremic patients. The accuracy of serological testing has improved substantially with the introduction of the second- and third-generation tests over the last decade, however. The prevalence of hepatitis C antibody positivity, however, has been unchanged overall (8.1% in 1992 and 8.4% in 1999) despite effective screening of blood products for HCV, highlighting the role of HCV transmission within HD units in maintaining a high prevalence of HCV infection in this population [1]. Risk factors for hepatitis C infection in dialysis patients include a history of intravenous drug abuse, prior RT, multiple blood transfusions, and markers of prior HBV infection. The natural history of HCV in dialysis patients is difficult to define in part because of its indolent course that extends over decades, whereas dialysis patients generally have shortened life expectancy. Retrospective

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analyses reveal the death rate of dialysis patients with cirrhosis was 35% higher compared to noncirrhotics. A prospective study with 6-year followup by Nakayama et al in 1470 dialysis patients suggested that positive anti-HCV serology was an independent risk factor for death, with a relative risk of 1.57(confidence interval [CI], 1.2 to 2) [4]. Hepatocellular carcinoma accounted for 5.5% of all death, and cirrhosis was documented in 8.8% of patients. Clearly, some deaths in HCV dialysis patients are related to liver disease. The evaluation of HCV is complicated by the observation that aminotransferase values are typically lower in dialysis patients than the nonuremic population. Although HCV dialysis patients have higher aminotransferase levels compared with noninfected dialysis patients, the levels are typically within normal range. Only a few investigators have evaluated histologic severity of liver disease in HCV dialysis patients who were evaluated for RT candidacy. In one report, 37 HCV-infected ESRD RT candidates underwent liver biopsy. Mild or moderate necroinflammatory activity occurred in all patients. Bridging fibrosis was present in three patients (8%), and frank cirrhosis was present in nine (24%). No relationship between severity of histologic changes and HCV viral load or genotype or aminotransferase levels was detected in this study. Sterling et al performed liver biopsies in 50 consecutive patients with chronic HCV evaluated for RT. Bridging fibrosis or cirrhosis was found in 22%, which was not different from a control group of HCV patients with normal renal function and normal aminotransferase level. Bridging fibrosis in HCV-positive ESRD patients is less common than in those HCV positive patients with normal function but elevated aminotransferases level in this study, however. A previous failed renal allograft was found to be a risk factor for more extensive fibrosis. Numerous recent studies have demonstrated an adverse effect of HCV infection on patient and graft survival in renal transplant recipients [5,6]. HCV infection at the time of referral for transplantation is associated with an increased risk of death, irrespective of whether a patient remains on dialysis or undergoes transplantation. Natov et al reported 224 patients on the renal transplant waiting list with HCV antibody positivity at the New England Organ Bank who underwent HCV genotyping and quantitative RNA measurements [7]. Ninety percent of patients were infected with a single HCV single genotype; 9% were infected with two genotypes, and 1% were infected with three genotypes. Among the 180 patients in the final study cohort, 48% underwent transplantation, and 37% patients died during follow-up. Specific HCV genotypes did not affect patient survival among renal transplant survival. Transplantation however, has a beneficial rather than adverse effect on long-term survival in anti-HCV positive recipients. Hence, anti-HCV positive status alone is not a contraindication to RT [8]. A large French study, however, showed poor outcomes of HCVinfected recipients with a 10-year patient and graft survival of 55% and 36%, respectively [9]. Because pre-RT liver biopsies were not available, it

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is unclear whether the increased mortality occurred only in patients with more severe hepatitis and fibrosis at baseline.

Therapy of hepatitis C in dialysis patients Interferon (IFN) remains the mainstay of treatment for chronic HCV infection. Several controlled and uncontrolled trials (with different regimens of interferon-a monotherapy) have been published in dialysis patients with HCV infection [10] (Table 1). Sustained biochemical and virologic response rates have varied widely from 0% to 67% and 15.8% to 64%, respectively [11]. In a large, controlled trial, Huraib et al [11] showed a significant decrease in the histologic activity index (HAI) after IFN therapy, 4.27 plus or minus 1.19 to 1.64 plus or minus 0.67 (P = 0.004). A significant difference between the HAI scores at the end of the study periods between IFN and placebo groups also occurred, 1.64 plus or minus 0.67 versus 5.5 plus or minus 1.35 (P = 0.007) [11]. Response rates to IFN monotherapy for HCV infection, as evaluated by the sustained virologic response (SVR), paradoxically appear to be higher in the chronic hemodialysis population than in nonuremic patients [10]. Potential mechanisms may include relatively low viral loads. Also, there is reduced clearance of IFN in HD patients [12]. IFN treatment may help to restore cell-mediated immunity depressed by uremia, aiding in response to therapy. In addition, HCV-related liver disease is frequently mild histologically in dialysis patients, which may enhance IFN responsiveness further. The frequency of adverse effects in the dialysis population appears to be higher than that in reported in immunocompetent individuals. The rate of discontinuation of IFN therapy in recent trials is shown in Table 2 [10]. An altered pharmacokinetic profile of IFN in patients on maintenance dialysis resulting in a significantly longer IFN half-life compared with nonuremic controls has been demonstrated and may be an explanation in part for enhanced IFN’s efficacy and also adverse effects [12]. Interferon therapy is complex, expensive, and associated with frequent adverse effects. For these reasons, nephrologists have been reluctant to offer IFN to their patients. In addition, the potential advantages of IFN typically are measured over years or decades, whereas many dialysis patients have a diminished life expectancy because of their comorbidities. Patients with likely shorter survivals (ie, patients with diabetes, congestive heart failure, and/or clinical evidence of malnourishment) are probably not ideal candidates for IFN therapy. Antiviral therapy should be considered in dialysis patients with persistent HCV viremia and histological features of potentially significant chronic hepatitis. Absence of biochemical abnormality in this population does not preclude histologically significant liver diseases. It seems reasonable to offer IFN to those patients considered for RT.

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Table 1 Trials with interferon in dialysis patients with chronic hepatitis C Authors

Patients (n)

IFN (dose)

IFN (months)

SVR

Koenig P, et al Pol S, et al Raptopoulou-Gigi M, et al Fernandez JL, et al Izopet J, et al Chan TM, et al Uchihara M, et al Huraib S, et al Campistol JM, et al Espinosa M, et al Casanovas-Taltavull T, et al Hanrotel C, et al Degos F, et al

37 19 19 14 11 11 9 15 19 13 29 12 37

5 MU 3 MU 3 MU 1.5 MU 3 MU 3 MU 3-6 MU 3 MU 3 MU 3 MU 1.5-3 MU 3 MU 3 MU

4 6 6 6 12 6 6 12 6 12 12 12 12

30% 20% 68% 21% 64% 27% 33% 27% 42% 46% 62% 33% 19%

Reference year (11/37) (3/15) (13/19) (3/14) (7/11) (3/11) (3/9) (4/15) (8/19) (6/13) (18/29) (4/12) (7/37)

1994 1995 1995 1997 1997 1997 1998 2001 1999 2001 2001 2001 2001

Therapeutic options for hepatitis C virus-related liver disease in dialysis population Only preliminary data on the use of combination therapy (IFN plus ribavirin) in dialysis patients have been reported. Bruchfeld et al [13] treated five patients on HD and one patient on peritoneal dialysis for chronic HCV. In order to distinguish between adverse effects of the two agents, IFN-a2b was given initially as monotherapy at a dose of 3 MU three times weekly subcutaneously after dialysis for 4 weeks. Oral ribavirin subsequently was added at a low starting dose of 200 to 400 mg once a day for a 6-month period. Ribavirin then was dosed according to its plasma concentration. Five of six patients (83.3%) became HCV RNA negative during treatment, but four relapsed after discontinuation of treatment. Two patients had a virological response during IFN monotherapy, and three other patients had a virological response during combination therapy. All patients required increased doses of erythropoietin and iron during antiviral therapy. One patient did not become negative for HCV RNA during treatment, but Table 2 Frequency of dialysis patients discontinuing interferon treatment

Izopet J, et al Espinosa M, et al Huraib S, et al Degos F, et al Campistol JM, et al Casanovas-Taltavull T, et al Gursoy M, et al Hanrotel C, et al

Patients discontinuing IFN

Reference year

13% 23% 0% 51% 53% 0% 17% 8.3%

1997 2001 2001 2001 1999 2001 2001 2001

(3/23) (3/13) (0/15) (19/37) (10/19) (0/28) (6/36) (1/12)

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the HCV RNA levels fell to the cutoff level after 14 weeks of treatment. A biochemical response was obtained in all, with normalization of ALT values during treatment. The use of ribavirin had been avoided in dialysis patients mainly because of fear of metabolite accumulation resulting in toxicity. In their concentration-controlled safety study, Bruchfeld et al observed that three important modifications are crucial for the use of ribavirin in dialysis patients [13]. First, the ribavirin dose should be reduced markedly. Second, the dose of erythropoietin needs to be increased to compensate for ribavirin-associated hemolytic anemia. Third, consideration should be given to monitoring plasma concentrations of ribavirin. Average daily doses of ribavirin were in the range of 170 to 300 mg in this study. A second pilot trial was reported by Tan et al [14] from the Netherlands. Five patients with chronic hepatitis C on chronic hemodialysis received subcutaneous interferon-a2b 3
106 U three times weekly plus oral ribavirin. The duration of therapy was unclear. Ribavirin was discontinued in two patients because of severe anemia, while one patient suffered adverse effects (fever, chills) that resolved after stopping IFN. Interim analysis showed that in all patients, serum HCV RNA levels decreased markedly, resulting in a loss of HCV RNA in four (80%) of five patients during treatment. The ribavirin dose in dialysis patients (200 mg three times weekly) was only one sixth of the normal daily ribavirin dose Clearly, larger randomized trials are needed to investigate the effect and optimal duration of IFN plus ribavirin in dialysis patients. Role of peginterferon In August 2001, the US Food and Drug Administration (FDA) approved the combination of peginterferon alfa-2b (PEG IFN-a2b) plus oral ribavirin for the treatment of chronic hepatitis C in patients with normal renal function. Covalently attached polyethylene glycol (PEG) delays protein clearance and reduces immunogenicity. The resulting longer plasma half-life increases exposure to the drug and therefore may improve efficacy and allow for less frequent dosing. Less frequent dosing, in turn, may improve compliance and quality of life. The introduction of the PEG IFNs has resulted in an increased interest in the treatment of HCV-infected patients with ESRD. A recent pharmacokinetic study was performed with PEG IFN-a2a in patients with various degrees of impaired renal function who were not yet dialysis-dependent [15]. The absorption and distribution of PEG IFN-a2a were similar in subjects with stable chronic renal impairment versus individuals with normal renal function. There was no significant difference in apparent body clearance between individuals with normal renal function (creatinine clearance [ClCr] greater than 100 mL/min) and patients with severe renal failure (ClCr ranging between 20 and 40 mL per minute) [15].

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A single dose study in patients on chronic HD identified no additional toxicity although there was a 30% reduction in IFN clearance [16].

Treatment of chronic hepatitis C after renal transplant There is no effective and safe therapy for HCV-related liver disease after RT. A very high frequency of acute impairment of allograft function with IFN treatment has precluded its use. The frequency of acute renal failure in controlled and uncontrolled trials using recombinant IFN-a after RT ranges between 15.4% and 64% (Table 3) [17]. Renal allograft biopsies frequently demonstrated acute cellular rejection, with some component of vascular involvement and severe acute humoral rejection (C4dþ, DSAþ) [18]. Many of these episodes were not reversible by pulse methylprednisolone therapy and resulted in a return to dialysis. No predictive factors for IFN-induced renal failure were identified. Preliminary results with monotherapy with ribavirin [19] or amantadine [20] have not been encouraging in RT recipients. No information exists on the use of combination therapy (IFN plus ribavirin) or PEG IFN after RT, but it is highly unlikely that any interferon based therapy will gain acceptance in RT recipients.

Treatment of hepatitis C in renal transplant candidates: results after renal transplant There are several reports of successful therapy for HCV in dialysis patients who subsequently underwent renal transplantation. CasanovasTaltavull et al [21] reported that seven (50%) of 14 patients with sustained clearance of HCV viremia after IFN monotherapy remained HCV RNA negative, with a mean follow-up time after RT of 41 plus or minus 28 months. Campistol et al [22] observed that one out of the three treated patients who were HCV RNA negative at RT had a relapse at 20 months post-transplantation, while the other two remained HCV RNA negative at 3 and 24 months post-RT. Following RT, aminotransferase levels remained

Table 3 Adverse-effects of therapy with recombinant interferon after reneal transplantation Authors

N

Ozgur O, et al Magnone M, et al Thervet E, et al

5 11 13

Rostaing L, et al

16

IFN dose 6

4.5
10 1.5 – 5
106 3
106 (n = 9) 5
106 (n=4) 3
106

Drop-out rate

Acute renal failure

40% (2/5) 64% (7/11) 54% (7/13)

40% (2/5) 64% (7/11) 15% (2/13)

56% (9/16)

37.5% (6/16)

SVR Not available Not available Not available 0% (0/16)

The evaluation of response was made according to an intent-to-treat analysis.

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within normal limits in all patients in the IFN treated group, except for a transient increase in the patient who had a relapse of HCV infection. Tokumoto et al [23] treated six patients on maintenance HD with IFN monotherapy. The SVR was 50% at a mean follow-up of 15.4 months after completion of antiviral therapy. Two of six HD patients underwent RT after HCV RNA was negative. They remained HCV RNA negative with functioning grafts at a mean follow-up of 16.8 months. The authors recently reported the sustained clearance of HCV infection in a dialysis patient who was treated successfully with IFN and underwent subsequent RT [24]. Regular follow-up with ALT and HCV RNA testing showed a complete absence of biochemical and virological relapse over a 6year post-transplantation period despite aggressive therapy for episodes of acute rejection. Cruzado et al reported on 78 HCV-positive RT recipients. Fifteen (20%) had received pretransplant IFN for 1 year. The authors assessed HCVrelated de novo glomerulonephritis (membranoproliferative or membranous) by testing for proteinuria (greater than 1.5 g every 24 hours) and/or microhematuria and confirmed by renal biopsy. Of 15 HCV-positive recipients who had received pretransplant IFN, 10 (67%) were HCVRNA negative by the time of transplantation. Only one out of the treated patients (6.7%) developed de novo glomerulonephritis and had been HCVRNA positive at time of transplantation). Among the non-IFN-treated allograft recipients, 12 out of 63 (19%) developed de novo glomerulonephritis (nine membranoproliferative, three membranous), and all 12 were HCV-RNA positive at time of transplantation (P less than 0.0001). The authors suggested that pretransplant IFN should be considered to treat all HCV RNA-positive candidates for renal transplantation to lessen allograft injury caused by HCV post-RT [25]. Treatment of hepatitis B-related liver disease in dialysis patients According to currently accepted recommendations, antiviral therapy should be considered in HBsAg positive patients on dialysis with persistent HBeAg, or HBV DNA in serum, raised aminotransferase activity, and histological features of chronic hepatitis, if a liver biopsy has been performed. As noted earlier, however, aminotransferase levels tend to be low in HD patients with viral hepatitis despite significant histological changes. Therefore, it seems reasonable to offer antiviral therapy to all HBsAg positive RT candidates to lessen the risk of enhanced HBV replication and progression of liver disease post-RT. IFN generally is effective only in a subset of patients with chronic HBV infection who have low viral load or active immune responses reflected by elevated aminotransferases. Only anecdotal experience is available regarding therapy of chronic HBV in the dialysis population. Duarte et al [26] treated two HBVinfected patients undergoing maintenance HD who were HBeAg positive

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and had raised aminotransferase with IFN (3 MU three times weekly subcutaneously) for 3 months. Both patients had clearance of HBe antigen, and serum transaminase values fell into the normal range. Lamivudine is a nucleoside analogue with proven efficacy in suppressing HBV viremia (HBV DNA) and normalizing aminotransferase and histologic abnormalities in nonimmunosuppressed patients with chronic HBV. It is administered orally, it is less expensive then IFN and offers benefits in terms of clinical efficacy and tolerance compared with IFN-a. Lamivudine has broadened the spectrum of indications for HBV therapy to include patients with HBV-related cirrhosis. Fontaine et al [27] published their observations on lamivudine use in chronic dialysis patients. In a prospective although uncontrolled fashion, in five patients on HD treated with lamivudine for 12 months, serum HBV DNA became negative, and one patient seroconverted from HBeAg to anti-HBe. Breakthrough, defined by the reappearance of detectable serum HBV DNA, was seen in 2 (40%) of 50 patients at the 7th and the 18th month of treatment. No information was provided about aminotransferase activity or liver histology after lamivudine therapy. Treatment of hepatitis B-related liver disease after renal transplant Lamivudine therapy has been given for de novo HBV infection and reactivation HBV after RT [6]. Its potent antiviral activity and lack of adverse effects have led many RT centers to use it routinely. Most clinical experiences with lamivudine consist of open-labeled, uncontrolled trials including a limited number of patients (Table 4). Chan et al [28] gave pre-emptive therapy with lamivudine (100 mg daily) to HBsAg positive RT recipients. Lamivudine was started when serum HBV DNA level was in excess of 2.8
108 copies/mL in patients with normal ALT activity and an HBV DNA level greater than 2.8
107 copies/mL in patients with a raised ALT level and/or liver biopsy revealing evidence for active hepatitis. There were 12 HBsAg positive patients who received RT between 1996 and 2000 (group 2), 11 of them receiving lamivudine and 52 patients who had undergone RT between 1983 and 1995 (group 1). Fifteen received lamivudine therapy. Antiviral therapy was started 1 to 18 months after RT in group 2 versus 15 to 118 months in group 1 and was continued for an average duration of 27.6  14.5 months and 36.3  11.4 months, respectively. Importantly, results of the survival of patients in group 2 were similar to that of HBsAg negative controls, whereas group 1 HBsAg positive patients who underwent RT before 1996 (15 of them were treated with lamivudine several years after RT) had lower survival (relative risk of death, 9.7 [P less than 0.001], and an increased relative risk of liver-related mortality, 68.0 [P less than 0.0001]. Lamivudine resistance occurred in 11 (40.7%) patients after 30.7  14.9 months of treatment. The impact of lamivudine-resistant HBV mutants on post-RT outcome requires further investigation, as group 2 RT recipients had a short follow-up (36  17

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Table 4 Outcomes of clinical trials with lamivudine after renal transplant Authors

ALT normalization

HBsAg clearance

HBeAg clearance

HBV DNA clearance

Chan TM, et al Lewandoska D, et al Antoine C, et al Tsai MK, et al Fontaine H, et al Mouquet C, et al Han DJ, et al Goffin E, et al Rostaing L, et al

100% 60% NA NA NA 50% 50% 100% 80%

0 0 0 0 0 0 0 0 0

21% (3/14) 8% (8/28) 67% 0 46% (6/13) NA 37.5% (3/8) 0 0

100 (26/26) NA 83% (10/12) 87.5% (7/8) 100% (26/26) 87% (13/15) 77% (10/13) 75% (3/4) 67% (4/6)

(26/26)

(3/6) (4/4) (4/5)

months). The authors concluded that lamivudine therapy initiated shortly after RT had enhanced virologic and biochemical efficacy compared with therapy in those who had received it many months post-transplant. Park et al reported that in 17 HBsAg positive RT recipients, lamivudine was initially effective in decreasing serum HBV DNA titers and in normalizing hepatic enzymes. Lamivudine was tolerated well without significant adverse effects for 35.5 plus or minus 8.9 months after initiation of treatment. HBV DNA became negative in nine patients but remained positive in one patient. Among the nine patients with initial clearance of HBV DNA, two developed transient reappearance of serum HBV DNA, and two others had persistent HBV viremia. Among patients with normal liver histology pre-RT, 41.6% (5/12) developed liver pathology progression after immunosuppression. All 17 patients had functioning grafts, except for one patient, who developed relapsed IgA nephropathy [29]. Numerous issues concerning the management of HBV-related liver disease after RT remain unresolved. These include the optimal duration of antiviral therapy, the optimal time to initiate lamivudine therapy, and the approach and the management of potential lamivudine resistance caused by mutations in the HBV DNA polymerase gene (YMDD motif). Adefovir is efficacious in patients with decompensated cirrhosis and recurrent HBV following liver transplant. No data exist about its use and safety in RT recipients, however, and dose reduction will be necessary in the presence of renal impairment.

Treatment of hepatitis C virus-associated cryoglobulinemic glomerulonephritis Types II and III essential mixed cryoglobulinemia (EMC) may result in a syndrome characterized by purpura, weakness, and arthralgia. With type II EMC only, in which an IgMk is a monoclonal rheumatoid factor (RF), membranoproliferative glomerulonephritis (MPGN) can occur and is termed cryoglobulinemic glomerulonephritis with specific histologic characteristics.

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The relationship between EMC and HCV infection provides a rationale for antiviral treatment of the systemic and renal manifestation of mixed cryoglobinemia (MC), although IFN-a had been used in EMC prior to identification of HCV infection in this syndrome [30] because of its antiproliferative and immunomodulating activity in a disease thought to be expression of a low-grade malignant lymphomatous disorder. Numerous reports have appeared on the treatment of HCV-related MC. Few prospective and controlled trials have been performed, however. In addition, the nature and severity of renal involvement in most patients enrolled in these studies were unclear. About three quarters of patients included reported by Misiani et al [31] had renal involvement, manifested by microscopic hematuria, hypertension, proteinuria, or mild-to-moderate renal failure. In this study, there was a significant decrease in serum creatinine levels in 15 patients in whom HCV RNA disappeared from serum as a result of the IFN-a therapy only. The beneficial effects of IFN-a therapy were limited to the patients in whom HCV RNA disappeared from serum. The decrease in serum creatinine levels was not accompanied by a reduction in proteinuria, and no follow-up renal biopsy findings were available. Finally, all patients relapsed after IFN-a was discontinued. In the same year, the results of a large, uncontrolled trial by Johnson et al [32] were published. Fourteen patients with HCV-associated glomerulonephritis (GN) received IFN-a for 6 to 12 months resulting in a significant decrease in proteinuria but no change in renal function. Clinical response was associated with the eradication of HCV RNA from serum during treatment; however, relapse of viremia and renal disease was typical after completion of therapy. Many isolated case reports on the therapy of cryoglobulinemic GN also have been published. Misiani et al [33] treated a patient with cryoglobulinemic GN with standard doses of recombinant IFN-a without response. Thus, the patient was retreated with human leukocyte IFN-a (3 MU three times weekly) and ribavirin (5 mg/kg/d), respectively. After 4 months of treatment, ribavirin was withdrawn because of pruritus and anemia; the patient continued treatment with IFN-a alone for 12 months. Two years after the end of treatment, the patient was still in clinical, virologic, biochemical, and immunologic remission. He remained asymptomatic; serum creatinine level was decreased markedly and proteinuria was reduced by half. Quigg et al [34] successfully treated a 54-year old man with cryoglobulinemia, chronic HCV, and progressive renal failure caused by MPGN. Because of a steady decline in renal function, cyclophosphamide therapy was instituted for 1 year. During daily cyclophosphamide treatment, cryoglobulins level declined rapidly, with improved renal function and a reduction in proteinuria. Renal improvement has been maintained for 14 months off therapy. HCV RNA levels substantially increased despite reduction in cryoglobulinemia. Gilli et al [35] reported that IFN-a (3 MU three times weekly for 10 months) was effective with complete resolution of nephrotic syndrome and

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reduction in HCV RNA. Additionally, modification of the renal histopathological picture was observed in a patient with HCV-related MPGN. Sarac et al [36] treated a 42-year-old man with HCV-associated MC and nephrotic syndrome by IFN-a (3 MU three times weekly for a total of 6 months), but he continued to have hypocomplementemia, cryoglobulinemia, and nephrosis. After a course of high-dose IFN-a treatment (10 MU daily for 2 weeks followed by 10 MU three times weekly for an additional 6 weeks), however, HCV RNA and cryoglobulins became negative; complement levels returned to normal values, and nephrotic syndrome remitted. Garini et al [37] treated two patients with chronic HCV infection, type-II MC, and MPGN, manifesting as nephrotic syndrome, with IFN-a (3 MU three times weekly) and ribavirin (15 mg/kg daily) for 6 months. Viremia and cryoglobulinemia were suppressed in both patients. Complete remission of proteinuria was observed in one patient only, however. Subsequent evaluation by renal biopsy revealed a mild MPGN (activity score: 5/24) in the patient with remission of proteinuria and a severe MPGN (activity score: 15/24) in the patient who maintained nephrotic-range proteinuria, suggesting that the latter renal injury was too severe to reverse completely. Recently, cryoglobulinemic MPGN associated with chronic HCV treated successfully with mycophenolate mofetil and IFN-a [38] has been reported. An unusual course of HCV-associated cryoglobulinemic MPGN has been described by Dussol et al [39] in a patient who had reached end-stage renal failure necessitating HD. The patient was given high oral doses of prednisone and intravenous cyclophosphamide, which yielded no improvement in nephrotic syndrome or renal function. Spontaneous improvement in renal function as shown by the dramatic improvement of the renal lesions in the second biopsy was noted six months later, however. Fludarabine is an antimetabolite agent with great potency against B lymphocytes, which may be useful in the treatment of mixed cryoglobulinemia, as mixed cryoglobulinemia shows often evidence of clonal B-cell expansion. In 2002, Rosenstock et al [40] reported on three patients (one hepatitis C positive) with renal insufficiency and nephrotic-range proteinuria resulting from MC and GN. All three patients received two to four cycles of intravenous fludarabine (25 to 50 mg/day for 4 to 5 days). All patients responded to therapy with a decreased in proteinuria, increase in serum albumin, and decrease in serum creatinine. This response was evident by 2 months and persisted for 2 to 5 years. In two patients, this response was accompanied by disappearance of cryoglobulins, at least transiently. One patient developed tuberculosis with neutropenia. The HCV-infected patient complained of transient blindness and neutropenia; she remained free of renal disease at 2 years of follow-up but after 1.5 years developed recurrence of cryoglobulins with hypocomplementemia and vasculitis of the central nervous system (without recurrence of proteinuria or kidney dysfunction). Her hepatitis C viral load remained high, at greater than 1 million copies. She subsequently died from septic complications.

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Identification of HCV infection in a patient with symptomatic cryoglobulinemia is therefore an appropriate indication for antiviral therapy. Large-scale trials are necessary to evaluate the optimal regimen. Summary Patients with ESRD remain at increased risk for HCV/HBV-related liver disease. The recent availability of effective antiviral agents offers new options in the management of chronic hepatitis in infected dialysis and RT recipients. Randomized trials, however, are warranted to clarify the efficacy of IFN plus ribavirin in the management of HCV-related liver disease in patients with ESRD. Lamivudine has been an important addition to the management of HBV-infected RT candidates, lessening the risk of hepatic decompensation. Still, larger scale clinical trials are necessary. Adefovir also required further evaluation in this population. In both HBV- and HCVinfected patients with ESRD, liver biopsy remains an important part of the evaluation of severity of liver disease given the frequent absence of elevated aminotransferases despite chronic viral hepatitis in the population. Identification of HCV’s role in GN in native and transplanted kidneys also provides another important rationale for antiviral therapy in patients with renal disease and viral hepatitis. Use of IFN after renal transplantation for HCV infected recipients is precluded by the high frequency of impairment of the graft. IFN can lead to excellent results in selected patients on dialysis with long term remission durable even after RT. Absorption and distribution of PEG IFN are similar in patients with stable chronic renal impairment and individuals with normal renal function; studies are underway to evaluate the efficacy of PEG IFNs in individuals with HCV infection and renal insufficiency. Preliminary data encourage cautious ribavirin use in conjunction with IFN therapy in dialysis populations. There is no standard effective therapy for mixed cryoglobulinemic glomerulonephritis, although IFN-alpha, with or without ribavirin, has been used successfully. Alternative therapeutic options are also under evaluation. References [1] Tokars J, Frank M, Alter M, et al. National surveillance of dialysis-associated diseases in the United States, 2000. Semin Dial 2002;15(3):162–71. [2] Lee BW, Yap HK, Tan M, et al. Cell-mediated immunity in patients on hemodialysis: relationship with hepatitis B carrier status. Am J Nephrol 1991;11(2):98–101. [3] Guh J, Lai Y, Yang C, et al. Impact of decreased serum transaminase levels on the evaluation of viral hepatitis in hemodialysis patients. Nephron 1995;69(4):459–65. [4] Nakayama E, Akiba T, Marumo F, et al. Prognosis of antihepatitis C virus antibodypositive patients on regular hemodialysis therapy. J Am Soc Nephrol 2000;11(10):1896–902. [5] Fabrizi F, Poordad FF, Martin P. Hepatitis C infection and the patient with end-stage renal disease. Hepatology 2002;36(1):3–10.

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[6] Fabrizi F, Martin P, Ponticelli C. Hepatitis B virus and renal transplantation. Nephron 2002;90(3):241–51. [7] Natov S, Lau J, Ruthazer R, et al. Hepatitis C virus genotype does not affect patient survival among renal transplant candidates. The New England Organ Bank Hepatitis C Study Group. Kidney Int 1999;56(2):700–6. [8] Pereira B, Natov S, Bouthot B, et al. Effects of hepatitis C infection and renal transplantation on survival in end-stage renal disease. The New England Organ Bank Hepatitis C Study Group. Kidney Int 1998;53(5):1374–81. [9] Mathurin P, Mouquet C, Poynard T, et al. Impact of hepatitis B and C virus on kidney transplantation outcome. Hepatology 1999;29(1):257–63. [10] Fabrizi F, Lunghi G, Martin P. Recent advances in the management of hepatitis C in the dialysis population. Int J Artif Organs 2002;25(6):503–11. [11] Huraib S, Iqbal A, Tanimu D, et al. Sustained virological and histological response with pretransplant interferon therapy in renal transplant patients with chronic viral hepatitis C. Am J Nephrol 2001;21(6):435–40. [12] Rostaing L, Chatelut E, Payen JL, et al. Pharmacokinetics of alfa IFN-2b in chronic hepatitis C virus patients undergoing chronic hemodialysis or with normal renal function: clinical implications. J Am Soc Nephrol 1998;9(12):2344–8. [13] Bruchfeld A, Stahle L, Andersson J, et al. Ribavirin treatment in dialysis patients with chronic hepatitis C virus infection—a pilot study. J Viral Hepat 2001;8(4):287–92. [14] Tan AC, Brouwer JT, Glue P, et al. Safety of interferon and ribavirin therapy in haemodialysis patients with chronic hepatitis C: results of a pilot study. Nephrol Dial Transplant 2001;16(1):193–5. [15] Martin P, Mitra S, Farrington K, et al. Pegylated(40KDA) interferon alfa-2A(Pegasys) is unaffected by renal impairment. Hepatology 2000;32(2):842. [16] Lamb M, Marks I, Wynohradnyk L, et al. 40 Kda Peginteferon alfa-2A(Pegasys) can be administered safely in patients with end-stage renal disease. Hepatology 2001;34(4):34–190. [17] Fabrizi F, Martin P, Ponticelli C. Hepatitis C virus infection and renal transplantation. Am J Kidney Dis 2001;38(5):919–34. [18] Baid S, Tolkoff-Rubin N, Saidman S, et al. Acute humoral rejection in hepatitis C-infected renal transplant recipients receiving antiviral therapy. Am J Transplant 2003;3(1):74–8. [19] Garnier JL, Chevallier P, Dubernard JM, et al. Treatment of hepatitis C virus infection with ribavirin in kidney transplant patients. Transplant Proc 1997;29:783. [20] Rostaing L. Treatment of hepatitis C virus infection after renal transplantation: new insights. Nephrology Dialysis Transplantation 2000;15(Suppl 8):74–6. [21] Casanovas-Taltavull T, Baliellas C, Benasco C, et al. Efficacy of interferon for chronic hepatitis C virus-related hepatitis in kidney transplant candidates on hemodialysis: results after transplantation. Am J Gastroenterol 2001;96(4):1170–7. [22] Campistol JM, Esforzado N, Martinez J, et al. Efficacy and tolerance of interferon-alfa(2b) in the treatment of chronic hepatitis C virus infection in haemodialysis patients. Pre- and postrenal transplantation assessment. Nephrology Dialysis Transplantation 1999;14(11):2704–9. [23] Tokumoto T, Tanabe K, Ishikawa N, et al. Effect of interferon-alfa treatment in hemodialysis patients and renal transplant recipients with chronic hepatitis C. Transplant Proc 1999;31(7):2887–9. [24] Bunnapradist S, Fabrizi F, Vierling J, et al. Hepatitis C therapy with long-term remission after renal transplantation. Int J Artif Organs 2002;25(12):1189–93. [25] Cruzado J, Casanovas-Taltavull T, Torras J, et al. Pretransplant interferon prevents hepatitis C virus-associated glomerulonephritis in renal allografts by HCV-RNA clearance. Am J Transplant 2003;3(3):357–60. [26] Duarte R, Huraib S, Said R, et al. Interferon-alfa facilitates renal transplantation in hemodialysis patients with chronic viral hepatitis. Am J Kidney Dis 1995;25(1):40–5. [27] Fontaine H, Thiers V, Chretien Y, et al. HBV genotypic resistance to lamivudine in kidney recipients and hemodialyzed patients. Transplantation 2000;69(10):2090–4.

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[28] Chan TM, Fang GX, Tang CS, et al. Pre-emptive lamivudine therapy based on HBV DNA level in HBsAg-positive kidney allograft recipients. Hepatology 2002;36(5):1246–52. [29] Park S, Yang W, Lee Y, et al. Outcome of renal transplantation in hepatitis B surface antigen-positive patients after introduction of lamivudine. Nephrology Dialysis Transplantation 2001;16(11):2222–8. [30] Fabrizi F, Colucci P, Ponticelli C, et al. Kidney and liver involvement in cryoglobulinemia. Semin Nephrol 2002;22(4):309–18. [31] Misiani R, Bellavita P, Fenilli D. Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C infection. N Engl J Med 1994;330:751–6. [32] Johnson R, Gretch D, Couser W. Hepatitis C virus-associated glomerulonephritis. Kidney International 1994;46:1700–4. [33] Misiani R, Bellavita P, Baio P, et al. Successful treatment of HCV-associated cryoglobulinaemic glomerulonephritis with a combination of interferon-alpha and ribavirin. Nephrology Dialysis Transplantation 1999;14(6):1558–60. [34] Quigg RJ, Brathwaite M, Gardner DF, et al. Successful cyclophosphamide treatment of cryoglobulinemic membranoproliferative glomerulonephritis associated with hepatitis C virus infection. Am J Kidney Dis 1995;25(5):798–800. [35] Gilli P, Stabellini N, Storari A, et al. Effect of human leukocyte alpha interferon on cryoglobulinaemic membranoproliferative glomerulonephritis associated with hepatitis C virus infection. Nephrology Dialysis Transplantation 1996;11(3):526–8. [36] Sarac E, Bastacky S, Johnson JP. Response to high-dose interferon-alfa after failure of standard therapy in MPGN associated with hepatitis C virus infection. Am J Kidney Dis Jul 1997;30(1):113–5. [37] Garini G, Allegri L, Carnevali L, et al. Interferon-alfa in combination with ribavirin as initial treatment for hepatitis C virus-associated cryoglobulinemic membranoproliferative glomerulonephritis. Am J Kidney Dis 2001;38(6):E35. [38] Reed MJ, Alexander GJ, Thiru S, et al. Hepatitis C-associated glomerulonephritis—a novel therapeutic approach. Nephrology Dialysis Transplantation 2001;16(4):869–71. [39] Dussol B, Moal V, Daniel L, et al. Spontaneous remission of HCV-induced cryoglobulinaemic glomerulonephritis. Nephrol Dial Transplant Jan 2001;16(1):156–9. [40] Rosenstock JL, Stern L, Sherman WH, et al. Fludarabine treatment of cryoglobulinemic glomerulonephritis. Am J Kidney Dis 2002;40(3):644–8.

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Screening and treatment for hepatocellular carcinoma Morris Sherman, MB, BCh, PhD, FRCP(C)*, Yuji Takayama, MD Department of Medicine, University of Toronto and Toronto General Hospital, EN9-223, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada

The objective of surveillance programs for hepatocellular carcinoma (HCC) is to decrease the mortality from HCC in a population at risk for the disease. This may be accomplished by finding early disease and applying therapy at a stage when cure is more likely. No study has demonstrated that this objective can be achieved for HCC surveillance. To prove or disprove the efficacy of surveillance would involve many thousands of subjects followed for many years. Additionally, at least in the Western world, it would be difficult to recruit a control group that would accept not being screened. Even if subjects agreed to enter such a study, the likelihood of being screened outside of the study (contamination) is so high as to preclude the possibility of meaningful results. When discussing surveillance, there are additional considerations in addition to considering the process of submitting patients to tests. The whole process can and should, for the purposes of study, be divided into separate, but perhaps overlapping parts. These are: identification of at-risk subjects, application of appropriate screening tests, recall procedures for those with abnormal screening tests, and finally, enhanced follow-up for those with suspicion of, but not yet proven HCC. The subsequent sections will follow this general outline followed by a discussion about therapy.

Identification of ‘‘at-risk’’ population Most HCCs develop in the setting of pre-existing liver disease, and the presence of these liver diseases can be used to identify individuals at risk for

* Corresponding author. E-mail address: [email protected] (M. Sherman). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.04.012

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HCC versus those not at risk. Actually, because HCC arises in a previously normal liver in about 5% to 10% of cases [1], risk can be regarded as a continuous variable ranging from very low in those with no pre-existing liver disease, to up to 8% per year in patients in selected populations with liver disease (Fig. 1). The challenge is to determine at which point in this spectrum surveillance becomes necessary. No one would suggest routine surveillance in a population at minimal, but finite risk, such as the general population. At the other end of the spectrum, few would withhold surveillance from patients with cirrhosis secondary to viral hepatitis. Where, along the continuum of risk, does surveillance in a population become effective? There are no studies to guide clinicians, but modeling analyses have provided some insight. At least two cost/efficacy analyses of surveillance in cirrhotic patients [2,3] have shown that in a theoretical cohort of Child’s A class cirrhotics surveillance resulted in an increase in life expectancy of about 3 months. One study showed that if the incidence of HCC was 6%, the increase in life expectancy was about 9 months. This study did not include transplantation as a treatment option. The other study included transplantation but found no substantial difference in survival compared with the study in which transplantation did not occur [2]. Another study in chronic hepatitis B carriers found that when the HCC incidence was about 0.2% per year, there was an increase in survival, again, of about 3 months [4]. This study also did not include liver transplantation. The threshold is different in the two studies because of the high proportion of noncirrhotics in the hepatitis B group, allowing more patients to have resection as a treatment option. Both studies found that the efficacy of surveillance was highly dependent on HCC incidence. This provides a basis for selecting subjects who might benefit from HCC surveillance. The following discussion and recommendations are based on published incidence rates where available, and on expert opinion where not available. Chronic hepatitis B Based on the cost/efficacy models, if the incidence of HCC in a hepatitis B population exceeds 0.2% per year, surveillance is effective. Beasley et al, in Normal liver (0.001-0.55%/year) Non-cirrhotic hepatitis C (0.05-0.6%/year) Non-cirrhotic hepatitis B (males)(0.05-0.6%/year) Alcoholic cirrhosis (0.01-1.0%/year)(?) Cirrhotic hepatitis B or C (0.05-8.0%/year) 0.001%

0.01%

0.1%

1%

10%

Fig. 1. Spectrum of HCC incidence in normals and in different liver diseases.

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a now classic study, followed 3454 male hepatitis B carriers and 19,253 uninfected male controls [5]. In the initial report of this study, the relative risk of HCC in the hepatitis B virus (HBV) carriers was 223 [5]. A subsequent report found the relative risk to have fallen to 101 [6]. The yearly incidence of HCC in the hepatitis B surface antigen (HBsAg)-positive group was 0.5%, increasing to 1% at age 70. In cirrhotic HBV carriers, the relative risk was 961. The incidence of HCC in cirrhotics was 2.5% per year. Sakuma et al [7] found the relative risk of HCC in male Japanese railway workers to be 50. The incidence of HCC was 0.4% year. In these populations, hepatitis B infection likely was acquired at birth or in early childhood. The incidence of HCC in male hepatitis B carriers from Southeast Asia starts to exceed 0.2% per year at about age 40 [8]. The incidence of HCC in women is lower than in men, although age-specific incidence rates are hard to come by. Nonetheless, it seems appropriate to start screening at about age 50 in Asian women. In Asian hepatitis B carriers, a history of a first degree relative with HCC is another risk factor for HCC [9]. In the presence of such a history, surveillance should start at a younger age than 40, although what that age should be is hard to define. Africans with hepatitis B also seem to develop HCC at a younger age [10,11]. Whether this is true in African Americans or blacks from the Caribbean is uncertain. Although it is not possible to accurately define an appropriate age to start surveillance in these populations, surveillance should start at a younger age than 40 years. In Caucasian hepatitis B carriers, HCC largely occurs in the cirrhotic population, and thus surveillance should be limited to known cirrhotics [12]. Chronic hepatitis C The risk of HCC in patients with hepatitis C is limited to those with cirrhosis. The reported incidence varies between 2% and 8% per year [13– 15] (ie, exceeding the 1.5% per year cut-off that identifies cost-effective surveillance in cirrhotics) [2]. It should be noted that these are mostly clinicbased studies. There is a prospective population-based study of the risk of HCC in patients with hepatitis C [16]. In a study of 12,008 men, being anti-hepatitis C virus (anti-HCV)-positive conferred a 20-fold increased risk of HCC compared with being anti-HCV negative. The presence or absence of cirrhosis was not evaluated. Hepatitis C carriers who are precirrhotic do not have a significant risk of developing HCC and may not warrant surveillance. The European Association for Study of the Liver (EASL) single topic conference on HCC [17], however, suggested that surveillance should be provided to patients with cirrhosis or bridging fibrosis, recognizing that bridging fibrosis may develop silently into cirrhosis. This raises the question of whether all patients with hepatitis C who have been infected longer than 20 years should undergo biopsy to determine stage of fibrosis. If the initial biopsy shows

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only mild disease, should the biopsy be repeated at intervals so that the onset of bridging fibrosis or cirrhosis can be identified so that surveillance can be undertaken? There are no data to provide guidance on this issue. Cirrhosis caused by alcoholic liver disease The incidence of HCC in alcoholic cirrhosis is not really known. Most studies of this relationship date from before the identification of HCV. Given that hepatitis C is relatively frequent in alcoholics, most of these estimates were likely overestimates. In cohort studies, however, the proportion of patients with HCC reported in these earlier studies who had alcoholic liver disease as the sole risk factor is significant [18]. In one study, alcoholic liver disease accounted for 32% of all HCCs [19]. In an Austrian cohort with HCC, alcoholic liver disease was the risk factor in 35% of subjects [20]. It is not clear whether surveillance is worthwhile in this population, but most clinicians will include these patients in HCC surveillance programs. Cirrhosis caused by nonalcoholic steatohepatitis With the new recognition of the role of steatohepatitis in the generation of cryptogenic cirrhosis has come the realization that this disease is also a risk factor for HCC. No study has followed a sufficiently large group of such patients for long enough to describe an incidence rate for HCC. In one cohort study of patients with HCC, diabetes was found in 20% of patients and was the only risk factor for HCC [20]. Whether these patients were cirrhotic was not noted. Nonalcoholic fatty liver disease (NAFLD) has been described in cohorts of patients with HCC [21]. Again, in the absence of a control population, it is difficult to know whether the prevalence of diabetes or NAFLD in the HCC population was different than it would have been in a similar population without HCC. No recommendations can be made about surveillance in this population. Other liver diseases In other forms of chronic liver disease, the link between the underlying disease and the development of HCC is less well established. Nonetheless, cirrhosis caused by hemochromatosis or alpha 1-antitrypsin deficiency does appear increase the risk of HCC significantly [22–25]. Cirrhosis caused by autoimmune hepatitis and biliary cirrhosis may increase the risk of HCC, but the incidence likely does not exceed the threshold of 1.5% [26]. The potential target populations for HCC surveillance are listed in Table 1. Treated chronic viral hepatitis There is no clear evidence that treatment of chronic viral hepatitis reduces the incidence of HCC. There are no data on the incidence of HCC in

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Table 1 Groups in which HCC incidence is high enough to consider surveillance Hepatitis B carriers

Cirrhosis secondary to:

Asian males over 40 years of age Asian females over 50 years of age Asians of any age with a family history of HCC Africans, African Americans, or blacks from other countries over age 20 Any patient with cirrhosis

Chronic hepatitis C Genetic hemochromatosis Alpha 1-antitrypsin deficiency Alcoholic liver disease

patients treated with lamivudine. A European study suggested that interferon (IFN) therapy for chronic hepatitis B reduced HCC incidence [27]. A study from Taiwan indicated that successful IFN therapy (ie, those who developed anti-HBe) had a reduced incidence of HCC [28]. In contrast, a study from Hong Kong that included a larger cohort followed for longer periods found that the incidence of HCC was not decreased in the treated group [29]. Thus, it seems prudent to continue to offer surveillance to hepatitis B carriers with cirrhosis, even after therapy-induced seroconversion. Whether surveillance is required for noncirrhotic patients who respond to therapy is still an open question. There are several studies on the effect of treatment of chronic hepatitis C on the incidence of HCC. The results of these studies are summarized in a meta-analysis, which concluded that the benefit is seen only in those who were treated successfully (ie, had a sustained virological response), and even then, the effect was small [30]. Studies in Japan, however, have suggested that there is a reduced incidence of HCC in all treated patients, regardless of response [31–33]. Patients with hepatitis C and cirrhosis should, at least for now, continue to undergo surveillance even after successful antiviral therapy.

Surveillance tests The tests most commonly used for surveillance are serial serum alpha fetoprotein (AFP) assays and ultrasonography. Serological tests Although AFP traditionally has been used for HCC surveillance, it is in fact not very useful. AFP was useful as a diagnostic test in an era before the availability of abdominal CT scans and ultrasounds. A strongly positive AFP test confirmed the diagnosis of HCC and did away with the need for angiography to make the diagnosis. In that era, however, HCC presented late, when the cancers were often very large. Thus, it was not unusual to have AFP values that exceeded 100,000 ng/mL. With surveillance, the objective is to find small lesions, between 1 and 3 cm in diameter. Under

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these circumstances, AFP rarely is elevated in the diagnostic range. Trevisani et al [34] have shown that AFP is a poor diagnostic test when used to diagnose small cancers. They created a receiver operating characteristic (ROC) curve for AFP. At the optimal cut-off of the ROC curve (ie, the point at which fewest classification errors occurred), the sensitivity was only 0.6 (ie, 40% of HCCs would be missed). This was in a population in which half were known to have a mass in the liver on ultrasound (ie, a group in which the pretest probability of HCC was substantial). When using a 5.0% incidence of HCC, such as may be seen in many populations of hepatitis C cirrhotics, the positive predictive value was too low to be useful. In a screening population, where the incidence may be even lower, AFP will perform even less well. Others have come to the same conclusion in cohort studies of populations undergoing surveillance [35–37]. The AFP only rarely was elevated in the diagnostic range (more than 200 ng/mL). Another study [38] described a Youden index ([sensitivity + specificity]-1) of 0.422, which is poor. Alpha fetoprotein in serum exists as a heterogeneous population of molecules with different degrees of glycosylation [39]. These fractions can be separated by electrophoresis. One fraction, the AFP-L3 fraction, is said to be elevated in patients with HCC [40]. Even if the total AFP is not elevated, an increase of the AFP-L3 fraction is thought to indicate the presence of HCC [41]. The AFP-L3/total AFP ratio, which provides the optimal sensitivity and specificity for HCC surveillance, usually is set at 10% or 15% [40,42]. AFP-L3 seems to correlate better with larger tumors and less well-differentiated tumors [43]. These are not the types of cancers that surveillance programs are designed to find. Wang et al [44] have compared AFP-L3 performance characteristics in two populations. In one population of 70 patients with HCC, the sensitivity was 57% and specificity 89%. The positive predictive value was 83%, and the negative predictive value was 67%. In a population undergoing surveillance, the sensitivity was higher, at 75%; specificity was lower, at 83%, and the positive predictive value was only 60%. The performance characteristics of the test remain to be defined fully. AFP-L3 is a cumbersome and expensive assay, which is not widely available and is therefore not yet ready to be used as a surveillance test. Two other serological tests have been described as surveillance tests, the desgammacarboxyprothrombin (DGCP) activity [45,46] and serum afucosidase [47,48]. Of these, the DGCP has been investigated more extensively. Marrero et al [49] examined the performance characteristics of DGCP as a diagnostic marker. They constructed an ROC curve, and found that at the optimal cut-off, the sensitivity was 89%, and the specificity was 95%. Others have found the DGCP to be no better than AFP [50]. It has been suggested that use of both AFP and DCGP improves accuracy of detection of small HCCs, but this remains to be established firmly. Grazi et al [50] reported that the use of both assays increased the

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sensitivity from about 54% for either AFP or DCGP, to 74%. The specificity was lower for the combination than for AFP (87% versus 97%, respectively). Diagnostic accuracy increased by less than 10%. Alphafucosidase has not been studied adequately and cannot be recommended for routine use. It has been suggested, however, that the sensitivity of alpha-fucosidase is better than AFP (82% versus 39%), but the specificity is worse (71% versus 99%) [51]. Ultrasonography Ultrasonography (US) is the most widely used radiological test for surveillance. In reports of the performance characteristics of US, it was not always clear that the US was being used in a surveillance mode, as opposed to being used for diagnosis. The performance characteristics are likely to be different in the two circumstances. The performance characteristics of ultrasound as a screening test for HCC have been defined by Sherman et al [36] in a study of healthy HBsAg carriers, and by Pateron [37] in a surveillance study of patients with cirrhosis. The sensitivity was 71% and 78%, respectively, and specificity was 93%. The positive predictive value was 14% and 73%, respectively. When used as a surveillance test, ultrasound is a better test than serological assays, but there are still many false-positives and falsenegatives. Ultrasound is highly operator-dependent, and if performed in a cursory manner, it may result in small HCCs being missed. Some have suggested that a combination of AFP and US provides better performance than either alone. In one study [52], AFP plus US resulted in a higher detection rate than either test alone, but at the cost of a lower positive predictive value and a higher cost than either test alone. The problems of interpretation of ultrasound results in a cirrhotic liver will be discussed further in the next section. Surveillance interval The surveillance interval does not depend on the degree of risk of HCC, or on the incidence. The likelihood of finding a tumor small enough to allow curative therapy depends on the growth rate of the HCC. Ideally, the interval between examinations should be selected to cover the interval between an HCC being undetectable (eg, less than 2 to 3 mm) and being about 2 cm in size. Unfortunately, tumor growth rate varies greatly. Yoshino et al found a median tumor doubling time of 117 days [53]. AFP levels corresponded with tumor doubling time in 17 of 31 tumors studied. Sheu et al found that the most rapidly dividing tumor took 5 months to increase in size from 1 to 3 cm [54]. The surveillance interval also depends on the critical size of an HCC that is associated with a change in prognosis. For example, the prognosis of

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a 1 or 2 cm lesion is probably similar, whereas the prognosis of a 5 cm lesion is usually worse than that of a 1 to 2 cm lesion. There are two studies that clearly show that outcome is no different when patients undergo surveillance every 6 or 12 months. These studies evaluated mainly patients with chronic hepatitis C or alcoholic cirrhosis. Whether these results are applicable to patients with chronic hepatitis B or patients with other risk factors for HCC is not clear [55,56]. Recall procedures Recall includes determining when a surveillance test is sufficiently abnormal to trigger further investigation, what investigations should be performed, and if these are initially negative, when and how often should they be repeated. Before considering this, it is worth briefly reviewing the differential diagnosis and how it may be possible to confirm the presence of HCC. Of the many nodules that can be identified on US, only a few are relevant here. Hemangioma is the most frequent abnormal solid liver lesion found. The presence of a hemangioma, even in the setting of a cirrhotic liver in a patient with chronic viral hepatitis should not trigger an extensive search for HCC. If the radiologist is confident that the lesion is a hemangioma, it should be accepted as such and not pursued further. If the radiologist is uncertain, then it may be necessary to undertake additional investigations. Given the big differences in ultrasound quality, however, it is probably worth repeating the ultrasound at an institution where the interpretation can be trusted. When cirrhotic nodules are present, most often there is a diffuse nodularity, with no dominant nodule being present. This also does not warrant additional investigation. If there is a dominant nodule or a nodule that is larger than its neighbors, however, it may be a cirrhotic nodule, but HCC or dysplastic nodule becomes a possibility. On CT scanning and MRI, HCC is diagnosed by its vascularity. The lesion enhances during the arterial phase studies and washes out during the venous phase. Unfortunately, these characteristics also characterize some cirrhotic and dysplastic nodules and several other completely unrelated lesions (called pseudolesions by Japanese radiologists) [57–59]. These latter lesions are caused by portal vein inflow obstruction, arterio–portal shunting, steal phenomenon by hyper-vascular tumors, inflammatory changes, and aberrant blood supply caused by anatomic variants. Investigation of abnormal surveillance results If the first abnormal test result is an elevated AFP level, the next step is usually ultrasound. If the abnormal test is an ultrasound, the next step is usually triphasic spiral CT scan, or less commonly, MRI.

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US is limited in the detection of HCC because of the background heterogeneity of the cirrhotic liver and the technical difficulty of scanning patients with late-stage cirrhosis (small nodular liver). This results in an unacceptably low sensitivity of 45% [60,61]. The sensitivity is better in noncirrhotics [36]. CT scan is the next investigation of choice. In one study, sensitivity of the use of three-phase helical dynamic CT to detect HCC was 71% [62,63]. Dysplastic nodules were identified, with a sensitivity of only 39%. In this study, the radiological findings were compared with findings in the explanted liver. Helical dynamic CT is thus relatively insensitive for detection of small HCCs and dysplastic nodules in cirrhotic livers, especially for lesions smaller than 2 cm [62]. MRI is better at defining tumor morphology than CT scanning. The tumor capsule and central scar are seen more frequently than on CT. HCC demonstrates variable signal intensity on T1-weighted images and most HCCs are hyper-intense on T2-weighted images. Hypo-vascular or isovascular nodules of low T2 signal intensity are more likely to be dysplastic nodules, and hyper-vascular nodules of T2 high-signal intensity are more likely to be malignant. There is considerable overlap in the MRI characteristics, however. Because TI and T2 signal intensity alone is insufficient to distinguish HCC from dysplasia, contrast enhancement is necessary [60,64– 66]. In small HCC lesions, of 1 to 2 cm in diameter, the sensitivity of MRI is not good, about 50%. As the HCC size decreases, so does MRI sensitivity. The sensitivity of detection of HCCs smaller than 1 cm is only about 33% [60]. MRI detects only 15% of dysplastic nodules [60]. These findings have been confirmed by others [64–66]. Lesions smaller than 1 cm are difficult to diagnose by any means. Such lesions should be followed by serial US. Tissue diagnosis Early enhancement of a nodule on arterial phase of dynamic CT and MRI imaging is suggestive of HCC but also may be a benign lesion such as pseudo-lesion, hemangioma, or dysplastic nodule. Small size HCCs are not diagnosed easily on imaging or biopsy. If an area of early enhancement on dynamic CT or MRI can be seen as a nodule on abdominal US, diagnosis may be possible by histological examination. But many small nodules shown on CT image may not be seen on US and therefore cannot be biopsied, especially if the nodule is seen only on arterial phase. Additionally, a needle biopsy specimen is often not sufficient for definitive histology diagnosis. Fine needle biopsy and aspiration are safe and may allow a definitive diagnosis to be made [67]. In one study, fine needle aspiration was less accurate (48%) than intranodular fine biopsy (67%), and the highest diagnostic accuracy (96%) was obtained by the combined analysis of fine needle aspiration plus intranodular and extranodular fine biopsy [68]. In contrast, for lesions larger than about 2 cm, if two different imaging

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modalities show typical vascular lesions in the appropriate setting, this is sufficiently accurate that biopsy is not necessary [67–69]. Algorithm for investigation of initially abnormal surveillance tests If AFP is being used as the surveillance tool, many investigators will set the AFP level to trigger recall at about 10 to 20 ng/mL. The next step is usually an ultrasound. If there is a mass on the ultrasound, further investigations are undertaken, usually a CT scan or MRI. Depending on the tumor size, a biopsy may be undertaken. The EASL consensus conference on hepatocellular carcinoma recommended that if the lesion seen on ultrasound is smaller than 1 cm in diameter, it should be followed only by serial ultrasound [17]. Biopsy of such small lesions is difficult, and particularly with fine needle aspiration, loss of architectural features may make it impossible to distinguish a well-differentiated HCC from normal hepatocytes. Even expert pathologists may have difficulty with such small lesions. Nonexpert pathologists are less likely to call the lesion correctly. Second, when such small lesions are found on ultrasound, they usually are confirmed to be vascular on CT or MRI. Various studies have shown that up to 50% of such small vascular lesions less than 2 cm in diameter disappear with time. Shimizu et al [70] followed small (less than or equal to 2 cm) arterial enhancing lesions found on MRI for a mean follow-up period of nearly 2 years. For round or oval lesions, 52% disappeared over time. These are presumably vascular cirrhotic nodules, which remodel, or dysplastic nodules, which regress. Twenty percent were stable, and only 28% grew and were diagnosed as HCC. For lesions of other shapes (wedge-shape or geographic), the regression rate was about 70%. The EASL consensus conference also suggested that if the lesion is larger than 2 cm in the correct clinical setting (cirrhosis), and if two radiological techniques indicate appropriate vascularity, the likelihood is high that it is HCC, and biopsy is not necessary [17]. There are several studies showing that the sensitivity of the clinical/radiological assessment in lesions larger than 2 cm is better than 90% [67,69]. This is true in the setting of cirrhosis caused by chronic viral hepatitis. In noncirrhotic patients with hepatitis B, the question has not been studied as well, but in the absence of background nodularity, a new nodule larger than 2 cm is almost certainly HCC. The EASL consensus conference suggested that if the lesion was between 1 and 2 cm in diameter, a biopsy should be performed. This is expert opinion, however, rather than evidence-based. There are no studies looking at the accuracy of biopsy of nodules in this size range. Furthermore, given the radiological studies that suggest that many of these nodules are transient, it is likely that many unnecessary biopsies will be performed if this algorithm is followed. If the ultrasound does not show a mass, but the AFP is elevated, however, the investigator has to decide whether this is a true or false

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negative. This decision usually involves serial radiological and serological investigations. This enhanced follow-up will be discussed in the next section. Enhanced follow-up Enhanced follow-up is the process set in place once the initial round of investigations has not diagnosed HCC convincingly or clearly excluded HCC (Fig. 2). This is the most common scenario after initial investigation of

A US nodule < 1 cm in diameter

CT Scan or MRI

Non vascular lesion

Vascular lesion

Ignore

Enhanced follow-up

B US nodule 1-2 cm in diameter

CT scan/MRI

Non vascular lesion

Ignore

Vascular lesion

AFP < ~150 ng/ml

Negative for HCC

Treat as HCC

AFP > ~ 150 ng/ml

Biopsy

Positive for HCC

Enhanced follow-up

C US lesion > 2 cm in diameter

CT scan and MRI

Vascular with typical HCC Non-vascular characteristics

Enhanced follow-up

Treat as HCC

Fig. 2. Possible algorithms for the investigation of abnormal screening test results.

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abnormal surveillance tests. For example, investigation of a rising AFP may have included negative ultrasounds, CT scan, and MRI. Clearly, such a patient is at high risk of having an undiagnosed HCC. Similarly, a patient with a mass on ultrasound, which cannot be seen on CT or MRI, is at high risk of having HCC. How should such patients be followed to ensure that the HCC is diagnosed in a timely manner? The sequence of investigations and periodicity of follow-up should be designed to maximize the likelihood of excluding the presence of HCC with a high degree of certainty. In this situation, no specific recommendations have been made, because there are no studies addressing the appropriate algorithm for these situations. Follow-up should be more frequent, because the starting point is not a invisible lesion, but a lesion that is already up to 2 cm in diameter. Many experts evaluate these patients at 3- to 4-month intervals. Whether the follow-up should be by US or by CT scanning, however, is not clear. Experts also recommend that if an initial biopsy is negative and the nodule enlarges, another biopsy should be performed. Treatment of HCC Evaluation of the efficacy of different treatment modalities for HCC is difficult because of the dearth of randomized controlled trials. Potentially curative forms of therapy include resection, liver transplantation, and possibly ethanol injection or other forms of local ablation. Many of the reported studies have compared surgical with nonsurgical therapy in groups of patients with different degrees of severity of liver disease, or tumors at different stages. Alternatively, some studies have compared results of resection of small tumors with results of resection of large tumors. These studies are particularly difficult to interpret because of lead-time bias. Because the natural history of small HCCs has been so poorly described, Llovet et al undertook a review of the literature and added data of their own in an attempt to describe the natural history based on features at presentation [71]. They found that for patients who were the best treatment candidates (ie, good liver function and small cancers [smaller than about 2.5 to 3 cm in diameter]) the 1-year untreated survival rate was about 80%; the 3-year survival rate was about 50%, and the 5-year survival rate was 16%. Studies on treatment outcome without a control group should be compared with these data. Resection Resection, in the best of hands, offers a 70% 5-year survival rate, but at the cost of about 50% recurrence rate. Surgical resection is a potentially curative therapy. Perioperative mortality, at between 3% and 10%, has improved over the last decade, possibly a reflection of better patient selection and better surgical technique [72–75]. When Llovet’s best candidates underwent re-

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section, the survival rate at 1-year was better than 90%, and the 5-year survival rate was 74% [71]. Among patients who were marginal candidates for surgery, however, the 5-year survival rate after resection was only 25% [71]. Resection is limited to patients with good liver function (ie, Child’s A cirrhosis with no or only minimal portal hypertension). Thus patients with poor liver function probably should not be screened, if liver transplantation is not an option. Furthermore, some patients with asymptomatic lesions found by surveillance will not tolerate major hepatic resections even if they are Child’s A cirrhotics. Evaluation of liver function before resection is an imperfect science, despite recent advances in the use of indocyanine green clearance, and does not distinguish those who will do poorly after resection versus those who will do well [76]. Another factor influencing whether a resection will be performed is the location of the lesion and the amount of liver to be removed. The size of the lesion is less of a factor, but because large lesions often are associated with satellite lesions or other intrahepatic spread, these factors may limit resection. Vascular invasion seen macroscopically or radiologically is a poor prognostic factor and may induce a change of mind about undertaking resection, because cure is unlikely [77]. Local ablation Local ablation, of which there are several forms, can be used with curative intent. Most reports have described the use of injection of alcohol to coagulate the HCC. Most authors would not treat lesions larger than about 5 cm, but treatment of larger lesions under general anesthetic has been described [78,79]. The survival rate after local ablation is about 40% to 50% at 5 years, but the recurrence rate is also about 50% [79]. Given that most local ablation procedures are performed for small tumors (less than 3 cm in diameter), it not certain that survival is enhanced compared with no treatment. There have not been any randomized controlled trials comparing any form of local ablation to resection or to no therapy. In a nonrandomized study, however, Livraghi et al have reported a 71% 3-year survival rate in 155 patients with unifocal tumors less than 5 cm treated with ethanol injection, compared with a 79% survival rate in 120 patients undergoing hepatic resection, and 26% in 116 untreated patients [80]. Although this was not a randomized trial, the results suggest that ethanol therapy may be a therapeutic option in a subset of patients. The long-term outcome after ethanol injection is less clear. Other forms of local ablation include injection of concentrated acetic acid, injection of hot saline, and tumor coagulation with microwave- or radio wave-generated heat. Radiofrequency ablation (RFA) has become very popular. Its advantage over ethanol injection is that ablation usually can be accomplished in a single sitting, rather than the several sittings required to achieve complete ablation with ethanol. There are no long-term

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survival data available for RFA. RFA has been compared with ethanol injection. Complete necrosis is achieved more often with RFA, requiring fewer sessions, but the complication rate is higher [81]. Some authors have cautioned against the use of RFA, suggesting that there is a high rate of needle track seeding [82]. Chemoembolization Chemoembolization involves injection of a chemotherapeutic agent, usually Adriamycin or epirubicin, mixed with an oily radiographic contrast agent, Lipiodol, into the branch of the hepatic artery, which feeds the tumor. After the injection of the chemotherapeutic agent, the feeding artery is embolized using gelfoam or other agents. This causes transient obstruction to blood flow. Early studies of chemoembolization did not show any survival benefit [83,84]. Two recent studies, however, have shown that chemoembolization does enhance survival [85,86]. A meta-analysis of all the studies confirmed the efficacy of chemoembolization [87]. Why, then, were so many studies negative? One explanation is that chemoembolization may be quite injurious to the liver. For example, one study that found no effect had a high early death rate in the treated group, higher than would be expected [83]. It is likely that patient selection is the key to optimizing results, with patients with good liver function (Child’s A cirrhosis) better able to tolerate the loss of liver function that sometimes accompanies chemoembolization. Patients with chronic hepatitis B must be covered with lamivudine to prevent enhanced viral replication that might occur on recovery of immune function after the effects of the chemotherapy have worn off [88]. Liver transplantation Although initial results of liver transplantation for HCC were poor (less than 50% survival at 5 years), more recent studies have shown that this is perhaps the best option for suitable patients. Llovet’s analysis [71] showed that the 5-year survival rate in the transplanted group (74%) far exceeded survival with any other form of treatment. The standard criteria are that there should be either only a single lesion smaller than 5 cm, or up to three lesions, none larger than 3 cm diameter [89]. Transplantation of such patients is associated with a better than 70% 5-year survival rate, and a recurrence rate that is less than 15%. These are not intention-to-treat analyses, however. The studies only reported on those who actually received a new liver, and did not describe what happened to those who for various reasons did not get transplanted. Llovet at al [90] have reported survival after listing for orthotopic liver transplantation (ie, an intention-to-treat analysis). They showed that survival was critically dependent on the waiting time before transplant was performed. If the dropouts on the list were included in the analysis (intention to treat), the 5-year survival fell to about 50%. These considerations led the United Network for Organ Sharing to

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agree that patients with HCC should get preferential listing. The effect that this might have on waiting lists for patients with other liver diseases has not been evaluated. Recent studies have shown that the criteria for accepting a patient for transplantation can be liberalized somewhat [91,92]. A single mass larger than 5 cm, or multiple masses exceeding the guidelines a little can be transplanted with minimal reduction in survival. Now that liver transplantation has become an accepted treatment for patients with HCC, investigators have attempted to determine whether patients should undergo therapy for HCC while on the waiting list. There are no randomized controlled studies, although there are studies in which either local ablation or chemoembolization have been used as a bridge to transplantation [93,94]. Whether these strategies will have any impact on the long-term outcome of these patients is not known. Llovet et al [95] used modeling techniques to determine whether patients on the waiting list for liver transplantation should be treated with resection or local ablation as a bridge to transplantation. Their results suggested that if the waiting time was shorter than 6 months, the gain in life expectancy was insignificant in patients who were candidates for resection. As the waiting times increase, however, the gain in life expectancy increases. At 12 months waiting time, the gain in life expectancy was 4.8 months, and at 18 months or more, the gain was about 6 months. In subjects who were candidates for local ablation but not resection, if the waiting time was 6 months or more, the gain in life expectancy exceeded 5 months. Thus, this study found that local ablation was worth performing in all suitable candidates, unless the waiting time was shorter than 6 months. It was only worth undertaking resection, however, if the waiting list exceeded 6 months. Palliative therapy Standard chemotherapy is of little benefit in patients with HCC not amenable to the therapies discussed previously. At best, chemotherapy provides additional survival of only a few weeks [96]. Several experimental therapies have been studied in phase II trials. They include: I131 Lipiodol Radiolabeled antiferritin antibodies BCL-2 antisense mRNA Doxorubicin bound to iron particles Conformational radiotherapy Long-acting somatostatin infusion Seocalcitol Thymitaq Thalidomide Some of these agents look promising, but none has been developed further into phase III studies. As a result, none of these agents can be recommended as standard therapy in patients with HCC.

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In summary, liver transplantation is the treatment of choice if it is available and if the waiting time is not too long. If liver transplantation is not available, or not available for sufficient numbers of patients, for those with good liver function, resection is the treatment of choice. Local ablation should be reserved for those with smaller lesions. There is probably a limitation to the number of lesions that can be successfully treated, but that limit is not known at present. Finally, chemoembolization should be reserved for patients with more extensive disease. A suggested algorithm for management of HCC has been presented by the Barcelona Cancer of the Liver Clinic [17]. References [1] Donato F, Gelatti U, Chiesa R, Albertini A, Bucella E, Boffetta P, et al. A case-control study on family history of liver cancer as a risk factor for hepatocellular carcinoma in North Italy. Brescia HCC Study. Cancer Causes Control 1999;10:417–21. [2] Sarasin FP, Giostra E, Hadengue A. Cost-effectiveness of screening for detection of small hepatocellular carcinoma in Western patients with Child-Pugh class A cirrhosis. Am J Med 1996;171:422–34. [3] Arguedas MR, Chen V, Eloubedi M, Fallon MB. Screening for hepatocellular carcinoma in patients with hepatitis C cirrhosis: a cost–utility analysis. Am J Gastroenterol 2003;98: 679–90. [4] Collier J, Krahn M, Sherman M. A cost–benefit analysis of the benefit of screening for hepatocellular carcinoma in hepatitis B carriers. Hepatology 1999;30:481A. [5] Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus: a prospective study of 22,700 men in Taiwan. Lancet 1981;2:1129–33. [6] Beasley RP. Hepatitis B virus. Cancer 1988;61:1942–56. [7] Sakuma K, Saitoh N, Kasai M, Jitsukawa H, Yoshino I, Yamaguchi M, et al. Relative risks of death due to liver disease among Japanese male adults having various statuses for hepatitis B s and e antigen/antibody in serum: a prospective study. Hepatology 1988;8: 1642–6. [8] Beasley RP, Hwang LY. Epidemiology of hepatocellular carcinoma. In: Vyas GN, Dienstag JL, Hoofnagle JH, editors. Viral hepatitis and liver disease. New York: Grune & Stratton; 1984. p. 209–24. [9] Yu MW, Chang HC, Liaw YF, Lin SM, Lee SD, Liu CJ, et al. Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives. J Natl Cancer Inst 2000;92:1159–64. [10] Kew MC, Macerollo P. Effect of age on the etiologic role of the hepatitis B virus in hepatocellular carcinoma in blacks. Gastroenterology 1988;94:439–42. [11] Kew MC, Marcus R, Geddes EW. Some characteristics of Mozambican Shangaans with primary hepatocellular cancer. S Afr Med J 1977;51:306–9. [12] Fattovich G, Brollo L, Giustina G, Noventa F, Pontisso P, Alberti A, et al. Natural history and prognostic factors for chronic hepatitis type B. Gut 1991;32:294–8. [13] Fattovich G, Giustina G, Degos F, Tremolada F, Diodati G, Almasio P, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology 1997;2:463–72. [14] Bruix J, Barrera JM, Calvet X, Ercilla G, Costa J, Sanchez-Tapias JM, et al. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatitis cirrhosis. Lancet 1989;2:1004–6. [15] Niederau C, Heintges T, Lange S, Goldmann G, Niederau CM, Mohr L, et al. Prognosis of chronic hepatitis C: result of a large prospective cohort study. Hepatology 1998;28: 1687–95.

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Gastroenterol Clin N Am 33 (2004) 693–708

Antiviral therapy: role in the management of extrahepatic diseases Jae D. Kim, MDa, Averell H. Sherker, MD, FRCP(C)a,b,* a

Section of Gastroenterology and Hepatology, Washington Hospital Center, 110 Irving Street Northwest, Washington, DC 20010, USA b Center for Liver Diseases, Washington Hospital Center, 110 Irving Street Northwest, Washington, DC 20010, USA

It long has been recognized that infection with hepatitis viruses can be associated with pathological processes outside the liver. The extrahepatic manifestations of hepatitis B virus (HBV) and hepatitis C virus (HCV) largely are believed to relate to immune-mediated mechanisms. This frequently involves the deposition of immune complexes in involved tissues. Additionally, these viruses have been shown to replicate at relatively low levels in some cells outside the liver, and this may be an additional mechanism for extrahepatic disease. In some disorders, association with hepatitis infection has been made on epidemiological grounds alone, with no obvious pathophysiological mechanism identified. In individual disorders, depending on the believed pathological mechanism, rational therapy may involve treatments directed at the immune system, the virus, or a combination thereof. As immunosuppressive therapy may be associated with detrimental effects in viral hepatitis, especially HBV infection, therapeutic decisions are often difficult and must be considered carefully. In some processes, the extrahepatic involvement commonly is self-limited, and conservative management may be appropriate. This article considers the extrahepatic manifestations associated with HBV and HCV infection, the strength of the evidence for the association, potential pathological mechanisms, and evidence-based therapeutic recommendations. As many of these extrahepatic conditions are uncommon, published reports have been largely uncontrolled or anecdotal.

* Corresponding author. E-mail address: [email protected] (A.H. Sherker). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.04.013

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Extrahepatic manifestations of hepatitis B Polyarteritis nodosa Polyarteritis nodosa (PAN) is a necrotizing vasculitis of small- to mediumsized arteries. Symptoms include fever, abdominal pain, and polyarthropathy. Renal involvement, cutaneous vasculitis, and bowel ischemia are some of the more serious manifestations of this disease. Factors that portend a poor prognosis include proteinuria greater than 1 g per day, creatinine greater than 1.6 mg/dL, gastrointestinal involvement, and central nervous system involvement [1]. PAN has a well-established and long-recognized link with chronic HBV. The range of HBV prevalence reported in PAN has been 10% to 54% [2]. The conventional treatment of PAN involves immunosuppressive therapies such as corticosteroids and cyclophosphamide. Also, plasma exchange has been used with some success [3]. Unfortunately, immunosuppression may enhance viral replication in HBV-associated PAN [4]. Furthermore, withdrawal of immunosuppression can lead to reactivation of HBV [5,6]. McMahon et al reported on 15 patients of Yupik Eskimo origin who presented with PAN during acute HBV infection. All were positive for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg). Two patients who received no therapy and five patients who received corticosteroids died. Six patients who received corticosteroids and cyclophosphamide survived for a mean of 55 months [7]. Guillevin et al reported on a series of six patients with HBV-associated PAN treated with plasma exchange and interferon (IFN)-a2b [2]. All were positive for HBsAg and HBeAg at the start of therapy. All six patients experienced a resolution of their PAN symptoms, and four seroconverted HBeAg with or without HBsAg seroconversion. This series had significantly higher rates of seroconversion than older series treated with immunosuppressive therapies alone. It is not proven that seroconversion is associated with greater improvement of PAN manifestations, but immunosuppressive therapy can enhance HBV replication, further exacerbating the liver disease. The combination of immunosuppressive therapy with the antiviral nucleoside analog, lamivudine (Epivir HB), or the nucleotide analog, adefovir dipivoxil (Hepsera), may be a rational approach to treatment of PAN, but data supporting this strategy are limited. One case report describes lamivudine treatment of an HBV-infected renal transplantation patient who developed cutaneous PAN. He was positive for HBsAg, HBeAg, and HBV DNA. Lamivudine (100 mg per day) resulted in clinical resolution of PAN and loss of detectable HBV DNA. Long-term efficacy remains an open question, given the propensity of HBV to develop lamivudine resistance [8]. Glomerulonephritis The association between HBV and glomerulonephritis (GN) is well established. Histologically, membranous glomerulonephritis (MGN) and

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membranoproliferative glomerulonephritis (MPGN) are the most commonly encountered entities in HBV-associated GN. The highest prevalence is found in children and in areas where HBV is endemic, such as Asia and sub-Saharan Africa [9]. The most common clinical presentation is proteinuria and nephrotic syndrome. The pathogenesis of HBV-associated GN is unknown. Immune complexes involving all three major HBV antigens (HBsAg, HBcAg, and HBeAg), however, have been isolated from glomeruli of affected patients [10]. Uncertainty exists as to which antigen is the most important inciting antigen. In case series, the course of HBV-associated GN is self-limited, usually lasting 6 months to 2 years. This is particularly so in children with MGN. MPGN, more common in adults, may not resolve as readily, especially if it is diffuse [9]. In most cases, clinical resolution of GN coincides with seroconversion of HBeAg or HBsAg. Rarely, chronic renal failure will ensue. Corticosteroids and cytotoxic treatments are not indicated in HBVassociated GN. Most case series show no benefit, or, at best, transient benefit from immunosuppressive therapy. Additionally, immunosuppression may enhance viral replication [11], and its withdrawal may lead to a potentially severe flare of hepatitis [12,13]. Antiviral therapy of HBV-associated GN is predicated on the notion that HBV antigen–antibody complexes are responsible for the renal disease. Lisker-Melman et al treated five patients with HBV-associated GN and persistent HBsAg and HBeAg with IFN. All patients had chronic hepatitis on liver biopsy and more than 2 g per day of proteinuria. Four of five patients showed improvement in proteinuria to less than 1 g per day and return of serum albumin to normal levels. These results correlated with improvements in aminotransferase levels and liver histology and seroconversion of HBeAg [14]. Conjeevaram et al showed that patients who responded to IFN therapy could anticipate long-term remission of their glomerulonephritides. In a study of 15 patients with HBV-associated GN, eight had sustained loss of HBeAg and HBV DNA after IFNa treatment. Seven of eight responders showed sustained improvement in proteinuria, followed over a 1- to 7-year period. The seven nonresponders continued to have renal disease. All responders had MGN, whereas four of seven nonresponders had MPGN [15]. Many papers in the literature do not clearly distinguish between the effects of IFN therapy upon HBV-associated MGN and MPGN. IFN treatment of HBV-associated MPGN is limited to small case series, which split evenly between improvement and continued proteinuria [16]. There are no controlled studies that demonstrate that antiviral therapy hastens recovery or improves outcome when compared with conservative management. The observation that most reported remissions of renal disease are accompanied by seroconversion of HBV antigens, however, provides a compelling argument for the use of antiviral therapy.

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Extrahepatic manifestations of hepatitis C Cryoglobulinemia There are three types of cryoglobulinemia. Type I is associated with the expression of monoclonal immunoglobulin. Type II consists of polyclonal IgG and a monoclonal IgM rheumatoid factor, while type III has polyclonal IgG and rheumatoid factor. The term mixed cryoglobulinemia encompasses types II and III. Mixed cryoglobulinemia without a defined cause is termed essential mixed cryoglobulinemia (EMC), perhaps a misnomer now that it is recognized that the vast majority of these cases are HCV-associated. EMC may present with arthralgias, purpura, and peripheral neuropathy, but many cases are subclinical. Pathologically, vasculitis and glomerulonephritis can occur. All of these effects stem from deposition of immune complexes and complement in small- to medium-sized vessels [17,18]. Links between EMC and HBV in the literature are equivocal, and largely date to the era before the identification of HCV [19,20]. In contrast, the connection between EMC and HCV is well established [21–24]. In some studies, the incidence of HCV antibody in EMC populations approaches 90% [25–27]. Conversely, serologic evidence of EMC is detected in 36% of HCV populations [28]. Several studies report HCV RNA and HCV antibody within cryoprecipitates [29,30]. Agnello et al further describe the tenfold concentration of HCV antibody and the 1000-fold concentration of HCV RNA in cryoprecipitate relative to serum [24], as have others [22]. The classical treatment of EMC consists of corticosteroids, cytotoxic agents, and plasmapheresis [18]. In light of the high prevalence of HCV in EMC, much data regarding antiviral treatment have accrued. Dammacco et al completed a prospective randomized study of EMC patients, of whom 80% were HCV-positive [31]. Patients were treated for one year with natural interferon a (nIFN-a), nIFN-a plus prednisone, prednisone alone, or placebo. More than half of patients treated with nIFNa—with or without prednisone—achieved a complete clinical response. The prednisone and placebo groups achieved much lower rates of clinical response. Ferri et al conducted a study of 20 patients with HCV and EMC [32]. Treatment consisted of 6 months of IFN-a or no antiviral therapy followed by a crossover to 6 months of the other therapy. A significant improvement in EMC symptoms and serum cryoglobulin levels were observed during IFNa treatment. Misiani et al conducted a prospective, randomized, and controlled trial of recombinant IFN-a2a in EMC. Twenty-seven patients were treated with IFN-a2a, and 26 control patients received no antiviral therapy. At the end of the treatment period, significant improvements in EMC symptoms, cryoglobulin levels, and creatinine were observed. A unifying characteristic of all three studies was a strong correlation between clinical response of EMC and the disappearance of HCV RNA in serum. This lends powerful

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support to the etiologic role of HCV in EMC [33–35]. Unfortunately, another common finding in these and other uncontrolled series was a rebound of symptoms upon withdrawal of IFN [32–36]. Caution must be exercised in the treatment of cryoglobulinemia, as cases have been reported of exacerbation of cryoglobulinemia, and even fatality, on IFN [37–39]. More recently, several investigators have studied combination IFN and ribavirin therapy in EMC. Cacoub et al performed a retrospective study of 14 patients, who underwent combination IFN-a and ribavirin treatment for at least 6 months. They were followed for 6 months after stopping therapy. Ten patients had complete clinical and immunologic response at the end of their follow-up [40]. Calleja et al treated eight nonresponders and five relapsers to IFN-a monotherapy. All had cryoglobulinemia and were treated with combination IFN-a and ribavirin for 12 months and then followed for an additional 12 months. Sustained remission of HCV was seen in 37.5% of nonresponders and 80% of relapsers [41]. As with IFN monotherapy, the correlation between clinical response of EMC and disappearance of HCV RNA held true. Finally, ribavirin monotherapy has been studied in five EMC patients with HCV who were nonresponders to IFN monotherapy. Oral ribavirin was given for a period of 10 to 36 months. Although rapid improvement in EMC symptoms was observed, relapse occurred within 3 months of ribavirin cessation. Of note, none of these patients achieved eradication of HCV RNA [42]. Potential treatments of hepatitis C-associated cryoglobulinemia are summarized in Box 1. Lymphoma Viral etiologies of lymphoma are well established. Epstein-Barr virus and human T-cell leukemia viruses I and II have been associated with human

Box 1. Management of hepatitis C-associated mixed cryoglobulinemia First-line therapy Interferon with or without ribavirin Second-line therapy for nonresponse or relapse of symptomatic cryoglobulinemia Corticosteroids Cyclophosphamide Plasmapheresis Unproven therapy Ribavirin monotherapy

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lymphomas. Several studies have suggested a similar link between HCV and B-cell non-Hodgkin lymphoma (NHL) [43–48]. It has been established that HCV is a lymphotropic and hepatotrophic pathogen [49]. Ferri et al found that patients with EMC and HCV were more likely to have HCV RNA in their peripheral blood mononuclear cells (PBMC) than those without EMC [50]. The implication of these results is that HCV may cause the clonal expansion of B cells, necessary for the clinical manifestations of EMC and NHL. This is supported by the results of by Pozzato et al, who found that 12 of 31 patients with HCV and EMC had low-grade NHL discovered on bone marrow biopsy [51]. Several Italian studies consistently have found a significantly higher prevalence of HCV infection in NHL patients than in controls, whether they were healthy or had other lymphoproliferative disorders. Prevalence ranged from 28% to 42% [43,44,48,52]. Similar findings were seen in French populations [46]. Zuckerman et al found a significantly high prevalence of HCV (22%) in an ethnically diverse cohort of NHL patients in California [45]. Consensus is lacking regarding the association of HCV with NHL, however, casting doubts on the proposed association. A Canadian study by Collier et al determined the prevalence of HCV in 100 NHL subjects and compared it with 100 control subjects with nonhematologic malignancies. No difference in HCV prevalence was found [53]. An uncontrolled British study found no increased prevalence of HCV antibody in NHL patients compared with the general population [54]. Finally, the recent multi-center Veteran’s Administration (VA) study, involving 34,204 patients with HCV and 136,816 HCV-negative controls, found no increased prevalence of NHL in its HCV population relative to controls [55]. Data on treatment of NHL with antiviral therapies are limited to small studies, mostly uncontrolled. Mazzaro et al performed bone marrow biopsies on 20 patients with HCV and EMC. Six were found to have lowgrade NHL, and all were treated with IFN-a. Among the patients with NHL, three patients achieved remission at the end of therapy. The patients with remission all had serum HCV RNA become undetectable [56]. Zuckerman et al studied the effect of antiviral treatment on immunoglobulin heavy chain rearrangement and chromosomal translocation t(14;18) in HCV patients. Fifteen patients with either of these alterations were treated with IFN-a and ribavirin for 6 to 12 months. A control group of 16 patients with the same genetic findings was not treated. A significantly increased rate of normalization of immunoglobulin heavy chain rearrangement and t(14;18) translocation was seen in the treated group [57]. Hermine et al studied the effect of antiviral therapy on splenic lymphoma. The study group (n = 9) was HCV infected, and the control group (n = 6) was negative for HCV markers. All were treated with IFN-a2b with or without ribavirin. None of the HCV-negative patients had a response to IFN. In contrast, seven of the HCV-positive patients had a complete response of their lymphomas to IFN

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monotherapy. The remaining two patients were treated with IFN-a2b and ribavirin. One had a complete response, and the other had a partial response. All responders, whether partial or complete, had loss of detectable HCV RNA [58]. Glomerulonephritis The association between HCV and glomerular disease has been proposed for some time. One Japanese series found a 60% prevalence of HCV antibody in patients with MPGN [59]. Additionally, HCV has been associated with MGN and the glomerulonephritis occurring in the context of cryoglobulinemia [60]. The pathogenesis of glomerular disease likely involves immune complex deposition. Indeed, Johnson et al found glomerular deposits of IgG, IgM, and C3 in renal biopsies of eight patients with HCV and proteinuria. Deposition of HCV RNA or antigens could not be demonstrated in this series [29]. In another study, however, Sabry et al demonstrated virus-like particles in subendothelial and mesangial areas by electron microscopy [61]. Interferon monotherapy has not been as promising for the treatment of HCV-associated glomerulonephritis as it appears to be for HCV-associated cryoglobulinemia. In one study, 14 patients received 3 million units of IFN-a thrice weekly for 6 to 12 months. Significant improvements in proteinuria were observed, but renal function was unchanged. Those patients with disappearance of HCV RNA had a better clinical response, but all relapsed after discontinuing IFN-a therapy [62]. In another study, 20 patients with HCV glomerulopathy underwent IFN-a monotherapy. In the 16 patients who remained viremic at 3 months, ribavirin was added. Overall, the median level of proteinuria and serum albumin improved. On an individual basis, however, 15 patients showed improvement in their renal function, while five had deterioration. There was no association between loss of HCV RNA and clinical improvement [61]. The reported follow-up, however, was limited to the end of treatment, so the durability of the effects of combination therapy remains unknown. On a cautionary note, it is important be aware that nephrotoxicity has been associated with IFN treatment on rare occasions [63–67]. Diabetes mellitus There are conflicting epidemiological data regarding the association of HCV and diabetes mellitus (DM). Mehta et al analyzed 9841 people in whom HCV status and presence or absence of diabetes were documented. People 40 years of age or older with HCV were more likely to have DM type 2, with an odds ratio of 3.77 (95% confidence interval [CI], 1.8 to 7.87) [68]. Simo et al compared 176 diabetic patients with 6172 blood donors matched by risk factors for HCV infection. The diabetic group was more likely to be

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infected by HCV, with an odds ratio of 4.39 (95% CI, 2.61 to 7.24) [69]. Several studies have documented higher rates of diabetes in HCV populations compared with HBV populations [70–73]. In the large multicenter VA study, however, DM type 2 was decreased in individuals with HCV compared with uninfected controls [55]. No antiviral therapy trials targeted specifically at diabetics have been reported. One study, however, looked at the effect of recombinant IFN-a monotherapy on glucose tolerance of patients with HCV. Fifteen patients underwent measurement of insulin sensitivity before and after 4 months of therapy. A significant improvement in insulin sensitivity was observed in patients with normal glucose tolerance at baseline and in those with diabetes [74], suggesting that IFN can be used safely in diabetics. Several case reports, however, document the onset of diabetes type I in HCV patients undergoing IFN-a treatment. All affected patients showed some predilection for diabetes as evidenced by HLA II markers, and all developed new or increased levels of specific autoantibodies such as glutamic acid decarboxylase antibody, islet cell antibody, and insulin autoantibody [75–78].

Porphyria cutanea tarda Porphyria cutanea tarda (PCT) is the most common form of porphyria. This disease results from a deficiency of uroporphyrinogen decarboxylase. In type I PCT, a sporadic form, the enzyme is decreased to 50% of normal levels within hepatocytes. In the familial type II PCT, the enzyme defect occurs in hepatocytes and erythrocytes. The enzymatic defect is a necessary but not sufficient condition to affect clinical manifestations. There is typically an additional triggering factor, such as alcohol, estrogen, or iron overload. PCT occurs commonly in the setting of liver dysfunction. Thus, investigators hypothesized a connection between PCT and HCV soon after the virus was identified [79–81]. In the multi-center VA study, PCT was 12 times more prevalent in patients with HCV compared with controls (95% CI, 9.63-15.64) [55]. Most other epidemiologic studies have studied populations of patients with PCT, looking for the prevalence of HCV. A prevalence ranging from 21% to 76% has been documented in these studies [79–87]. Of studies that were controlled, HCV prevalence was significantly higher in patients with PCT than in control groups consisting of patients with various other liver disease and healthy individuals. Sporadic PCT had a greater association with HCV than familial PCT [80,87]. Although only case reports exist describing IFN-a treatment for HCV PCT, all report dramatic improvement in skin lesions, urine porphyria, and serum aminotransferase levels. Eradication of virus was not a prerequisite for resolution of PCT [88–90].

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Lichen planus Lichen planus (LP) has been associated with several chronic liver diseases. Its association with HCV was confirmed in the large VA study, where its prevalence in the HCV population was twice that of controls (95% CI, 1.84-2.98) [55]. Certain geographic regions display strong associations between HCV and LP, as reported in Japanese [91] and Italian [92] studies. Pilli et al suggested that oral LP resulted from recruitment of T cells against epithelial cells expressing HCV antigens [93]. The frequency of HCV-specific CD8þ cells was significantly higher in LP tissue compared with serum. Unfortunately, IFN has not been shown to be helpful in HCV-associated LP. On the contrary, Dalekos et al reported that in 2 of his 46 HCV patients treated with IFN-a, new-onset LP developed [94]. In a small Japanese series, LP even developed in patients who lost HCV RNA on IFN-a [95].

Mooren’s corneal ulcer Mooren’s corneal ulcer is a painful disorder affecting the peripheral region of the cornea and insidiously progressing to blindness. Immunosuppression has been the conventional treatment for this disease. Wilson et al reported two patients with HCV and Mooren’s corneal ulcer. Both responded to IFN-a2b within 6 months. One patient maintained a sustained remission after cessation of therapy, without loss of detectable HCV RNA. Although preliminary, the results encourage the use of IFN for Mooren’s corneal ulcer in the context of HCV [96].

Sjogren’s syndrome Sjogren’s syndrome has been linked to HCV, especially given its common occurrence in cryoglobulinemia. In a study by Haddad et al, lymphocytic sialadenitis was seen in 16 of 28 patients with HCV, but in only 1 of 20 control patients [97]. Other reports, however, have failed to show an association between HCV infection and Sjogren’s syndrome [98,99].

Thyroid disorder Thyroid disorders have been connected to HCV infection by means of an autoimmune mechanism. To support this assertion, Tran et al demonstrated a high prevalence of thyroid autoantibodies in IFN-naive HCV patients [100]. Other studies, however, have failed to establish an epidemiologic link between the HCV infection and thyroid disease. It is established that IFN therapy can elicit both biochemical and clinical thyroid disease, especially in those with a personal or familial predisposition to autoimmune conditions [101].

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Table 1 Extrahepatic manifestations of hepatitis B virus Extrahepatic manifestation

Strength of evidence of association

Role for antiviral treatment

Polyarteritis nodosum Membranous glomerulonephritis Membranoproliferative glomerulonephritis

Strong Strong Strong

þ þ o

Summary Several extrahepatic conditions have been associated with viral hepatitis. Often these associations have been reported in small, uncontrolled case series, but many have been confirmed in large epidemiological surveys. It is rational to expect that in those conditions believed to be caused by direct infection of extrahepatic tissue or deposition of immune complexes containing virus or viral proteins, strategies aimed at reducing viral replication may ameliorate the condition. In conditions where the virus has triggered a pathological immune response, however, immunosuppressive therapy may be a more appropriate strategy. It is important that immunosuppression be used with caution because of its possible detrimental effects on the virus-induced liver disease, especially in the case of HBV. Treatment strategies must balance the potential risks and benefits of specific therapies. The most commonly reported extrahepatic manifestations of HBV (Table 1) and HCV (Table 2) have been summarized, including the potential roles for antiviral therapy. Investigations that may be helpful in the diagnosis of these conditions are listed in Table 3. As these conditions tend to be uncommon, and there are relatively few controlled therapeutic data to guide the clinician, the management of the extrahepatic manifestations of HBV and

Table 2 Extrahepatic manifestations of hepatitis C virus Extrahepatic manifestation

Strength of evidence of association

Role for antiviral treatment

Essential mixed cryoglobulinemia Porphyria cutanea tarda Membranoproliferative glomerulonephritis Lichen planus Non-Hodgkin lymphoma Autoimmune thyroiditis Diabetes mellitus, type II Sjo¨gren syndrome Mooren’s corneal ulcers

Strong Strong Strong Strong Contradictory Weak Weak Weak Weak

Probable Possible Unlikely Possibly detrimental Possible Unknown Unknown Unknown Possible

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Table 3 Useful investigations in the diagnosis of extrahepatic manifestations of hepatitis C infection Extrahepatic manifestations

Diagnostic modality

Mixed cryoglobulinemia

Serum cryoglobulin (quantitative preferred) Rheumatoid factor Serum creatinine Urinalysis for protein Arteriography Histology (skin, other) Urinalysis for blood and protein Renal biopsy Skin or mucosal biopsy Skin biopsy 24-h urine for coproporphyrin and uroporphyrin

Polyarteritis nodosa Glomerulonephritis Lichen planus Porphyria cutanea tarda

HCV is challenging and must be individualized for affected patients. One must be mindful of the potential for immunosuppressive or antiviral therapy to worsen the overall condition of the patient.

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Preface

Maximizing the benefits of antiviral therapy for HCV: the advantages of treating side effects

Robert G. Gish, MD, FACP Guest Editor

Hepatitis C infects between 4 and 5 million people in the United States and an even larger number of individuals worldwide. It appears that at least 20% of patients have the risk of serious outcomes including cirrhosis, liver failure, liver cancer, death, or perhaps a need for liver transplantation. We are now clearly able to treat and potentially ‘‘cure’’ more than half of patients with the standard of care: pegylated interferon and ribavirin therapy. In pursuit of a high rate of sustained viral response or ‘‘cure,’’ we are trying to optimize therapy in terms of patient selection and—for patients whom we decide to treat—optimal patient management. We now have very clear guidelines from the National Institutes of Health and other national and international organizations in terms of duration of therapy and common relationship to genotype, as well as the ability to predict early (through early virologic response criteria) which patients should have therapy discontinued or continued for a full treatment interval. There are potentially serious complications of interferon and ribavirin. To optimize treatment outcomes, we must look at both toxicity and qualityof-life issues during treatment. In patients who receive ribavirin, anemia develops in a significant number of patients, and either dose reduction or administration of growth factors such as erythropoietin (epoetin alfa) are options in managing these patients. Epoetin alfa has been shown to improve quality of life and adherence to optimal doses of ribavirin. Clearly, ribavirin 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.01.001

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at full or weight-based dosing is very important in hepatitis C genotype 1 and may be important in other genotypes as well. In patients with a history of psychiatric abnormalities or the development of psychological problems, clinicians should consider whether or not the administration of antidepressants or other medications during interferon and ribavirin therapy (either prophylactically or immediately on the presentation of symptoms) will affect a patient’s psychological status. In the future, there appears to be great hope for new and additional treatment options to manage hepatitis C. These include agents that directly attack the viral machinery that is required for replication. In addition, we are continuing to gain information on alcohol abstinence, fatty liver, iron, and other cofactors that may accelerate liver disease or impede the use of antiviral therapy. I am honored to serve as Guest Editor for this issue of the Gastroenterology Clinics of North America and to work with these expert authors. Dr. Manns addresses adherence; Dr. Afdhal discusses the role of epoetin alfa in maintaining ribavirin doses; and Dr. Hauser offers guidelines on the treatment and management of neuropsychiatric side effects of hepatitis C. Dr. McHutchison provides hope to our patients for the future management of hepatitis C, hopefully reaching a higher cure rate and shorter treatment intervals for patients infected with hepatitis C who are either symptomatic or have a high risk of progressive liver disease. Robert G. Gish, MD, FACP Medical Director Liver Transplant Program California Pacific Medical Center 2340 Clay Street San Francisco, CA 94115, USA E-mail address: [email protected]

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Treating hepatitis C: the state of the art Robert G. Gish, MD, FACP California Pacific Medical Center, 2340 Clay Street #233, San Francisco, CA 94115, USA

Based on data from the third National Health and Nutrition Examination Survey (NHANES III), it is estimated that 3.9 million persons in the United States (95% confidence interval [CI]: 3.1–4.8 million persons) are infected with hepatitis C virus (HCV) [1]. The number of persons who have chronic HCV infection is estimated to be 2.7 million (95% CI: 2.4–3.0 million) [1]. Because the NHANES III excluded groups such as the incarcerated, homeless, or institutionalized persons—some of which are known to have high prevalence rates of HCV infection—these estimates are likely conservative, and the upper ranges are probably better estimates. Based on the limited knowledge of the natural history of this infection in the general population, chronically infected patients are believed to have a 10% to 15% risk of developing cirrhosis, and they presently account for approximately one third of hepatocellular carcinoma cases in the United States [2]. These complications increase as the disease advances to the third and fourth decades after acute infection [3]. Based on available epidemiologic estimates, the number of individuals who have chronic, long-standing infection and the associated health and economic burden of the disease are anticipated to increase markedly over the next two decades [4–6]. Approximately 70% to 75% of individuals who are infected with HCV in the United States are infected with genotype 1, which is associated with a lower rate of response to treatment. The remainder of patients is infected primarily with genotypes 2 and 3 [1,2]. Thus, while new therapies are being developed and evaluated, it is important to optimize the use of currently available treatments.

Dr. Gish has received grants and research support from Roche Pharmaceuticals, Amgen, Intermune, ICN, Schering-Plough Corporation, Ortho Biotech Products, L.P., and Bayer Pharmaceuticals and has consulted for Roche Pharmaceuticals, Schering-Plough Corporation, Ortho Biotech Products, L.P., and Bayer Pharmaceuticals. E-mail address: [email protected] 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2003.12.006

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Current treatment recommendations Great strides have been made in the knowledge and management of chronic hepatitis C in the past decade. Current recommendations for initial treatment of HCV infection are combination therapy with standard interferon (IFN)a-2a or IFNa-2b or peginterferon (PEG-IFN)a-2a or PEG-IFNa-2b, plus ribavirin (RBV) [2]. Combination therapy is more effective than monotherapy with IFN or PEG-IFN, and the genotype influences treatment decisions. With PEG-IFN/RBV combination therapy, a sustained virologic response (SVR), defined as the absence of detectable HCV RNA in the serum by a qualitative HCV RNA assay with a lower limit of detection of 50 IU/mL or less at 24 weeks after the end of treatment, can be achieved in 42% to 51% of patients who have genotype 1 and in 73% to 82% of patients who have genotypes 2 and 3 [7–9]. In patients who have genotype 1, PEG-IFN/RBV regimens are more effective than standard IFN/RBV regimens, but among patients who have genotypes 2 or 3, SVR rates are comparable with PEG-IFN/RBV or standard IFN/RBV regimens [7,8]. PEG-IFN/RBV or standard IFN/RBV regimens may be used to treat patients who have genotypes 2 or 3 [2]. Maintaining doses of IFN or PEG-IFN and RBV and patient adherence to treatment, particularly in individuals who have genotype 1, has been shown recently to be critically important for viral eradication and achievement of an SVR [7,10,11]. Weight-based treatment has been established for PEG-IFNa-2b (under evaluation for PEG-IFNa-2a) and RBV for genotype 1 patients [2,7]. For patients who have genotype 1, 48 weeks of treatment and standard doses of RBV (1000–1200 mg/d) are necessary, whereas 24 weeks of treatment and an RBV dose of 800 mg daily appear to be sufficient for patients who have genotypes 2 or 3 [2,9]. Early virologic response (EVR), defined as a greater than or equal to 2-log10 decrease in HCV RNA after 12 weeks of therapy, is predictive of SVR [8,12] and is recommended as a routine part of monitoring patients who have genotype 1 [2]. Because of the high response rates in patients who have genotypes 2 and 3, early testing in these patients is not necessary. In patients who have genotype 1 who demonstrate EVR, adherence to treatment can have a substantial impact on the likelihood of achieving an SVR [10]. Patients who fail to achieve SVR at 12 weeks of treatment have only a small chance of subsequently achieving SVR, even with continued therapy for 48 weeks [2,8,12]; however, a clinical decision to maintain therapy beyond 12 weeks should take into account other factors (eg, patient tolerance and stabilization of fibrosis progression in patients who have advanced histology). In addition to pretreatment genotype determination and early testing of viral response during treatment, a follow-up qualitative HCV RNA assay should be performed, particularly at the end of treatment, to confirm the absence of active HCV replication [2]. Until further studies determine whether or not SVR will be sustained over the long term following successful antiviral treatment, periodic measurements of HCV

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RNA might need to be performed. A recently developed transcriptionmediated amplification (TMA) assay, with a lower limit of detection of approximately 5 to 10 IU/mL [13,14], might prove to be especially useful at the end of treatment in helping to define long-term response and in longterm management strategies and decisions. Which patients to treat remains a challenging area for clinicians managing patients infected with HCV, but many patients who are diagnosed with HCV infection do not require immediate treatment. Many patient subgroups have been excluded from clinical trials because of injection drug use, significant alcohol use, age, and various comorbid medical and neuropsychiatric conditions [2], and knowledge regarding therapy with current treatments for patients in these subgroups is very limited [15–18]. Efforts to diagnose HCV infection in these subgroups and increase the availability of current treatments to these patients are recommended [2]. Antiviral treatment is currently recommended for naı¨ ve patients who are infected with HCV who have an increased risk of developing cirrhosis that is characterized by detectable HCV RNA levels > 50 IU/mL, a liver biopsy with portal or bridging fibrosis, and at least moderate inflammation and necrosis [2]. Most of these patients also exhibit persistently elevated alanine aminotransferase (ALT) values. In other patient subgroups the risks and benefits of therapy are less clear and should be determined on an individual basis or in the context of clinical trials, many of which are ongoing. Selected patients who fail to achieve SVR might benefit from retreatment with PEGIFN–based regimens including maintenance therapy. Retreatment decisions are based on previous type of response, previous therapy, the difference in potency of the new therapy, severity of the underlying liver disease, viral genotype, other factors predictive for response, and tolerance of previous therapy and adherence [2]. Even in the absence of achieving SVR, treatment might be associated with improved histology [2,19]. The latest guidelines and available clinical trial data should be reviewed and consulted for specific treatment and retreatment decisions [2]. Side effects of treatment Standard combination antiviral therapy for the treatment of chronic hepatitis C is associated with numerous side effects involving multiple body systems (Fig. 1). The most frequent or serious side effects include fatigue, influenza-like symptoms (fever, myalgia, arthralgia, rigors), gastrointestinal disturbances (nausea, diarrhea, anorexia, weight loss), hematologic abnormalities (neutropenia, thrombocytopenia, anemia), dermatologic symptoms (alopecia, dermatitis, pruritus), nervous system symptoms (depression, insomnia, irritability, emotional lability, impaired concentration), autoimmune and infectious disorders (cryoglobulinemia, hypothyroidism, hyperthyroidism, associated bacterial infections), pulmonary disorders (interstitial pneumonia), cardiac symptoms (arrhythmias, congestive heart failure,

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Fig. 1. Patients infected with HCV who are treated with standard IFN/RBV or PEG-IFN/RBV therapy might experience various psychiatric, immunologic, renal, neurologic, hematologic, cardiologic, and ophthalmologic side effects, the management of which might involve various disciplines of health care professionals and a range of potential medications (including others beyond those shown). NSAIDs, nonsteroidal anti-inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors.

myocardial infarction, angina pectoris), and ophthalmic symptoms (retinopathy, retinal hemorrhage, visual loss or disturbance) [7,8,20–22]. The primary side effect of RBV is dose-related hemolytic anemia, which can worsen existing cardiac disease and has resulted in fatal and nonfatal myocardial infarction in some patients [23,24], but other side effects might include asthenia, abdominal pain, headache, and cough [23]. The range of these side effects and their management might involve health care professionals from a variety of disciplines and the use of various other pharmacologic agents for symptomatic treatment (see Fig. 1). The most frequent reason for nonadherence to standard combination therapy is treatment-related side effects (>75% of patients) [11]. Failure to attend scheduled appointments, withdrawal of consent, and nonadherence in the absence of apparent side effects are other reasons. The importance of discussing adherence with patients before treatment is initiated, and educating patients, family members, and caregivers about side effects and helping patients maximize their adherence during treatment have been emphasized in recent management guidelines [2]. Strategies to improve adherence to therapy might involve other interventions directed at the patient and the support staff and modifications to the treatment regimen. Potential strategies include the use of medication diaries, electronic monitoring devices, and directly observed therapy for selected patients

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who are at high risk of nonadherence [11]. Follow-up telephone calls from support staff and patient education designed to provide feedback regarding viral loads, management of treatment-related side effects, and the need for lifestyle changes might also be beneficial. Interim results of a recent prospective, randomized, controlled multicenter study indicate that active intervention with patient education, aggressive side effect management, and expanded supportive nursing intervention with cognitive behavioral therapy by way of telephone calls for patients infected with HCV who are treated with PEG-IFN/RBV therapy is feasible, can decrease the dropout rate in the first 12 weeks of therapy, and is associated with significant improvements in patient quality of life at early time points in treatment [25]. Now that the importance of adherence has been made clear, further research on strategies to improve adherence is needed. The potentially significant impact of hematologic and neuropsychiatric side effects associated with combination anti-HCV therapy was underscored in the recently updated management guidelines [2]. Monitoring and management of these particular side effects might play a substantial role in increasing adherence and achieving a successful treatment outcome. Hematologic side effects (neutropenia, thrombocytopenia, anemia) associated with anti-HCV therapy are a major reason for dose reduction, but these side effects require therapy to be discontinued only rarely [7,8,22]. Treatment with hematopoietic growth factors might be useful to reduce symptoms and maintain adherence to antiviral therapy in selected patients who develop persistent cytopenias despite dose reductions, although many questions remain regarding their use in this patient population [2]. Recent studies suggest that recombinant human erythropoietin (epoetin alfa) might represent an alternative to RBV dose reduction or cessation of therapy in patients who are anemic during standard combination therapy [26,27]. Additional studies are needed to determine whether or not the use of hematopoietic growth factors will enhance the likelihood of SVR [2]. IFN causes numerous neuropsychiatric side effects, particularly depression [21,28–30]. These side effects are among the most frequent causes of dose reduction or discontinuation of therapy [22,31,32], and they might adversely affect patient quality of life [21,28,29]. Based on recent randomized trials using standardized psychiatric evaluation methods, the incidence of IFN-associated depression is approximately 20% to 30% [7,22,32,33]. Most patients respond to antidepressant treatment, particularly selective serotonin receptor inhibitors (SSRIs), allowing continuation or completion of antiviral therapy [34–40]. Because the incidence is so high, identification and appropriate management of neuropsychiatric side effects (in consultation with a mental health care professional) can help ensure that patients who have hepatitis C who develop neuropsychiatric side effects have an increased likelihood of completing antiviral therapy, thus improving their chances for a successful treatment outcome [41].

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Many subgroups of individuals have high prevalence rates of HCV infection and comorbid psychiatric and substance use disorders, including veterans, injection drug users, and homeless and incarcerated individuals [2,29,42–44]. All patients who are infected with HCV should be screened for psychiatric and substance use disorders. If such disorders are present, patients should be referred to a mental health care provider for appropriate treatment before antiviral therapy is considered and for follow-up management during antiviral therapy. Recent management guidelines no longer contain cautionary advice involving psychiatric and substance use disorder comorbidities; they now recommend clinical and research efforts to increase the availability of IFN-based therapy for individuals who were previously considered to be ineligible because of these comorbidities [2,41]. Relatively few specifics regarding treatment in these subgroups have been offered, however, and much more clinical research and new management strategies and models of care are needed to translate the benefits of recent advances in anti-HCV therapy to those who have HCV and comorbid psychiatric and substance use disorders [41].

Summary Treatment of chronic hepatitis C has improved significantly, with higher rates of SVR and patient compliance, but it remains less than satisfactory. Although current therapies will continue to be the primary treatments for the next decade, more effective and well-tolerated therapies are needed. Current treatment regimens are associated with substantial side effects, particularly hematologic and neuropsychiatric side effects that can lead to nonadherence, dose reduction, and treatment discontinuation. The early recognition and appropriate management of these side effects should lead to improved patient outcomes, including higher treatment completion rates. To continue making progress in this area, there is a need to maximize benefits for individuals who are infected with HCV through the appropriate selection of patients for antiviral treatment and increasing treatment adherence through better patient and caregiver education, closer patient follow-up, and more aggressive management of the side effects that lead to dose reduction or discontinuation. Optimum management of patients who have hepatitis C will involve a larger cooperative team effort that also includes physician specialists from various disciplines, including mental health care providers and physician extenders. Meanwhile, there is a need to continue to search for novel therapies and treatment approaches to benefit patients who do not respond to current therapies, to increase understanding of the natural history and pathology of HCV infection, and to promote public education to better identify infected individuals and improve hepatitis C prevention.

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References [1] Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341:556–62. [2] Boyer JL, Chang EB, Collyar DE, DeLeve LD, Feinberg J, Judge TA, et al. National Institutes of Health consensus development conference statement: management of hepatitis C. June 10–12 2002. Hepatology 2002;36(Suppl 1):S3–20. [3] Seeff LB. Natural history of hepatitis C. Hepatology 1997;26(Suppl 1):21S–8S. [4] Armstrong GL, Alter MJ, McQuillan GM, Margolis HS. The past incidence of hepatitis C virus infection: implications for the future burden of chronic liver disease in the United States. Hepatology 2000;31:777–82. [5] Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the United States. Am J Public Health 2000;90:1562–9. [6] Kim WR. The burden of hepatitis C in the United States. Hepatology 2002;36(Suppl 1): S30–4. [7] Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–65. [8] Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonc xales FL, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–82. [9] Hadziyannis SJ, Cheinquer H, Morgan T, Diago M, Jensen DM, Sette H Jr, et al. Peginterferon alpha-2A (40 KD) (PEGASYS) in combination with ribavirin (RBV): efficacy and safety results from a phase III, randomized, double-blind, multicentre study examining effect of duration of treatment and RBV dose [abstract]. J Hepatol 2002; 36(Suppl 1):3. [10] Ferenci P, Shiffman ML, Fried MW, Sulkowski MS, Haeussinger D, Zarski J-P, et al. Early prediction of response to 40 kDa peginterferon alfa-2a (PEGASYS) plus ribavirin in patients with chronic hepatitis C (CHC) [abstract]. Hepatology 2001;34(4 Pt 2):351A. [11] McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002;123:1061–9. [12] Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003;38:645–52. [13] Comanor L, Anderson F, Ghany M, Perrillo R, Heathcote EJ, Sherlock C, et al. Transcription-mediated amplification is more sensitive than conventional PCR-based assays for detecting residual serum HCV RNA at end of treatment. Am J Gastroenterol 2001;96:2968–72. [14] Gorrin G, Friesenhahn M, Lin P, Sanders M, Pollner R, Eguchi B, et al. Performance evaluation of the VERSANT HCV RNA qualitative assay by using transcription-mediated amplification. J Clin Microbiol 2003;41:310–7. [15] Van Thiel DH, Friedlader L, Molloy PJ, Fagiuoli S, Kania RJ, Caraceni P. Interferonalpha can be used successfully in patients with hepatitis C virus-positive chronic hepatitis who have a psychiatric illness. Eur J Gastroenterol Hepatol 1995;7:165–8. [16] Backmund M, Meyer K, Von Zielonka M, Eichenlaub D. Treatment of hepatitis C infection in injection drug users. Hepatology 2001;34:188–93. [17] Cawthorne CH, Rudat KR, Burton MS, Brown KE, Luxon BA, Janney CG, et al. Limited success of HCV antiviral therapy in United States veterans. Am J Gastroenterol 2002;97: 149–55. [18] Sylvestre DL. Injection drug use and hepatitis C: from transmission to treatment. Psychiatr Ann 2003;33:377–82.

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[19] Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002;122:1303–13. [20] Borden EC, Parkinson D. A perspective on the clinical effectiveness and tolerance of interferon-a. Semin Oncol 1998;25(Suppl 1):3–8. [21] Dieperink E, Willenbring M, Ho SB. Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: a review. Am J Psychiatry 2000;157:867–76. [22] Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology 2002; 36(Suppl 1):S237–44. [23] Bodenheimer HC Jr, Lindsay KL, Davis GL, Lewis JH, Thung SN, Seeff LB. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial. Hepatology 1997;26:473–7. [24] De Franceschi L, Fattovich G, Turrini F, Ayi K, Brugnara C, Manzato F, et al. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology 2000;31:997–1004. [25] Flamm SL, Eshelman A, Lyons M, Levin A, Gordon S, Muir A, et al. Improved medication adherence with cognitive behavioral therapy in patients receiving pegylated interferon alpha 2b (1.5 mcg/kg wk) + ribavirin (800–1400 mg/d): results of a prospective, randomized, controlled, multi-center trial [abstract]. Hepatology 2002;36(4 Pt 2):311A. [26] Dieterich DT, Wasserman R, Bra¨u N, Hassanein TI, Bini EJ, Bowers PJ, et al. Onceweekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa.. Am J Gastroenterol 2003;98:2491–9. [27] Afdhal NH, Dieterich DT, Pockros PJ, Schiff ER, Shiffman ML, Sulkowski MS, et al. Epoetin alfa treatment of anemic HCV-infected patients allows for maintenance of ribavirin dose, increases hemoglobin levels, and improves quality of life vs placebo: a randomized, double-blind, multicenter study [abstract]. Gastroenterology 2003;124(4 Suppl 1):A-714. [28] Valentine AD, Meyers CA, Kling MA, Richelson E, Hauser P. Mood and cognitive side effects of interferon-a therapy. Semin Oncol 1998;25(Suppl 1):39–47. [29] Zdilar D, Franco-Bronson K, Buchler N, Locala JA, Younossi ZM. Hepatitis C, interferon alfa, and depression. Hepatology 2000;31:1207–11. [30] Trask PC, Esper P, Riba M, Redman B. Psychiatric side effects of interferon therapy: prevalence, proposed mechanisms, and future directions. J Clin Oncol 2000;18:2316–26. [31] Renault PF, Hoofnagle JH, Park Y, Mullen KD, Peters M, Jones B, et al. Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 1987;147: 1577–80. [32] McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485–92. [33] Davis GL, Esteban-Mur R, Rustgi V, Hoefs J, Gordon SC, Trepo C, et al. Interferon alfa2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998;339:1493–9. [34] Gleason OC, Yates WR. Five cases of interferon-alfa–induced depression treated with antidepressant therapy. Psychosomatics 1999;40:510–2. [35] Schramm TM, Lawford BR, Macdonald GA, Cooksley WGE. Sertraline treatment of interferon-alfa-induced depressive disorder. MJA 2000;173:359–61. [36] Kraus MR, Schafer A, Faller H, Csef H, Scheurlen M. Paroxetine for the treatment of interferon-alpha–induced depression in chronic hepatitis C. Aliment Pharmacol Ther 2002; 16:1091–9. [37] Hauser P, Khosla J, Aurora H, Laurin J, Kling MA, Hill J, et al. A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C. Mol Psychiatry 2002;7:942–7.

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[38] Gleason OC, Yates WR, Isbell MD, Philipsen MA. An open-label trial of citalopram for major depression in patients with hepatitis C. J Clin Psychiatry 2002;63:194–8. [39] Dieperink E, Ho SB, Thuras P, Willenbring ML. A prospective study of neuropsychiatric symptoms associated with interferon-a-2b and ribavirin therapy for patients with chronic hepatitis C. Psychosomatics 2003;44:104–12. [40] Loftis JM, Hauser P. Comanagement of depressive and HCV treatment. Psychiatr Ann 2003;33:385–91. [41] Goldsmith J, Hauser P. Psychiatric issues in patients with hepatitis C [editorial]. Psychiatr Ann 2003;33:357–60. [42] Cheung R, Ahmed A. Treating chronic hepatitis C patients with psychiatric disorders: an uphill battle [editorial]. Am J Gastroenterol 2001;96:3–4. [43] Lehman CL, Cheung RC. Depression, anxiety, post-traumatic stress, and alcohol-related problems among veterans with chronic hepatitis C. Am J Gastroenterol 2002;97:2640–6. [44] El-Serag HB, Kunik M, Richardson P, Rabeneck L. Psychiatric disorders among veterans with hepatitis C infection. Gastroenterology 2002;123:476–82.

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Adherence to combination therapy: influence on sustained virologic response and economic impact Michael P. Manns, MD Department of Gastroenterology, Hepatology, and Endocrinology, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany

Estimating the incidence of new hepatitis C virus (HCV) infection accurately is very difficult [1,2]. Many patients who have acute HCV infection are asymptomatic and therefore are not identified [2]. Underreporting of diagnosed cases is also believed to be common, and individuals who are at high risk of infection may not have access to health care, decreasing the likelihood of a timely diagnosis [2]. Mathematical modeling suggests that the annual incidence of acute HCV infection in the United States decreased from an average of approximately 230,000 new cases per year in the 1980s to 38,000 cases per year in the 1990s [3]. Currently, approximately 35,000 new HCV infections are estimated to occur each year in the United States [1]. Although the incidence of HCV infection might be declining, the known prevalence of liver disease caused by HCV is increasing because of the significant lag between infection, diagnosis of existing symptomatic cases, and clinical manifestation of liver disease [2]. Between 1990 and 2015, the Centers for Disease Control and Prevention projects a fourfold increase in the number of adults diagnosed with long-standing HCV infection [4]. With the progressive liver fibrosis of chronic HCV infection leading to cirrhosis, end-stage liver disease, hepatocellular carcinoma, and possible liver transplantation, a significant and continued increase in the health and economic burden of the disease is anticipated over the next 10 to 20 years [2,4,5]. Based on a cohort simulation model, the direct medical care costs of HCV infection from the years 2010 through 2019 in the United States were projected to be $10.7 billion (range, $6.7–14.1 billion), and societal costs Dr. Manns has received grants and research support from Schering-Plough Corporation, Roche Pharmaceuticals, Yamanouchi Pharmaceuticals, Gilead Sciences, and Boehringer Ingelheim. E-mail address: [email protected]. 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2003.12.003

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related to deaths before the age of 65 from decompensated cirrhosis and hepatocellular carcinoma were projected to be approximately $21 and $54 billion, respectively [5]. Thus, improving the efficacy of anti-HCV therapy has the potential to significantly reduce the morbidity, mortality, and health care utilization associated with the disease. Effect of adherence and dose maintenance on sustained virologic response Important therapeutic advances for the treatment of chronic hepatitis C have occurred over the last decade as ribavirin (RBV) was combined with interferon (IFN) and, more recently, as pegylated interferons (PEG-IFNs) have been introduced and combined with RBV [1,6]. Overall, PEG-IFN/ RBV combinations have achieved the highest sustained virologic response (SVR) rates. In three randomized trials of PEG-IFN/RBV for 48 weeks in naı¨ ve patients, SVR rates of 42% to 51% were achieved in patients who had genotype 1 compared with SVR rates of 73% to 82% in patients who had genotypes 2 and 3 [7–9]. Among patients infected with genotypes 2 or 3, SVR rates with standard IFN plus RBV were comparable to those with PEGIFN/RBV in one study [7], but SVR rates were higher in patients who had genotype 1 treated with PEG-IFN/RBV [7–9]. Standard combination antiHCV therapy is associated with significant side effects [10] and necessitates a relatively complex regimen of injections, daily oral medication, frequent office visits, and blood tests for safety monitoring. Consequently, not all patients are able to complete the scheduled treatment [6]. The clinical significance of adhering to standard combination anti-HCV therapy and maintaining the doses of IFN/PEG-IFN and RBV in maximizing SVR rates has become evident recently. In a randomized trial that compared PEG-IFNa-2b/RBV with standard IFNa-2b/RBV in 1530 naı¨ ve patients who had chronic hepatitis C, doses of PEG-IFNa-2b and RBV were important in achieving SVR and significantly predicted SVR [7]. The likelihood of SVR increased as the RBV dose increased, and when the dose of RBV was controlled on a mg/kg basis, the effect of a higher dose of PEGIFNa-2b on SVR compared with a lower dose was larger than the estimate obtained in the primary analysis. The SVR rate was higher in all groups of patients stratified by genotype, none to minimal fibrosis, or bridging fibrosis to cirrhosis when RBV dosage was greater than 10.6 mg/kg. A retrospective analysis of the effect of treatment adherence on SVR rates [11] was undertaken recently based on data from three randomized trials of IFNa-2b/RBV or PEG-IFNa-2b/RBV [7,12,13]. Patients were divided into two groups for analysis: (1) patients who received greater than or equal to 80% of their total IFNa-2b/PEG-IFNa-2b dose and greater than or equal to 80% of their RBV dose who were treated for greater than or equal to 80% of the expected duration of therapy, and (2) patients who underwent dose reduction (ie, received \ 80% of one or both drugs for  80% of the expected duration of therapy) [11]. Overall, SVR rates were higher in

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patients who were more adherent to IFNa-2b/RBV (Fig. 1) or PEG-IFNa2b/RBV (Fig. 2) than in patients who were less adherent. When analyzing a regimen of PEG-IFNa-2b 1.5 lg/kg weekly plus RBV greater than 10.6 mg/kg daily, the overall SVR rate in patients who were more adherent was 72% compared with 57% in patients who were less adherent. In patients who had genotype 1 the SVR rate increased from 34% to 63% with greater adherence (Fig. 3). Regardless of the combination regimen, the effect was most apparent for patients infected with genotype 1, the most difficult-totreat subgroup. This might be most important during the first 12 to 24 weeks of therapy, when a determination regarding who is most likely to achieve an eventual SVR can be made [6]. A similar retrospective analysis was undertaken to determine the effect of HCV genotype and treatment adherence on predictive values for SVR using early virologic response (EVR) in patients in a large, randomized trial [8] who received PEG-IFNa-2a 180 lg weekly in combination with RBV 1000 to 1200 mg daily for 48 weeks [14]. Overall, SVR rates were 56% in all patients, 46% in patients who had genotype 1, and 76% in patients who had genotypes 2 or 3. In all patients the EVR positive predictive value was 65%. EVR subset analysis by genotype is shown in Fig. 4. For patients who had EVR who were adherent the SVR rate was 75%, compared with only 48% in patients who were less adherent. In the latter group the SVR rate was

Fig. 1. SVR rate according to adherence in patients who had chronic hepatitis C treated with standard IFNa-2b, 3 million IU subcutaneously three times weekly, and RBV, 1000–1200 mg/d. DUR, duration of treatment (genotype 1, 48 wk; genotypes 2 and 3, 24 wk). *P = 0.0018 versus original ITT analysis; yP = 0.0076 versus original ITT analysis. (Data from Refs. [12,13]; analyzed data from [11].)

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Fig. 2. SVR rate according to adherence in patients who had chronic hepatitis C treated with PEG-IFNa-2b, 1.5 lg/kg/wk, and RBV, 800 mg/d. DUR, duration of treatment (48 wk). *P = 0.01 versus original ITT analysis; yP = 0.04 versus less adherent group; zP = 0.034 versus original ITT analysis; §P = 0.011 versus less adherent group. (Data from Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–65; analyzed data from McHutchison JG, Manns MP, Patel K, Poynard T, Lindsay KL, Trepo C, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002;123:1061–9.)

67% overall in patients who had dose reduction but only 12% overall in patients who withdrew from the study early or dropped out, underscoring the importance of adherence in patients who demonstrate an early response to therapy in the absence of safety concerns that might preclude continued therapy. Similar results were reported recently based on a retrospective analysis [15] of results from a phase III PEG-IFNa-2b/RBV trial [7]. Reduction of PEG-IFNa-2b or RBV doses to less than 80% of the prescribed doses during the first 12 weeks of therapy decreased the chance of achieving EVR (although not significantly), but reduction or discontinuation of both drugs resulted in a marked decrease in EVR (33% versus 80%; P \ 0.001) [15]. Further, reduction of PEG-IFNa-2b or RBV to less than 80% of the prescribed doses after EVR was achieved reduced the chance of SVR from 72% to between 61% and 63%, depending on the treatment regimen, but early discontinuation or significant interruptions in treatment resulting in less than 80% of the expected duration of therapy decreased the chance of SVR to 50%.

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Fig. 3. SVR rate according to adherence in patients who had chronic hepatitis C treated with PEG-IFNa-2b, 1.5 lg/kg/wk, and RBV, >10.6 mg/kg/d. DUR, duration of treatment (48 wk). *P = 0.057 versus original ITT analysis; yP = 0.065 versus less adherent group; zP = 0.046 versus original ITT analysis; §P = 0.008 versus less adherent group. (Data from Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–65; analyzed data from McHutchison JG, Manns MP, Patel K, Poynard T, Lindsay KL, Trepo C, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002;123:1061–9.)

Preliminary results of a phase III randomized, double-blind trial evaluating the effect of duration of PEG-IFNa-2a (180 lg/wk)/RBV treatment and RBV dose (800 mg/d or 1000–1200 mg/d) in naı¨ ve patients stratified by genotype before randomization indicate that patients who have genotypes 2 or 3 who are treated for 24 weeks have similar SVR rates (78%) as patients who are treated for 48 weeks (73–78%) [9]. In patients who have these genotypes an RBV dose of 800 mg daily appeared to be adequate; however, for patients who had genotype 1, 48 weeks of treatment and standard doses of RBV (1000–1200 mg/d) appeared to be necessary to achieve optimum SVR rates (51%).

Dose reduction and discontinuation because of side effects Standard IFNs and PEG-IFNs are associated with a wide variety of side effects, particularly fatigue, influenza-like symptoms (fever, myalgia, rigors), gastrointestinal disturbances (nausea, diarrhea, weight loss), hematologic

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Fig. 4. SVR rate according to adherence in patients who had chronic hepatitis C treated with PEG-IFNa-2a, 180 lg/wk, and RBV, 1000–1200 mg/d, who had EVR (defined as 2 log10 decline in HCV RNA from baseline by week 12 of treatment). (Data from Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonc¸ales FL Jr, et al. Peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection. N Engl J Med 2002;347:975–82; analyzed data from Ferenci P, Shiffman ML, Fried MW, Sulkowski MS, Haeussinger D, Zarski J-P, et al. Early prediction of response to 40 kDa peginterferon alfa-2a (PEGASYS) plus ribavirin in patients with chronic hepatitis C (CHC) [abstract]. Hepatology 2001;34(4 Pt 2):351A.)

abnormalities (neutropenia, thrombocytopenia, anemia), dermatologic symptoms (alopecia, dermatitis, pruritus), and neuropsychiatric symptoms (particularly depression) [7,8,10,16,17]. The primary side effect of RBV is dose-related hemolytic anemia [18,19]. In a large, randomized trial comparing PEG-IFNa-2a/RBV and IFNa-2b/RBV, most side effects with both regimens occurred with similar frequency, although influenza-like symptoms, headache, alopecia, and depression occurred less frequently (by  5%) in patients receiving PEG-IFNa-2a/RBV [8,10]. In a large, randomized trial comparing PEG-IFNa-2b/RBV and IFNa-2b/RBV, the side effects were similar with both regimens, but influenza-like symptoms and some gastrointestinal disturbances (nausea, diarrhea, weight loss) occurred more frequently (by  5%) in patients receiving PEG-IFNa-2b/RBV [7,10]. The designs of the two studies differed, however, particularly regarding a different stopping rate for nonresponsive patients [7,8]. Treatment-related side effects might require dose reduction or discontinuation of therapy (Table 1) [7,8]. Hematologic side effects (neutropenia, thrombocytopenia, anemia) are the most common reasons for dose reductions in patients receiving PEG-IFN/RBV regimens, although they

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Table 1 Discontinuation and dose reductions because of side effects with standard combination antiHCV therapy Proportion of patients a

Study 2b

Study 1

Discontinuation for any side effect or laboratory abnormality Dose reduction for Any side effect Neutropenia Thrombocytopenia Anemia

PEG-IFNa-2b/ RBVc

IFNa-2b/ RBVd

PEG-IFNa-2a/ RBVe

IFNa-2a/ RBVf

13%

13%

10%

6%

42% 10% 3% 12%

34% 8% 1% 13%

33% 21% 4% 23%

33% 6% \1% 22%

a

Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–65. b Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Ganc¸ales FL Jr, et al. Peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection. N Engl J Med 2002;347:975–82. c PEG-IFNa-2b 1.5 lg/kg/wk plus RBV 800 mg/d for 48 wk. d IFNa-2b 3 M IU three times/wk plus RBV 1000–1200 mg/d for 48 wk. e PEG-IFNa-2a 180 lg/wk plus RBV 1000–1200 mg/d for 48 wk. f IFNa-2b 3 M IU three times/wk plus RBV 1000–1200 mg/d for 48 wk.

rarely require discontinuation of therapy ( 3% of patients) [7,8,10]. Other common reasons for dose reductions or discontinuation of PEG-IFN/RBV regimens include neuropsychiatric symptoms (depression, anxiety, insomnia), dermatologic and gastrointestinal side effects, and influenza-like symptoms [7,8,10]. Monitoring for side effects that cause the majority of dose reductions and discontinuation, with appropriate intervention, can be important in helping patients adhere to therapy successfully. Clinically relevant differences in available PEG-IFN formulations based on side-effect profiles have not been established. Improving treatment adherence in clinical practice Higher SVR rates have been achieved through improvements in available treatments, the optimization of dosing regimens, and changes in the on-trial management of patients. The main reason for lack of adherence to current therapy is side effects; other reasons include failure to attend scheduled clinic visits, voluntary withdrawal from therapy, and nonadherence in the absence of apparent side effects [11]. Achieving optimum SVR rates in clinical practice with current therapies and dosing regimens will require a multifactorial approach with particular attention paid to the management of side effects to maximize dose maintenance and adherence, as well as early

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identification of patients who are most likely to respond or not respond, better education for patients and caregivers, and closer patient follow-up. Before treatment with standard combination regimens is initiated, patients, their families, and their caregivers should be informed about the expectations of therapy, including the likelihood of multiple side effects that could temporarily adversely affect their quality of life (QOL; eg, flu-like symptoms, fatigue, depression) and the prospective management of such side effects [1,10]. The importance of adherence should also be discussed [1]. Patients can play an active role in their treatment through self-management techniques such as early recognition of side effects that can necessitate dose reduction, maintaining adequate hydration and nutrition, changing dosing schedules to easier work days or to accommodate weekend activities, maintaining mild-to-moderate exercise schedules, and using analgesics and antipyretics for symptomatic treatment [10,16]. Pretreatment factors associated with a greater likelihood of achieving SVR include genotype 2 or 3 infection, lower viral load, absence of significant fibrosis, young age, and female gender [7]. Although such factors provide an estimate of the likelihood of achieving SVR, they are generally unhelpful in accurately identifying patients who will respond to therapy. The ideal test for predicting response should identify all nonresponders early so they may discontinue therapy and avoid the associated morbidity and expense while continuing treatment in patients who eventually will achieve SVR. By identifying likely responders, efforts to enhance treatment adherence can be focused on patients who are most likely to benefit. Testing response early (ie, at week 12 of therapy) helps predict who is likely to achieve SVR and, more accurately, who is likely to be a nonresponder. This practice should be a routine part of monitoring patients who have HCV genotype 1 [1]. Recent analyses support the predictive value of testing early response [8,15]. In a recent phase III trial of PEG-IFNa-2a/RBV, by week 12 of therapy EVR was achieved by 86% of patients; of these, 65% subsequently achieved SVR [8]. Conversely, among the 14% of patients who did not achieve EVR by week 12, only 3% went on to achieve SVR, resulting in a negative predictive value of 97%. In a retrospective analysis of results from a phase III PEGIFNa-2b/RBV trial [7] EVR was achieved by week 12 in 69% to 76% of patients, depending on treatment regimen, and SVR occurred in 67% to 80% of these patients [15]. All patients who failed to achieve a greater than or equal to 2-log10 reduction in serum HCV RNA or undetectable HCV RNA by polymerase chain reaction (PCR) by week 12 of therapy were eventual nonresponders. Sixty-seven patients who had EVR who still had residual virus detected by PCR at 12 weeks also had repeat HCV RNA testing at 24 weeks; of those who remained PCR positive at week 24, only 1 of 24 patients (4%) achieved SVR compared with 14 of 43 patients (33%) who lost virus between weeks 12 and 24 (P \ 0.01). These results suggest that patients who have EVR who remain PCR positive at 12 weeks should have PCR testing repeated after 24 weeks before making any decision about discontinuing

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therapy. Achievement of EVR can provide a goal to motivate patient adherence during the first months of therapy, and early testing provides the opportunity to reassess the need for continued treatment. Treatment discontinuation rules predict nonresponse most accurately, but they do not take into account the potential histologic benefits observed in nonresponders [20]. In addition, the precision and variability of quantitative HCV RNA assays can confound interpretation of viral load changes during therapy [21]. Consequently, when an EVR is absent, discontinuation of therapy should be considered because the likelihood of sustained response is negligible, but the decision must be made on an individual patient basis. If uncertainty exists, retesting should be considered before stopping therapy [6]. In addition to other approaches to enhance treatment adherence, providing the patient with regular follow-up visits within a supportive environment is important [10]. This practice has the potential to facilitate early detection of side effects and rapid intervention. Broadening the patient management team to include others such as nurse practitioners, physician assistants, pharmacists, and psychologists can also enhance the patient experience during antiviral therapy [10]. Preliminary data suggest that patient education, aggressive side effect management, and expanded supportive nursing intervention are practical approaches that can decrease the dropout rate in the first 12 weeks of therapy and improve patient quality of life significantly during early treatment [22]. Now that the importance of adherence has been recognized, further research on strategies for improving adherence is needed.

Relationship between sustained virologic response and quality of life Despite a continuing impression that chronic hepatitis C does not impact patient QOL adversely, several studies have now shown that the disease is associated with impaired QOL [23–25]. Treatment-induced side effects can adversely affect patient tolerability and QOL, leading to dose reduction or discontinuation of therapy before completion [10]. Worsening fatigue and QOL scores during therapy are significant predictors of treatment discontinuation [26]. Although QOL can worsen during standard antiHCV therapy, achievement of SVR is associated with significant, clinically and socially relevant improvements in patient energy levels, general functioning, and well-being [24–26]. QOL benefits of SVR also appear to occur among patients who have advanced liver disease [26]. Maintenance of an acceptable QOL during therapy is important for patient adherence and acceptance of treatment. Early identification of the side effects that frequently lead to dose reduction or treatment discontinuation, with appropriate management and intervention, should help lessen the degree of early withdrawal. QOL issues should be considered in conjunction with

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safety and efficacy concerns in choosing optimal therapy for the treatment of patients who have chronic hepatitis C. Evaluating cost effectiveness of anti-hepatitis C virus therapy Because of the projected health care burden of chronic hepatitis C, a substantial effort has been applied to understanding the potential economic impact of combination anti-HCV therapy. Several modeling studies based on treatment in the United States or Europe that take into account appropriate treatment decisions based mainly on genotype and early response to therapy have suggested that standard IFN/RBV therapy is a cost-effective treatment option that is superior to standard IFN monotherapy [27–30]. Additional modeling studies on the treatment of chronic hepatitis C in the United States and Europe were undertaken recently to address the impact of higher SVR rates with PEG-IFNs, early testing for virologic response, the application of treatment management algorithms, and the role of adherence in achieving SVR [31–37]. Preliminary findings from these recent modeling studies suggest that (1) PEG-IFN/RBV therapy increases life expectancy and is cost effective compared with standard IFN/RBV regardless of genotype [32,33,36,37]; (2) the use of treatment management algorithms can reduce antiviral drug costs substantially and further improve the cost effectiveness of therapy, especially for patients who have HCV genotypes 2 and 3 [32,34,35]; (3) PEG-IFN/RBV therapy is cost effective when compared with other well-accepted medical interventions such as the treatment of hypertension, coronary-artery bypass graft surgery, hemodialysis, and the use of trastuzumab in the treatment of breast cancer [3,33]; and (4) increasing adherence to PEG-IFN/RBV therapy is associated with increased life expectancy, decreased lifetime HCV costs, and increased cost effectiveness [31]. For example, in a cohort simulation model in the United Kingdom that examined the cost effectiveness of PEGIFNa-2b/RBV treatment [34], treatment management algorithms that included discontinuing therapy at 12 or 24 weeks based on virologic testing were associated with a reduction in the mean duration of antiviral therapy by approximately 39% compared with 48 weeks of therapy. Evaluating EVR was associated with a reduction in antiviral drug costs of approximately 44%. Although the findings of these economic modeling studies are fairly consistent, they are based on complex assumptions and data from controlled clinical trials that might not be applicable to the general patient population [38]. The natural history of HCV infection in the general population remains incompletely understood, adding to the difficulty of estimating the economic burden of the disease. The overall impact of combination therapy in the general population also is not known. Considerable uncertainties also remain regarding appropriate management strategies in the populations excluded from controlled trials. For example, demographic groups that are at high risk of developing severe liver disease include older men who consume alcohol, racial minorities, and individuals whose personal problems

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(eg, homelessness, incarceration, active drug use) interfere with or preclude antiviral therapy [38]. In contrast, antiviral therapy is more effective in young and female patients and patients who do not consume alcohol. These patients might have the most benign natural history. Thus, patients who are treated successfully might not necessarily be those who would benefit most from viral clearance. In evaluating cost effectiveness modeling studies, it is important to evaluate the underlying assumptions and data [38]. Based on data from patients meeting eligibility criteria for recent controlled trials, PEG-IFN/RBV therapy appears to be cost effective. Additional modeling studies that include other groups of patients infected with HCV from the general population, including patients who have comorbidities, are needed. Summary Adherence to combination therapy and maintenance of IFN/PEG-IFN and RBV doses lead to significant improvement in SVR rates, particularly in patients infected with HCV genotype 1 [7–9,11,14,15]. For the initial therapy of patients who have chronic hepatitis C, PEG-IFN/RBV represents the most effective treatment available. A variety of factors are important in determining the outcome of antiviral therapy, including viral load, genotype, gender, age, and the presence or absence of fibrosis, which have been shown to be significant predictors of response. Dose maintenance and duration of treatment have greater impact for patients infected with HCV genotype 1. Because side effects are the primary reason for nonadherence, early identification and management of side effects to maximize adherence and dose maintenance may play a significant role in achieving SVR. In this regard, educating the patient, their family members, and their caregivers is particularly important. Patient QOL can decrease during treatment, but achievement of SVR is associated with improved QOL. Based on cohort models and available data from recent controlled trials, PEG-IFN/RBV treatment increases life expectancy and is cost effective, and cost savings are improved with increasing adherence and EVR-based treatment management algorithms. There is a continuing critical need for accurate data on the prevalence, incidence, mortality, morbidity, and health care costs of hepatitis C-related illnesses [2]. Chronic HCV infection is particularly common among specific populations such as the homeless and incarcerated. Although the incidence of HCV infection appears to have decreased, the morbidity, mortality, and health care utilization associated with the consequences of long-standing infection have increased since the early 1990s and are projected to continue rising over the next couple of decades. Specific studies on the incidence and prevalence of HCV infection and liver disease in populations at risk and in patients who have other comorbidities (eg, substance abuse, mental disorders) are needed. Determining the extent of the contribution of extraneous comorbidity is important because antiviral therapy alone is

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unlikely to be successful in improving the health of such individuals. Further research is needed to assist in the development of optimum and costeffective treatment strategies for the general population of individuals who are infected with HCV, particularly those who have comorbidities. References [1] Boyer JL, Chang EB, Collyar DE, DeLeve LD, Feinberg J, Judge TA, et al. National Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C: 2002. June 10–12, 2002. Hepatology 2002;36(Suppl 1):S3–20. [2] Kim WR. The burden of hepatitis C in the United States. Hepatology 2002;36(Suppl 1): S30–34. [3] Williams I. Epidemiology of hepatitis C in the United States. Am J Med 1999;107(6B): 2S–9S. [4] Armstrong GL, Alter MJ, McQuillan GM, Margolis HS. The past incidence of hepatitis C virus infection: implications for the future burden of chronic liver disease in the United States. Hepatology 2000;31:777–82. [5] Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the United States. Am J Public Health 2000;90:1562–9. [6] McHutchison JG, Fried MW. Current therapy for hepatitis C: pegylated interferon and ribavirin. Clin Liver Dis 2003;7:149–61. [7] Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–65. [8] Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonc¸ales FL Jr, et al. Peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection. N Engl J Med 2002;347:975–82. [9] Hadziyannis SJ, Cheinquer H, Morgan T, Diago M, Jensen DM, Sette H Jr, et al. Peginterferon alpha-2A (40 KD) (PEGASYS) in combination with ribavirin (RBV): efficacy and safety results from a phase III, randomized, double-blind, multicentre study examining effect of duration of treatment and RBV dose [abstract]. J Hepatol 2002; 36(Suppl 1):3. [10] Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology 2002; 36(Suppl 1):S237–44. [11] McHutchison JG, Manns MP, Patel K, Poynard T, Lindsay KL, Trepo C, et al. Adherence to combination therapy enhances sustained response in genotype-1–infected patients with chronic hepatitis C. Gastroenterology 2002;123:1061–9. [12] McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485–92. [13] Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomized trial of interferon a2b plus ribavirin for 48 weeks or for 24 weeks versus interferon a2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998; 352:1426–32. [14] Ferenci P, Shiffman ML, Fried MW, Sulkowski MS, Haeussinger D, Zarski J-P, et al. Early prediction of response to 40 kDa peginterferon alfa-2a (PEGASYS) plus ribavirin in patients with chronic hepatitis C (CHC) [abstract]. Hepatology 2001;34(4 Pt 2):351A. [15] Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003;38:645–52. [16] Borden EC, Parkinson D. A perspective on the clinical effectiveness and tolerance of interferon-a. Semin Oncol 1998;25(Suppl 1):3–8.

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[17] Dieperink E, Willenbring M, Ho SB. Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: a review. Am J Psychiatry 2000;157:867–76. [18] Bodenheimer HC Jr, Lindsay KL, Davis GL, Lewis JH, Thung SN, Seeff LB. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial. Hepatology 1997;26:473–7. [19] De Franceschi L, Fattovich G, Turrini F, Ayi K, Brugnara C, Manzato F, et al. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology 2000;31:997–1004. [20] Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002;122:1303–13. [21] Pawlotsky JM, Bouvier-Alias M, Hezode C, Darthuy F, Remire J, Dhumeaux D. Standardization of hepatitis C virus RNA quantification. Hepatology 2000;32:654–9. [22] Flamm SL, Eshelman A, Lyons M, Levin A, Gordon S, Muir A, et al. Improved medication adherence with cognitive behavioral therapy in patients receiving pegylated interferon alpha 2b (1.5 mcg/kg wk) + ribavirin (800–1400 mg/d): results of a prospective, randomized, controlled, multi-center trial [abstract]. Hepatology 2002;36(4 Pt 2): 311A. [23] Davis GL, Balart LA, Schiff ER, Lindsay K, Bodenheimer HC Jr, Perrillo RP, et al. Assessing health-related quality of life in chronic hepatitis C using the Sickness Impact Profile. Clin Ther 1994;16:334–43. [24] Bonkovsky HL, Woolley JM, The Consensus Interferon Study Group. Reduction of health-related quality of life in chronic hepatitis C and improvement with interferon therapy. Hepatology 1999;29:264–70. [25] Ware JE Jr, Bayless MS, Mannocchia M, Davis GL, the Interventional Therapy Group. Health-related quality of life in chronic hepatitis C: impact of disease and treatment response. Hepatology 1999;30:550–5. [26] Bernstein D, Kleinman L, Barker CM, Revicki DA, Green J. Relationship of healthrelated quality of life to treatment adherence and sustained response in chronic hepatitis C patients. Hepatology 2002;35:704–8. [27] Wong JB, Poynard T, Ling M-H, Albrecht JK, Pauker SG. The International Hepatitis Interventional Therapy (IHIT) Group. Cost-effectiveness of 24 or 48 weeks of interferon a2b alone or with ribavirin as initial treatment of chronic hepatitis C. Am J Gastroenterol 2000;95:1524–30. [28] Buti M, Casado MA, Fosbrook L, Wong JB, Esteban R. Cost-effectiveness of combination therapy for naı¨ ve patients with chronic hepatitis C. J Hepatol 2000;33:651–8. [29] Stein K, Rosenberg W, Wong J. Cost effectiveness of combination therapy for hepatitis C: a decision analytic model. Gut 2002;50:253–8. [30] Siebert U, Sroczynski G. Effectiveness and cost-effectiveness of initial antiviral treatment in patients with chronic hepatitis C. A German Health Technology Assessment and Decision Analysis commissioned by the German Federal Ministry of Health [abstract]. J Hepatol 2003;38(Suppl 2):173. [31] Wong JB, Davis GL, McHutchison JG, Manns MP, Albrecht JK. Economic and clinical implications of the loss of adherence to weight-based dosing of ribavirin and peginterferon alfa-2b for chronic hepatitis C [abstract]. Hepatology 2002;36(4 Pt 2):717A. [32] Wong JB, McHutchison JG, Manns MP, Davis GL, Albrecht JK. Impact of optimized treatment algorithms on the cost-effectiveness of ribavirin and peginterferon alfa-2b for chronic hepatitis C [abstract]. Hepatology 2002;36(4 Pt 2):717A. [33] Wong JB, Rosenberg WM, Manns MP, McHutchison JG, Davis GL, Albrecht JL, et al. Is peginterferon alfa-2b plus ribavirin cost-effective for treating chronic hepatitis C in the United Kingdom [abstract]? J Hepatol 2003;38(Suppl 2):181. [34] Wong JB, Rosenberg WM, Manns MP, Davis GL, McHutchison JG, Albrecht JK, et al. Evaluating rapid virological response reduces ribavirin and peginterferon alfa-2b treatment

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M.P. Manns / Gastroenterol Clin N Am 33 (2004) S11–S24 costs for chronic hepatitis C in the United Kingdom [abstract]. J Hepatol 2003;38(Suppl 2): 181. Siebert U, Sroczynski G, Wasem J, Aidelsburger P, Rosol S, Wong JB, et al. The influence of analytic time horizon and treatment management algorithms on the cost of peginterferon alfa-2b plus ribavirin therapy for chronic hepatitis C [abstract]. J Hepatol 2003;38(Suppl 2):173. Sullivan SD, Green J, Patel KK, Crtaxi A, Alberti A, Giuliani G, et al. A comparison of cost-effectiveness of peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) vs interferon alfa-2b plus ribavirin as first treatment of chronic hepatitis C (CHC) [abstract]. J Hepatol 2003;38(Suppl 2):174. Siebert U, Sroczynski G, Rossol S, Wassem J, Ravens-Sieberer U, Kurth BM, et al. Cost effectiveness of peginterferon alpha-2b plus ribavirin versus interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C. Gut 2003;52:425–32. Kim WR. Motion—the available treatments for hepatitis C are cost effective: arguments against the motion. Can J Gastroenterol 2002;16:710–5.

Gastroenterol Clin N Am 33 (2004) S25–S35

Role of epoetin alfa in maintaining ribavirin dose Nezam H. Afdhal, MD Department of Medicine, Liver Center, Beth Israel Deaconess Medical Center, 110 Francis Street, Suite 8E, Boston, MA 02215, USA

The current standard of care for the treatment of hepatitis C virus (HCV) infection is the use of interferon alfa-2a or alfa-2b, standard (IFN) or pegylated (PEG-IFN), in combination with ribavirin (RBV) [1]. PEG-IFN is now the most commonly used IFN formulation because of its less frequent dosing requirement and overall improved sustained virologic response (SVR) rates. Patient adherence to these combination treatment regimens, particularly patients who have genotype 1 infection, appears to be important for viral eradication and achievement of an SVR [2]. Hematologic toxicities (neutropenia, thrombocytopenia, anemia) associated with anti-HCV therapy are a major reason for dose reduction, although they require discontinuation of therapy only rarely (3% of patients; Fig. 1) [3–5]. In recent large, randomized trials of PEG-IFN/RBV therapy, neutropenia, thrombocytopenia, and anemia resulted in dose reductions in up to 21%, 4%, and 23% of patients, respectively [3,4]. In these trials dose reductions because of side effects occurred in 37% to 42% of patients (including those caused by laboratory abnormalities [hematologic side effects], which occurred in 25–27% of patients) [3–5]. Because maintaining IFN or PEGIFN and RBV doses is important to achieving SVR and hematologic side effects cause a large proportion of dose reductions, monitoring of hematologic side effects and appropriate management might play a substantial role in obtaining a successful treatment outcome.

Dr. Afdhal has received grants and research support from Schering-Plough Corporation, Ortho Biotech Products, L.P., and Idenix Pharmaceuticals and has consulted for ScheringPlough Corporation, Ortho Biotech Products, L.P., and Prometheus Laboratories. E-mail address: [email protected] 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2003.12.002

S26 N.H. Afdhal / Gastroenterol Clin N Am 33 (2004) S25–S35 Fig. 1. Incidence of dose reductions and therapy discontinuation related to adverse events or laboratory abnormalities based on two large, randomized clinical trials in patients who had chronic hepatitis C who were receiving PEG-IFN/RBV combination therapy. (Data from Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncxales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975–82.

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Neutropenia Decreases in neutrophil counts below normal occur in most patients receiving PEG-IFN monotherapy or PEG-IFN/RBV therapy [6,7]. Neutropenia (neutrophil count \ 750/lL) is caused primarily by IFN/PEGIFN–induced bone marrow suppression [8–10], with PEG-IFNs inducing neutropenia to a greater degree than standard IFNs [3,4]. Neutropenia has occurred in up to 21% of patients receiving PEG-IFN/RBV and is one of the most common causes of IFN or PEG-IFN dose reduction, but it rarely requires permanent dose reduction or permanent discontinuation of therapy [3,4,7]. Rapid decreases in neutrophil counts might be observed within the first 2 weeks after initiation of PEG-IFN therapy [5]. Decreased neutrophil counts typically stabilize over the next 4 weeks as steady-state concentrations of PEG-IFN are achieved. Recommendations for PEG-IFN or IFN dose reductions or discontinuation as a result of neutropenia are shown in Table 1. Neutrophil counts generally return to pretreatment levels rapidly within 2 to 4 weeks of treatment cessation [5]. Neutropenia is clearly a clinical concern because neutropenic patients might be at risk of potential infections. While it has not been clearly established that the occurrence of IFN/PEG-IFN–induced neutropenia is associated with an increased risk of infectious complications in patients who have chronic hepatitis C [11], serious and severe bacterial infections, some fatal, have occurred in patients treated with IFN or PEG-IFN, some in association with neutropenia [6,7]. IFN or PEG-IFN therapy should be discontinued in patients who develop severe infections and appropriate anti-infective therapy instituted. The growth factor granulocyte colonystimulating factor (G-CSF) is being used clinically at a dosage of 300 lg one to three times weekly to increase neutrophil counts in neutropenic patients who have chronic hepatitis C; however, published clinical experience with G-CSF or granulocyte-macrophage colony stimulating factor in patients who have chronic hepatitis C is limited [12–16]. Further investigation is required before hematopoietic growth factors can be recommended for routine use to treat neutropenia induced by IFN or PEG-IFN [5].

Thrombocytopenia Many patients receiving IFN or PEG-IFN experience decreases in platelet counts as a consequence of IFN/PEG-IFN–induced bone marrow suppression, but thrombocytopenia (platelet count \ 75,000/lL) occurs infrequently and rarely requires dose reduction or discontinuation [3,4,6,7,10,17–19]. Autoimmune thrombocytopenic purpura has been reported rarely with IFN or PEG-IFN; substantial decreases in platelet counts should be evaluated accordingly [5]. Recommendations for

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PEG-IFN or IFN dose reductions or discontinuation as a result of thrombocytopenia are shown in Table 1. Platelet counts generally return to pretreatment levels within 4 weeks after discontinuation of therapy [5,7]. Oprelvekin (recombinant human interleukin-11), which is used to prevent severe thrombocytopenia and to reduce the need for platelet transfusions following myelosuppressive chemotherapy in patients who have nonmyeloid malignancies and who are at high risk of severe thrombocytopenia, is undergoing evaluation as a therapeutic strategy to maintain platelet counts in patients who have chronic hepatitis C receiving standard combination therapy [20]; however, further study is needed.

Anemia Anemia, defined by the World Health Organization as hemoglobin (Hb) levels less than 13 g/dL in men or less than 12 g/dL in women, is frequently associated with IFN/RBV or PEG-IFN/RBV therapy [3–5]. Treatmentassociated anemia is a multifactorial hematologic side effect that results primarily from a dose-dependent hemolytic anemia induced by RBV [21,22], but also from IFN/PEG-IFN–induced bone marrow suppression of erythroid precursors [8,10,23]. The resulting anemia is associated with a diminished endogenous erythropoietin production for the degree of anemia [23], similar to the anemia observed in patients who have HIV infection [24] or cancer [25]. The anemia associated with standard combination therapy can exacerbate other treatment-related side effects such as dyspnea and fatigue with a marked adverse effect on quality of life [5]. In patients who do not have cardiac disease, RBV dose reductions and discontinuation of RBV therapy are recommended by the manufacturers when Hb levels decrease to less than 10 g/dL and less than 8.5 g/dL, respectively (see Table 1) [26,27]. The impact of standard combination therapy on the magnitude and frequency of Hb decline has been better characterized recently. In a retrospective analysis that evaluated treatment-related changes in Hb levels in patients infected with HCV who received IFN/RBV combination therapy for 48 weeks, approximately one third of the patients experienced a 25% reduction in Hb levels from baseline within the first several weeks of therapy, with 54% of the patients experiencing an Hb decrease of greater than or equal to 3 g/dL [28]. The incidence was significantly higher in men than in women. Ninety-five percent of patients experienced a decrease in Hb levels of greater than or equal to 1 g/dL, whereas more than 5% of patients experienced a decline in Hb levels of greater than 5 g/dL. Approximately 10% of patients had an Hb level of less than 10 g/dL. Women were four times as likely as men to experience a decrease in Hb to less than 10 g/dL, suggesting that women are more likely to undergo RBV dose reduction.

Table 1 Dose modifications for hematologic side effects of interferon/ribavirin therapy: manufacturer recommendations

Neutrophils

\ 750/lL \ 500/lL

Platelets

\ 75,000/lL \ 50,000/lL \ 25,000/lL

Hemoglobina

\ 10.0 g/dL \ 8.5 g/dL

PEG-IFNa-2ba

PEG-IFNa-2a

IFNa-2b

IFNa-2a

Ribavirina

Decrease dose by 50% Discontinue permanently

Decrease dose by 25%

Decrease dose by 50% Discontinue permanently

Decrease dose by 50% Discontinue permanently

–

–

–

–

Decrease dose by 50% Discontinue permanently –

Decrease dose by 50% Discontinue permanently –

Discontinue permanently

Discontinue permanently

Discontinue permanently Discontinue permanently Decrease by 200 mg/d Discontinue permanently

Decrease dose by 50% Discontinue permanently Discontinue permanently – Discontinue permanently

Discontinue until neutrophil count >1,000/lL; reinstitute at 50% of original dose and monitor neutrophil count – Decrease dose by 50% Discontinue permanently – Discontinue permanently

Discontinue permanently

Data from Refs. [6,7,17,18,26,27]. Patients who have no cardiac disease; for patients who have a history of stable cardiac disease receiving combination therapy, the PEG-IFNa-2b dose should be reduced by 50% and the RBV dose by 200 mg/day if a
2 g/dL decrease in hemoglobin occurs in any 4-week period. Both agents should be discontinued permanently if patients have hemoglobin \ 12.0 g/dL after this RBV dose reduction. a

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Hematologic parameter

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Overall, mean Hb levels decreased significantly by week 4 following the initiation of IFN/RBV therapy and remained decreased until treatment discontinuation. These findings suggest that using an absolute Hb level as the basis for RBV dose reduction might not take into account other potentially significant factors such as sex and the magnitude of the relative Hb decline. The strategy of RBV dose reduction to 600 mg/day was associated with only a modest increase in the Hb level (1 g/L within 4–8 weeks of dose reduction) [28]. It was reported recently that the decrease in Hb is correlated in a nonlinear manner with serum RBV concentration, not with the RBV dose based on body weight [29].

Treatment adherence and sustained virologic response A recent retrospective analysis of three clinical trials investigated the effect of adherence to IFN/RBV and PEG-IFN/RBV combination therapy on SVR rates [2]. Patients who received less than 80% of one or both drugs for greater than or equal to 80% of the expected duration of therapy showed lower SVR rates than those who received greater than or equal to 80% of both drugs for greater than or equal to 80% of the expected therapy duration; this was most apparent for patients infected with genotype 1. An assessment of SVR as a function of the amount of therapy received was determined at varying adherence levels and revealed a continuous, increasing relationship between adherence and SVR rates. Several other recent studies have suggested that higher dosages of RBV in standard combination therapy might be associated with higher rates of antiviral efficacy. Jen et al reported that higher serum concentrations of RBV at week 4 of therapy were associated with higher rates of viral response at 24 weeks follow-up after completion of 24 weeks of treatment [30]. In addition, Manns et al reported that RBV dosages of greater than 10.6 mg/kg of body weight were associated with higher rates of viral eradication in patients receiving IFN/RBV combination therapy [3]. The importance of RBV dose maintenance was also reported in patients who had previously failed to respond to IFN monotherapy or IFN/RBV who were retreated with PEG-IFN/RBV combination therapy [31]. A reduction in the PEGIFN dose alone had no significant effect on the end-of-treatment response rate compared with the rate in patients who had no dose reductions; however, a significantly decreased end-of-treatment response rate was observed in patients who had even small dose reductions in RBV. An even greater reduction in the end-of-treatment response rate was seen in patients who had reductions in PEG-IFN and RBV. Similarly, the SVR rate was significantly decreased in patients who had reductions in RBV only and reductions in PEG-IFN and RBV compared with no dose reductions or a reduction in PEG-IFN alone.

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Epoetin alfa and treatment-induced anemia Because treatment adherence and maintaining higher RBV dosages appear to be critical in achieving SVR, treating anemic patients infected with HCV during standard combination therapy with the erythropoietic growth factor epoetin alfa might represent an alternative to RBV dose reduction or discontinuation [32]. Data from two small series of patients who became anemic during IFN/RBV therapy and were treated with epoetin alfa suggested that such therapy could increase Hb levels and might facilitate maintenance of RBV dosage [33,34]. A recent multicenter, open-label study evaluated the efficacy of epoetin alfa 40,000 IU administered subcutaneously (SC) once weekly in alleviating anemia and minimizing RBV dose reduction in patients infected with HCV who were receiving IFN/RBV combination therapy [35]. Thirty-six patients were randomized to epoetin alfa and 28 patients to standard of care (SOC) for the management of IFN/RBV-induced anemia. Based on an intent-to-treat analysis, mean changes from baseline Hb levels at week 16 were +2.8 g/dL for epoetin alfa and +0.4 g/dL for the SOC group (P \ 0.0001; Fig. 2). Mean changes in RBV dosage were 34 mg/day in the epoetin alfa group and 146 mg/day in the SOC group (P = 0.06). Ontreatment changes in Hb and RBV dosage are shown in Fig. 2. At week 16 33.3% of patients in the epoetin alfa group did not have RBV dosage reductions compared with 5.7% in the SOC group (P \ 0.011). At the end of the study, 83% of patients in the epoetin alfa group maintained RBV dosages of greater than or equal to 800 mg/day compared with 54% of patients in the SOC group (P = 0.022). Thus, epoetin alfa increased Hb levels and maintained RBV dosing in this pilot randomized trial. Based on the reports using epoetin alfa for the treatment of IFN/RBVinduced anemia [33,34] and the encouraging results of the pilot study [35], a randomized, double-blind, placebo-controlled trial was undertaken to evaluate whether or not epoetin alfa could maintain RBV dosage in anemic patients infected with HCV who were receiving combination anti-HCV therapy [36]. Patients infected with HCV who were 18 to 75 years of age and who developed anemia (hemoglobin  12 g/dL) while receiving IFN/RBV or PEGIFN/RBV combination therapy for an additional 16 weeks were randomized to receive epoetin alfa 40,000 IU SC once weekly or matched placebo for an 8week, double-blind period. If the Hb level did not increase by 1 g/dL after 4 weeks, epoetin alfa dosage was increased to 60,000 IU once weekly. Following the double-blind period, eligible patients received open-label epoetin alfa for the remainder of their anti-HCV therapy. The primary efficacy endpoint was RBV dose success, which was assessed at the end of the 8-week double-blind period. RBV dose success was defined as an RBV dose at week 8 that was greater than or equal to the dose at randomization. Secondary efficacy endpoints assessed at weeks 9 and 17 were RBV dose, change in Hb level, and quality-of-life self-assessments determined by Linear Analog Scale Assessment (LASA) and the Medical Outcomes Study Short Form-36 Version 2.

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Fig. 2. Mean Hb levels and RBV dosages over time in a trial comparing epoetin alfa therapy with SOC management of IFN/RBV-induced anemia in patients who had chronic hepatitis C: on-treatment analysis. Mean Hb levels: epoetin alfa versus SOC, *P ¼ 0.0022 using Bonferroni adjustment, yP \ 0.0001 using Bonferroni adjustment; epoetin alfa versus study entry, zP \ 0.0001 using ANOVA and Bonferroni adjustment. Mean RBV dosages: epoetin alfa versus SOC, §P ¼ 0.0134, kP ¼ 0.0380; SOC versus study entry, {P \ 0.0056 using ANOVA and Bonferroni adjustment. #One patient in the epoetin alfa group and four patients in the SOC group did not have post-baseline measurements. LVCF, last value carried forward. (From Dieterich DT, Wasserman R, Bra¨u N, Hassanein TI, Bini EJ, Bowers PJ, et al. Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa. Am J Gastroenterol; 2003;98:2491–9; with permission.)

A total of 186 anemic patients (95 patients randomized to epoetin alfa and 91 patients to placebo) were enrolled in the study [36]. Patients were well-matched at entry for all baseline criteria including age, sex, ethnicity, weight, HCV genotype, HCV treatment status (nai¨ve or experienced), presence of fibrosis and cirrhosis, weeks on HCV therapy before randomization, HCV viral load, RBV dose, and Hb level. RBV dose

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success in the double-blind phase was achieved in significantly more patients treated with epoetin alfa than with placebo (P \ 0.001). The results also showed that all three secondary endpoints were achieved with maintenance of Hb, significant improvement in quality of life, and an overall increase in the total dose of RBV. At the end of the double-blind phase, patients who crossed over from placebo to epoetin alfa had similar effects on Hb and quality of life.

Summary The important role of treatment adherence and maintenance of IFN or PEG-IFN and RBV dosages in achieving SVR in patients who have chronic hepatitis C has become increasingly evident. Because hematologic side effects (neutropenia, thrombocytopenia, anemia) are a frequent reason for dose reduction or discontinuation of anti-HCV therapy, appropriate monitoring and management of these side effects might play a significant role in optimizing treatment outcomes. Neutropenia and thrombocytopenia are typically managed by IFN or PEG-IFN dose reduction; hematopoietic growth factors might be useful in treating these side effects, but reported clinical experience is limited. Although RBV-induced anemia has traditionally been managed by dose reduction or discontinuation, recent studies indicate that epoetin alfa therapy can increase Hb levels and facilitate maintenance of RBV dosage in patients who become anemic during standard combination therapy. The results of a randomized, double-blind, placebo-controlled trial of once-weekly epoetin alfa are consistent with this experience and suggest that this erythropoietic growth factor can increase Hb levels, maintain RBV dosage in a substantial proportion of patients, and improve patient quality of life significantly in this setting. Many clinical questions still exist concerning the adjunctive use of hematopoietic growth factors to ameliorate the hematologic side effects associated with standard combination therapy. Further prospective evaluation is needed to determine their utility in this setting, when to initiate treatment, the duration of therapy, and the potential impact on adherence, early response rates, and SVR rates. There are also economic issues relating to the long-term costs of therapy. Future clinical trials should address these considerations.

References [1] Boyer JL, Chang EB, Collyar DE, DeLeve LD, Feinberg J, Judge TA, et al. National Institutes of Health Consensus Development Conference statement: management of hepatitis C: 2002. June 10–12, 2002. Hepatology 2002;36(Suppl 1):S3–20. [2] McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, et al, The International Hepatitis Interventional Therapy Group. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002;123:1061–9.

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[3] Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al, The International Hepatitis Interventional Therapy Group. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–65. [4] Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonc¸ales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–82. [5] Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology 2002; 36(Suppl 1):S237–44. [6] PEG-Intron (peginterferon alfa-2b) powder for injection: prescribing information. Kenilworth (NJ): Schering Corporation; August 2001. [7] PEGASYS (peginterferon alfa-2a) prescribing information. Nutley (NJ): Hoffmann-La Roche Inc; December 2002. [8] Ernstoff MS, Kirkwood JM. Changes in the bone marrow of cancer patients treated with recombinant interferon alpha-2. Am J Med 1984;76:593–6. [9] Ganser A, Carlo-Stella C, Greher J, Vo¨lkers B, Hoelzer D. Effect of recombinant interferons alpha and gamma on human bone marrow-derived megakaryocytic progenitor cells. Blood 1987;70:1173–9. [10] Peck-Radosavljevic M, Wichlas M, Homoncik-Kraml M, Kreil A, Hofer H, Jessner W, et al. Rapid suppression of hematopoiesis by standard or pegylated interferon-a. Gastroenterology 2002;123:141–51. [11] Soza A, Everhart JE, Ghany MG, Doo E, Heller T, Promrat K, et al. Neutropenia during combination therapy of interferon alfa and ribavirin for chronic hepatitis C. Hepatology 2002;36:1273–9. [12] Van Thiel DH, Faruki H, Friedlander L, Fagiuoli S, Caraceni P, Molloy PJ, et al. Combination treatment of advanced HCV associated liver disease with interferon and G-CSF. Hepatogastroenterology 1995;42:907–12. [13] Higashi Y, Sakai K, Tada S, Miyase S, Nakamura T, Kamio T, et al. Case report: agranulocytosis induced by interferon-alpha therapy for chronic hepatitis C. J Gastroenterol Hepatol 1996;11:1012–5. [14] Shiffman ML, Hofmann CM, Luketic VA, Sanyal AJ. Use of granulocyte macrophage colony stimulating factor alone or in combination with interferon-alpha-2b for treatment of chronic hepatitis C. J Hepatol 1998;28:382–9. [15] Fukuda A, Kobayashi H, Teramura K, Yoshimoto S, Ohsawa N. Effects of interferonalpha on peripheral neutrophil counts and serum granulocyte colony-stimulating factor levels in chronic hepatitis C patients. Cytokines Cell Mol Ther 2000;6:149–54. [16] Carren˜o V, Mart´n J, Pardo M, Brotons A, Anchı´ a P, Navas S, et al. Randomized controlled trial of recombinant human granulocyte-macrophage colony-stimulating factor for the treatment of chronic hepatitis C. Cytokine 2000;12:165–70. [17] Intron A (interferon alfa-2b, recombinant) for injection: prescribing information. Kenilworth (NJ): Schering Corporation; August 2001. [18] Roferon-A (interferon alfa-2a, recombinant: prescribing information). Nutley (NJ): Roche Pharmaceuticals; March 2003. [19] Hoofnagle JH. Thrombocytopenia during interferon alfa therapy. JAMA 1991;266:849. [20] Rustgi VK, Lee P, Finnegan S, Ershler W. Safety and efficacy of recombinant human IL-11 (oprelvekin) in combination with interferon/ribavirin therapy in hepatitis C patients with thrombocytopenia [abstract]. Hepatology 2002;36(4 Pt 2):361A. [21] Bodenheimer HC Jr, Lindsay KL, Davis GL, Lewis JH, Thung SN, Seeff LB. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial. Hepatology 1997;26:473–7. [22] De Franceschi L, Fattovich G, Turrini F, Ayi K, Brugnara C, Manzato F, et al. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology 2000;31:997–1004.

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[23] Balan V, Wu GY, Muir AJ, Keeffe EB, Bowers PJ. Erythropoietic response to anemia is decreased in patients infected with hepatitis C virus (HCV) receiving combination ribavirin and pegylated interferon (RBV/PEG-IFN) therapy [abstract]. Gastroenterology 2003; 124(4 Suppl 1):A-751. [24] Spivak JL, Barnes DC, Fuchs E, Quinn TC. Serum immunoreactive erythropoietin in HIVinfected patients. JAMA 1989;261:3104–7. [25] Miller CB, Jones RJ, Piantadosi S, Abeloff MD, Spivak JL. Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med 1990;322:1689–92. [26] COPEGUS (ribavirin, USP) tablets: prescribing information. Nutley (NJ): Roche Laboratories Inc; December 2002. [27] Rebetron combination therapy containing Rebetol (ribavirin, USP) capsules and Intron A (interferon alfa-2b, recombinant) injection: prescribing information. Kenilworth (NJ): Schering Corporation; February 2002. [28] Sulkowski MS, Wasserman R, Brooks L, Ball L, Gish R. Changes in hemoglobin during interferon alfa-2b plus ribavirin combination therapy for chronic hepatitis C virus infection. J Viral Hepat 2004;11:1–8. [29] Lindahl K, Schvarcz R, Bruchfeld A, Sta˚hle L. Ribavirin serum concentration rather than dose per body weight determines the extent of anaemia in the treatment of chronic hepatitis C [abstract]. Antivir Ther 2002;7:L87–8. [30] Jen JF, Glue P, Gupta S, Zambas D, Hajian G. Population pharmacokinetic and pharmacodynamic analysis of ribavirin in patients with chronic hepatitis C. Ther Drug Monit 2000;22:555–65. [31] Shiffman M, HALT-C Investigators. Retreatment of HCV non-responders with peginterferon and ribavirin: results from the lead-in phase of the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial [abstract]. Hepatology 2002; 36(4 Pt 2):295A. [32] Devine EB, Kowdley KV, Veenstra DL, Sullivan SD. Management strategies for ribavirininduced hemolytic anemia in the treatment of hepatitis C: clinical and economical implications. Value Health 2001;4:376–84. [33] Talal AH, Weisz K, Hau T, Kreiswirth S, Dieterich DT. A preliminary study of erythropoietin for anemia associated with ribavirin and interferon-a [letter]. Am J Gastroenterol 2001;96:2802–4. [34] Gergely AE, Lafarge P, Fouchard-Hubert I, Lunel-Fabiani F. Treatment of ribavirin/ interferon-induced anemia with erythropoietin in patients with hepatitis C [letter]. Hepatology 2002;35:1281–2. [35] Dieterich DT, Wasserman R, Bra¨u N, Hassanein TI, Bini EJ, Bowers PJ, et al. Onceweekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa. Am J Gastroenterol 2003;98:2491–9. [36] Afdhal NH, Dieterich DT, Pockros PJ, Schiff ER, Shiffman ML, Sulkowski MS, et al. Epoetin alfa treatment of anemic HCV-infected patients allows for maintenance of ribavirin dose, increases hemoglobin levels, and improves quality of life vs placebo: a randomized, double-blind, multicenter study [abstract]. Gastroenterology 2003; 124(4 Suppl 1):A-714.

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Neuropsychiatric side effects of HCV therapy and their treatment: focus on IFNa-induced depression Peter Hauser, MDa,b,c,* a

Oregon Health and Science University, OR, USA b NW Hepatitis C Resource Center, OR, USA c Behavioral Health and Clinical Neurosciences Division, Portland VA Medical Center, (P3MHAdm), 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA

Hepatologists and other health care providers are increasingly recognizing the need for a systematic approach to managing hepatitis C virus (HCV) infection that takes into account the common comorbid conditions of psychiatric disorders and substance use disorders (SUDs) [1–7]. The majority of new and existing cases of HCV infection are related to injection drug use [8], and this patient population has a high prevalence of psychiatric comorbidity. In addition, interferon alfa (IFNa), a mainstay of HCV treatment, causes a variety of neuropsychiatric side effects, particularly depression, in a significant proportion of patients [1,2,5,9,10]. These side effects can result in dose reductions or necessitate discontinuation of IFNa therapy, and they can decrease patient quality of life significantly. In light of emerging data that HCV treatment adherence might be associated with improved antiviral therapy outcomes [11,12], the identification and appropriate management of psychiatric illness and neuropsychiatric side effects in patients who have hepatitis C might be particularly important in ensuring that such patients receive optimum antiviral therapy and experience potentially improved treatment outcomes [13].

Dr. Hauser has received grants and research support from Eli Lilly and Company, Forest Laboratories, Schering-Plough Corporation, GlaxoSmithKline; has consulted for Roche Pharmaceuticals; and is a member of Speaker’s Bureaus for Eli Lilly and Company, AstraZeneca Pharmaceuticals, GlaxoSmithKline, Forest Laboratories. * Behavioral Health and Clinical Neurosciences Division, Portland VA Medical Center (P3MHAdm), 3710 SW US Veterans Hospital Road, Portland, OR 97239. E-mail address: [email protected] 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2003.12.005

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Hepatitis C and psychiatric/substance use disorder comorbidity Psychiatric disorders and SUDs are frequent comorbidities in patients who have hepatitis C [1,3,4,6]. The only reported population-based prevalence rates of psychiatric disorders among HCV-infected patients are based on the United States veteran population. El-Serag and colleagues determined the prevalence of a broad spectrum of clinically significant psychiatric disorders and drug and alcohol use disorders among United States veterans in a hospital-based, retrospective case–control study [4]. Hospitalization records from 1.9 million veterans between 1992 and 1999 from the databases of the Department of Veterans Affairs (VA) were analyzed. Of these patients 33,824 were diagnosed with HCV (1.77%). Most of these patients (85%) had at least one past or present psychiatric, drug use, or alcohol use disorder, and, remarkably, 31% of the patients had an active psychiatric disorder or SUD (defined by hospitalization to psychiatric or drug rehabilitation bed sections). The majority of patients (78%) who had HCV had a history of substance use or an active SUD. Among the HCV patients who had used drugs, the most frequently used drugs were cocaine (69%) and opioids (48%). Only 6.5% of patients who had HCV had a past or present psychiatric disorder without drug or alcohol use disorders. Depression was the most frequent comorbid psychiatric diagnosis [4]. Among patients who had combined psychiatric and drug or alcohol use disorders 85% had been diagnosed with depression. Other comorbid diagnoses included anxiety disorders exclusive of posttraumatic stress disorder (PTSD; 71%), PTSD (43%), psychotic disorders (42%), and bipolar disorder (30%). There was no attempt to correlate IFNa therapy with the prevalence rates of psychiatric illness in this study. In approximately half of the patients the SUDs were diagnosed before the psychiatric illnesses were diagnosed. The interval between the substance use diagnosis and the psychiatric disorder diagnosis (mean 318  705 days) was significantly longer than that seen in the non-HCV controls (mean 114  797 days; P \ 0.0001). Although these results might not be applicable to other HCV-infected populations, they underscore the potential for a high prevalence of psychiatric disorders, including drug and alcohol use disorders, in patients who have hepatitis C and the need for screening for these disorders in this population.

Hepatitis C and depression An association between hepatitis C and depression in patients not treated with IFNa has not been clearly established, although patients who are infected with HCV tend to have high rates of depression [1,14–17], possibly because subgroups such as those who have drug or alcohol use disorders have increased prevalence rates of psychiatric illness, particularly major depression. In a study comparing depressive symptomatology in HCVinfected and noninfected drug users, the HCV-infected population tended to

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have higher levels of depression, particularly significantly lower levels of positive affect and higher levels of physiologic manifestations approaching statistical significance [14]. In a cross-sectional study of 43 patients who had chronic hepatitis C who were not receiving IFNa, Kraus et al found several factors that correlated significantly with depression [16]. Higher rates of depression were observed in older patients (50 years; P = 0.024), in patients who were aware of their hepatitis diagnosis for more than 5 years (P = 0.003), and in patients who were informed that they were not eligible for IFNa therapy (P = 0.001). Furthermore, a lower incidence of depression was noted in patients who had been diagnosed with HCV recently (1–6 months; P = 0.003). Although depression might not be directly related to hepatitis C, it is important to evaluate patients infected with HCV for depression during their first clinical visit and before and during IFNa therapy. Diabetes [18,19] and congestive heart failure [20–22] are also strongly associated with major depression. It is important to rule out these and other medical causes of depression along with other psychiatric disorders such as bipolar disorder and PTSD before initiating antidepressant treatment. Selective serotoninreuptake inhibitors (SSRIs) can induce mania or accelerate cycling in patients who have bipolar disorder [23,24], so it is important to exclude bipolar disorder as the cause of the depressive symptoms. Patients should be assessed for suicide risk and they should be advised to report any symptom of depression or suicidal ideation to their physician. Interferon a-induced depression Neuropsychiatric side effects (particularly depression), which can be severe and lead to cessation of treatment, occur in a significant proportion of patients treated with IFNa for hepatitis C, malignant melanoma, or other conditions [1,2,9,10]. These side effects include cognitive, affective, and behavioral components that are challenging to distinguish from each other and from depression [10]. IFNa-induced neuropsychiatric side effects include depression [9], irritability [25], anhedonia [9,26], fatigue [9], apathy [9], weight loss [25], sleep disturbance [25], sexual dysfunction [9], memory impairment [9], and cognitive dysfunction [9]. Although rare, suicidal ideation and successful suicides during or shortly after IFNa therapy for chronic viral hepatitis have been reported [27]. Most cases of depression are mild to moderate in severity [5]. The neuropsychiatric side effects of IFNa, particularly depression, are among the most common causes of dose reduction or discontinuation of therapy [5,25,28]. The incidence of IFNa-induced depression in patients who have hepatitis C reportedly ranges from 3% to 44% [11,25,29–38], but recent large, randomized trials that used standardized psychiatric evaluation methods indicate an incidence of approximately 20% to 30% (Table 1) [11,28,31,34]; however, it is important to note that almost all studies that had large sample sizes

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Table 1 Incidence of depression in patients treated with interferon a Study

N

Depression rate (%)

Dieperink et al 2003 [29] Horikawa et al 2003 [30] Fried et al 2002 [31] Manns et al 2001 [11] Miyaoka et al 1999 [32] McHutchison et al 1998 [28] Keefe et al 1998 [33] Davis et al 1998 [34] Farrell et al 1997 [35] Otsubo et al 1997 [36] Hunt et al 1997 [37] Okanoue et al 1996 [38] Renault et al 1987 [25]

42 99 1121 1530 66 912 632 172 1071 85 26 677 58

23 23 20–30 29–34 44 25–37 18–26 11 12–14 37 32 3 12

excluded patients who had past or present psychiatric illnesses, even if they were remote. Few studies to date were designed to specifically examine the frequency of IFNa-induced depression [39]. Studies using patient self-reports of depression might underestimate the prevalence of depression in the HCVpositive population [32]. The significant incidence underscores the importance and value of mental health care professionals participating in the overall management of patients who have hepatitis C. The author and colleagues recently prospectively assessed the incidence of IFNa-induced major depressive disorder (MDD) in a cohort of patients who had hepatitis C [39]. Ninety-two patients were referred by the Baltimore VA Medical Center Gastrointestinal Clinic and the University of Maryland Hospital Hepatitis C Clinic and screened for the study; 53 patients were enrolled in the study. The Structured Clinical Interview for DSM-IV Axis I Disorders, Version 2.0 (SCID-I/P) [40] was administered to determine the presence of psychiatric illness, and the Beck Depression Inventory (BDI) [41] was used before initiation of IFNa treatment then weekly thereafter to assess depressive symptoms. Patients must have had no psychiatric illness, no psychotropic medications, or psychoactive substance abuse for the previous 6 months to be eligible for the study. All patients had chronic hepatitis C and were eligible for IFNa therapy. Thirty-nine patients completed at least 2 months of IFNa therapy or had developed MDD during the course of treatment. Patients were treated with combination therapy consisting of IFNa-2b 3 million units injected three times a week and ribavirin 600–1200 mg orally in divided doses every day for 6 to 12 months. If BDI scores greater than or equal to 18 were observed, the SCID-I/P was used to determine the presence of MDD. If criteria for MDD were met, antidepressant therapy was initiated. One third of the patients in the study developed IFNa-induced MDD as defined by the SCID-I/P [39]. Advanced age, past MDD diagnosis, and past substance abuse were not more frequent in patients who developed MDD.

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More Caucasians developed MDD than African Americans (P \ 0.05). Other than race, the only observed difference between patients who developed MDD and those who did not was pre-IFNa therapy BDI scores. Baseline depression ratings were significantly higher in the patients who later developed MDD compared with the non-MDD patients (P = 0.005); however, the mean baseline BDI score in patients who later developed depression was relatively low and did not indicate significant depressive symptomatology. Similar observations regarding baseline depression ratings and the development of depression during IFNa therapy have been observed by others [29,32]. The mean time from initiation of IFNa therapy to development of MDD was 12.1 weeks (median 12 weeks, range 1–32 weeks) [39]. Most of these patients were diagnosed as having MDD between 6 and 22 weeks from baseline. The mean time to escalation of BDI scores was 1.8  2.4 weeks, with more than half of the patients exhibiting a rapid escalation of depressive symptoms in 2 weeks or less (Fig. 1). These results suggest that patients should be screened regularly for depression during the first 6 months of IFNa therapy and that screening only during the initial 12 weeks of IFNa treatment might underestimate the actual incidence substantially. Miyaoka et al reported an incidence of depression of 21.9%, 38.3%, and 27.1% at 4, 12, and 24 weeks, respectively [32], and Otsubo et al reported an incidence of 13%, 16.5%, 29%, and 18.8% at 2, 4, 12, and 24 weeks, respectively [36]. Although most cases of depression usually occur in the first 24 weeks of IFNa therapy, the risk continues and appears to be higher with longer duration of IFNa therapy ([ 24 weeks) [28]. Etiology of interferon a-induced depression The mechanisms of IFNa-induced depression are not fully understood, but effects can be mediated by way of neurotransmitter, neuroendocrine, or cytokine pathways [1,2,9]. Recent research in malignant melanoma patients has focused on IFNa’s effects on the neurotransmitter serotonin. IFNa can alter the metabolism of tryptophan by activating indoleamine 2,3-deoxygenase, which leads to increased production of L-kynurenine [42,43]. Because tryptophan is the metabolic precursor for serotonin, this mechanism can also reduce serotonin production (Fig. 2). Plasma concentrations of serotonin [43] and tryptophan [42,43] have been shown to be significantly reduced during IFNa therapy. The reduction in plasma serotonin concentration correlated with changes in the Montgomery Asberg Depression Rating Scale (MADRS) scores, supporting the serotonin-depletion hypothesis for IFNa-induced depression [43]. The development and severity of depressive symptoms measured by MADRS have also correlated positively with the magnitude of decreases in serum tryptophan concentrations during IFNa therapy [42]. The depletion of serotonin might be related to changes in serotonin transporter transcription and uptake activity of the serotonin transporter [43], which are

S42 P. Hauser / Gastroenterol Clin N Am 33 (2004) S37–S50 Fig. 1. The majority of patients experience an onset of depressive symptoms approximately 10 to 12 weeks after initiation of IFNa treatment. Depression develops very rapidly after the onset of symptoms in most patients over a period of approximately 2 weeks. BDI, Beck Depression Inventory; MDD, major depressive disorder.

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Fig. 2. Proposed mechanism of IFNa-induced depression. It has been suggested that IFNa activates indoleamine 2,3-deoxygenase, thereby lowering the energy of activation for L-kynurenine production and reducing the synthesis of serotonin. Lowered serotonin neurotransmission is one of the hypotheses for development of MDD, regardless of initiating factors.

consistent with the onset of MDD development. The evidence of SSRI efficacy in patients who have IFNa-induced depression is also consistent with this etiologic hypothesis [39,42,44–48].

Treatment of interferon a-induced depression Although no large, controlled studies have been reported, antidepressants appear to be safe and efficacious in treating IFNa-induced depression in patients who have hepatitis C [7,39,44–49]. There is growing evidence that SSRIs are beneficial and well tolerated in treating depression in this patient population [7,29,39,45–48]. With regard to antidepressant safety, hepatotoxicity has rarely been seen with SSRI treatment in the general population [50]. In an initial prospective case series, three of five HCV patients who had IFNa-induced depression responded to imipramine (tricyclic antidepressant), sertraline (SSRI), or paroxetine (SSRI), respectively [45]. The two patients who did not have a positive response were treated with paroxetine or sertraline. Subsequently, the same investigators treated 15 patients who had hepatitis C and major depression with citalopram, four of whom were receiving IFNa [48]. Thirteen of the patients (87%), including all four who were receiving IFNa, responded to antidepressant therapy. Liver function tests did not change in patients who were receiving citalopram 10 to 40 mg/ day (mean, 26.7 mg/day). In another series of 10 patients who had hepatitis C who developed IFNa-induced depressive disorder, all of the patients were

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treated with sertraline 50 mg/day and all 10 patients achieved rapid symptom relief with no dose reduction or discontinuation of IFNa [46]. In another group of 14 patients who had IFNa-induced depression without suicidal ideation 11 patients (79%) were able to complete IFNa therapy with concomitant treatment with paroxetine 20 mg/day [47]. Generally, SSRIs appear to be well tolerated in patients who have hepatitis C who are receiving IFNa, although headache, nausea, and insomnia are common side effects of both treatments. In the author and colleagues’ prospective study of 39 patients who had hepatitis C treated with IFNa, the use of antidepressant therapy in 13 patients who developed MDD during IFNa therapy was examined [39]. Overall, 11 of these patients (85%) were responsive to antidepressant therapy. One patient requested treatment with fluoxetine and responded to a dose of 20 mg/day. Nine of the 12 remaining patients responded well to citalopram (mean, 36.4 mg/day). Of the three patients who did not respond to citalopram, one patient was lost to follow-up, one patient discontinued IFNa treatment because of MDD with psychotic features, and one patient subsequently responded to bupropion at a dose of 300 mg/day. An average of 5.4  6.9 weeks of antidepressant therapy were necessary to reach efficacy (defined as a decrease in BDI by 50%), and an average of 9  11 weeks were needed to achieve a remission (defined as a BDI score  10). The majority of the patients who responded to antidepressant therapy (8 of 11 patients; 73%) were able to complete a full course of IFNa therapy.

Interferon a treatment in patients who have active psychiatric illnesses Several studies have addressed the issue of IFNa treatment in patients who have chronic hepatitis C who have concomitant, active psychiatric illness [51–53]. Van Thiel et al treated 13 patients who had active unipolar depression, 12 patients who had schizophrenia, and six patients who had bipolar disorder with 5 million IU IFNa five times a week for 6 months [51]. Only patients who had bipolar disorder (4 of 6 patients) experienced worsening of their symptoms; two of these patients discontinued IFNa therapy because of mania. The authors concluded that IFNa treatment of patients who have active comorbid psychiatric illnesses and hepatitis C can be managed well with active participation of a mental health care provider and continuation of appropriate psychiatric medication. Two other studies found no statistically significant difference in neuropsychiatric side effects that were present during IFNa therapy between patients who had preexisting psychiatric illnesses and patients who did not have preexisting psychiatric illnesses [52,53]. With improvements in antiviral therapy, patients who have preexisting psychiatric disorders can probably be offered such therapy safely with appropriate monitoring and management [13,52,53].

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Prophylactic antidepressant use Given the incidence and potential impact of IFNa-induced depression in patients who have hepatitis C, prophylactic treatment of depression is a consideration. Although prophylactic treatment can be considered before IFNa therapy is initiated in asymptomatic patients who have a past history of depression [54] or elevated baseline depression scores [29], no controlled studies have been reported [7]. The author and colleagues recently reported successful prophylactic administration of fluoxetine in a 67-year-old patient who had malignant melanoma who experienced recurrent depression during IFNa treatment [55]. The patient developed depression rapidly after initiation of IFNa, and when the treatment was halted his depression ceased (Fig. 3). This pattern was repeated during another course of IFNa therapy, with similar results. Following the second attempt to reinstitute IFNa treatment the patient agreed to a trial of an SSRI for prophylaxis before reintroduction of IFNa. Two weeks after taking fluoxetine 20 mg/day the patient was restarted on IFNa. BDI scores and self-reports indicated that fluoxetine suppressed IFNa-induced depression and this effect was sustained during increases in IFNa therapy to 20 million units/m2 daily. In a placebo-controlled, double-blind study in 40 patients who had malignant melanoma, patients were randomized to paroxetine or placebo beginning 2 weeks before IFNa therapy and were monitored for depression with several objective instruments [56]. A significant reduction in the incidence of MDD was observed in patients who were treated with paroxetine (P = 0.04). Retinal hemorrhages were noted in 3 of 20 patients in the paroxetine arm after the study period, with one patient experiencing irreversible retinal hemorrhaging; however, other risk factors might have contributed to the bleeding. Broad-based prophylactic therapy would likely be inappropriate for the 70% to 80% of patients who would not develop depression [5]. In carefully selected patients, however, such prophylactic antidepressant therapy might allow a full course of IFNa treatment [7]. Additional studies are needed to evaluate the potential risks and benefits of prophylactic antidepressant therapy in patients who have chronic hepatitis C and to develop a strategy to select patients at risk for IFN-induced depression [55]. Several well-controlled studies of antidepressant prophylaxis are ongoing [7].

Veterans Administration hepatitis C treatment recommendations The Veterans Health Administration updated its treatment guidelines recently for patients who have chronic HCV (Version 3.0, November 25, 2002) [57]. These guidelines recommend that all patients who have hapatitis C should undergo careful evaluation for psychiatric disorders, particularly depression and suicide risk. The psychiatric history of patients who have chronic hepatitis C, including determination of past or ongoing

S46 P. Hauser / Gastroenterol Clin N Am 33 (2004) S37–S50 Fig. 3. Repeated BDI scores over a period of 26 weeks in a patient who had IFNa-induced depression. SSRI, selective serotonin reuptake inhibitor. (Adapted from Hauser P, Soler R, Reed S, Kane R, Gulati M, Khosla J, et al. Prophylactic treatment of depression induced by interferon-a. Psychosomatics 2000;41:439–41; with permission.)

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psychiatric disorders and SUDs, should be assessed along with previous and current treatments and responses. Severe, uncontrolled psychiatric disease, particularly depression with current suicidal risk, is an absolute contraindication to IFNa-based therapy. Psychiatric disorders that are in remission or stabilized are not contraindications to IFNa therapy, although it is recommended that mental health care providers be involved with the patient during antiviral therapy. Patients who have MDD stabilized on antidepressant therapy should be considered for IFNa-based therapy provided that mental health care professionals monitor them closely. Patients who do not exhibit depression before antiviral therapy should be evaluated for depression regularly, and the use of a standardized questionnaire such as the BDI is encouraged at every office visit, particularly in patients who have symptoms of depression. It is also recommended that patients who have BDI scores above 18 (the cutoff for moderate depression) should be considered for antidepressant treatment and that patients whose scores increase but are still below this cutoff level should receive additional clinical evaluation by a mental health care professional.

Summary Increasingly, the medical community has recognized the need for a systemic approach to HCV that manages the interwoven triad of epidemics: HCV, SUDs, and psychiatric disorders. This methodology demands active involvement of mental health care professionals. A complicating factor is that depression also develops in at least 20% to 30% of patients treated with IFNa for HCV infection. Depression in patients who have hepatitis C is a significant clinical issue; it can interfere with treatment adherence, affect patient quality of life adversely, and might even lead to suicide in severe cases. All patients who have hepatitis C should be screened for psychiatric disorders and SUDs [1,7,57]. If these disorders are present, patients should be referred to a mental health care provider for appropriate treatment. This approach should help identify appropriate candidates for IFNa therapy and offer them the potential benefits of current antiviral treatment. If preexisting depression responds to antidepressant treatment, IFNa therapy can then be initiated provided that the patient is followed closely by a mental health care provider. Patients who have other active psychiatric disorders can probably be offered IFNa therapy safely with appropriate monitoring and management involving a mental health care professional. All patients taking IFNa should be evaluated for depression at least every 2 weeks using the BDI or other validated instruments [7]; however, there are woefully few empiric data that suggest risks, benefits, or useful management strategies. Before starting IFNa therapy patients should be informed about the risk of depression and educated on how to recognize the symptoms. If depression develops during

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IFNa therapy it should be treated with antidepressants. IFNa-induced depression responds to antidepressant therapy (SSRIs) in most patients, frequently allowing continuation and completion of IFNa therapy and minimizing the need for dose reduction or discontinuation. If the patient is suicidal or psychotic or the depression worsens, IFNa treatment should be discontinued and immediate psychiatric evaluation is indicated. Psychiatrists and other mental health care providers can play an important role in the prevention of unnecessary discontinuation of anti-HCV therapy [13]. The recognition and appropriate management of neuropsychiatric disorders and SUDs in patients who have HCV should lead to improved patient outcomes. References [1] Zdilar D, Franco-Bronson K, Buchler N, Locala JA, Younossi ZM. Hepatitis C, interferon alfa, and depression. Hepatology 2000;31:1207–11. [2] Trask PC, Esper P, Riba M, Redman B. Psychiatric side effects of interferon therapy: prevalence, proposed mechanisms, and future directions. J Clin Oncol 2000;18:2316–26. [3] Cheung R, Ahmed A. Treating chronic hepatitis C patients with psychiatric disorders: an uphill battle [editorial]. Am J Gastroenterol 2001;96:3–4. [4] El-Serag HB, Kunik M, Richardson P, Rabeneck L. Psychiatric disorders among veterans with hepatitis C infection. Gastroenterology 2002;123:476–82. [5] Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology 2002; 36(Suppl 1):S237–44. [6] Lehman CL, Cheung RC. Depression, anxiety, post-traumatic stress, and alcohol-related problems among veterans with chronic hepatitis C. Am J Gastroenterol 2002;97:2640–6. [7] Loftis JM, Hauser P. Comanagement of depression and HCV treatment. Psychiatr Ann 2003;33:385–91. [8] Coury-Cautilena C, Van Raden M, Gibble J, Melpolder J, Shakil AO, Viladomiu L, et al. Routes of infection, viremia, and liver disease in asymptomatic individuals with hepatitis C virus infection. N Engl J Med 1996;334:1691–6. [9] Valentine AD, Meyers CA, Kling MA, Richelson E, Hauser P. Mood and cognitive side effects of interferon-a therapy. Semin Oncol 1998;25(Suppl 1):39–47. [10] Dieperink E, Willenbring M, Ho SB. Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: a review. Am J Psychiatry 2000;157:867–76. [11] Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–65. [12] McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, et al. Adherence to combination therapy enhances sustained response in genotype-1–infected patients with chronic hepatitis C. Gastroenterology 2002;123:1061–9. [13] Goldsmith J, Hauser P. Psychiatric issues in patients with hepatitis C [editorial]. Psychiatr Ann 2003;33:357–60. [14] Johnson ME, Fisher DG, Fenaughty A, Theno SA. Hepatitis C virus and depression in drug users. Am J Gastroenterol 1998;93:785–9. [15] Dwight MM, Kowdley KV, Russo JE, Ciechanowski PS, Larson AM, Katon WJ. Depression, fatigue, and functional disability in patients with chronic hepatitis C. J Psychosom Res 2000;49:311–7. [16] Kraus MR, Scha¨fer A, Csef H, Scheurlen M, Faller H. Emotional state, coping styles, and somatic variables in patients with chronic hepatitis C. Psychosomatics 2000;41:377–8.

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[17] Wessely S, Pariante C. Fatigue, depression and chronic hepatitis C infection. Psychol Med 2002;32:1–10. [18] Eaton WW. Epidemiologic evidence on the comorbidity of depression and diabetes. J Psychosomat Res 2002;53:903–6. [19] Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The prevalence of comorbid depression in adults with diabetes. Diabetes Care 2001;24:1069–78. [20] Koenig HG. Depression in hospitalized older patients with congestive heart failure. Gen Hosp Psychiatry 1998;20:29–43. [21] Havranek EP, Ware MG, Lowes BD. Prevalence of depression in congestive heart failure. Am J Cardiol 1999;84:348–50. [22] Jiang W, Alexander J, Christopher E, Kuchibhatla M, Gaulden LH, Cuffe MS, et al. Relationship of depression to increased risk of mortality and rehospitalization in patients with congestive heart failure. Arch Intern Med 2001;161:1849–56. [23] Henry C, Sorbara F, Lacoste J, Gindre C, Leboyer M. Antidepressant-induced mania in bipolar patients: identification of risk factors. J Clin Psychiatry 2001;62:249–55. [24] Joffe RT, MacQueen GM, Marriott M, Robb J, Begin H, Young LT. Induction of mania and cycle acceleration in bipolar disorder: effect of different classes of antidepressant. Acta Psychiatr Scand 2002;105:427–30. [25] Renault PF, Hoofnagle JH, Park Y, Mullen KD, Peters M, Jones B, et al. Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 1987;147:1577–80. [26] Sammut S, Bethus I, Goodall G, Muscat R. Antidepressant reversal of interferona–induced anhedonia. Physiol Behav 2002;75:765–72. [27] Janssen HLA, Brouwer JT, van der Mast RC, Schalm SW. Suicide associated with alfainterferon therapy for chronic viral hepatitis. J Hepatol 1994;21:241–3. [28] McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485–92. [29] Dieperink E, Ho SB, Thuras P, Willenbring ML. A prospective study of neuropsychiatric symptoms associated with interferon-a-2b and ribavirin therapy for patients with chronic hepatitis C. Psychosomatics 2003;44:104–12. [30] Horikawa N, Yamazaki T, Izumi N, Uchihara M. Incidence and clinical course of major depression in patients with chronic hepatitis type C undergoing interferon-alpha therapy: a prospective study. Gen Hosp Psychiatry 2003;25:34–8. [31] Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonc¸ales FL, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–82. [32] Miyaoka H, Otsubo T, Kamijima K, Ishii M, Onuki M, Mitamura K. Depression from interferon therapy in patients with hepatitis C [letter]. Am J Psychiatry 1999;156:1120. [33] Keefe EB, Hollinger FB. The Consensus Interferon Study Group. Therapy of hepatitis C: consensus interferon trials. Hepatology 1998;26(Suppl 1):101S–7S. [34] Davis GL, Esteban-Mur R, Rustgi V, Hoefs J, Gordon SC, Trepo C, et al. Interferon alfa2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998;339:1493–9. [35] Farrell GC. Therapy of hepatitis C: interferon alfa-n1 trials. Hepatology 1997;26(Suppl 1): 96S–100S. [36] Otsubo T, Miyaoka H, Kamijima K, Onuki M, Ishii M, Mitamura K. Depression during interferon therapy in chronic hepatitis C patients—a prospective study. Seishin Shinkeigaku Zasshi 1997;99:101–127 [in Japanese]. [37] Hunt CM, Dominitz JA, Bute BP, Waters B, Blasi U, Williams DM. Effect of interferon-a treatment of chronic hepatitis C on health-related quality of life. Dig Dis Sci 1997;42: 2482–6. [38] Okanoue T, Sakamoto S, Itoh Y, Minami M, Yasui K, Sakamoto M, et al. Side effects of high-dose interferon therapy for chronic hepatitis C. J Hepatol 1996;25:283–91.

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[39] Hauser P, Khosla J, Aurora H, Laurin J, Kling MA, Hill J, et al. A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C. Mol Psychiatry 2002;7:942–7. [40] First M, Spitzer R, Gibbon M, Williams J. Structured clinical interview for DSM-IV axis I disorders–patient edition (SCID-I/P, Version 2.0). New York: New York State Psychiatric Institute; 1995. [41] Beck A, Ward C, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561–71. [42] Capuron L, Ravaud A, Neveu PJ, Miller AH, Maes M, Dantzer R. Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 2002;7:468–73. [43] Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M, Artini M, et al. Increased depressive ratings in patients with hepatitis C receiving interferon-a–based immunotherapy are related to interferon-a–induced changes in the serotonergic system. J Clin Psychopharmacol 2002;22:86–90. [44] Levenson JL, Fallon HJ. Fluoxetine treatment of depression caused by interferon-a. Am J Gastroenterol 1993;88:760–1. [45] Gleason OC, Yates WR. Five cases of interferon-alfa–induced depression treated with antidepressant therapy. Psychosomatics 1999;40:510–2. [46] Schramm TM, Lawford BR, Macdonald GA, Cooksley WGE. Sertraline treatment of interferon-alfa-induced depressive disorder. MJA 2000;173:359–61. [47] Kraus MR, Schafer A, Faller H, Csef H, Scheurlen M. Paroxetine for the treatment of interferon-a-induced depression in chronic hepatitis C. Aliment Pharmacol Ther 2002;16: 1091–9. [48] Gleason OC, Yates WR, Isbell MD, Philipsen MA. An open-label trial of citalopram for major depression in patients with hepatitis C. J Clin Psychiatry 2002;63:194–8. [49] Goldman LS. Successful treatment of interferon alfa-induced mood disorder with nortriptyline. Psychosomatics 1994;35:412–3. [50] Garcı´ a-Pando AC, Garcı´ a del Pozo J, Sa´nchez AS, Martı´ n AV, Rueda de Castro AM, Lucena MI. Hepatotoxicity associated with the new antidepressants. J Clin Psychiatry 2002;63:135–7. [51] Van Thiel DH, Friedlander L, Molloy PJ, Fagiuoli S, Kania RJ, Caraceni P. Interferonalpha can be used successfully in patients with hepatitis C virus-positive chronic hepatitis who have a psychiatric illness. Eur J Gastroenterol Hepatol 1995;7:165–8. [52] Ho SB, Nguyen H, Tetrick LL, Opitz GA, Basara ML, Dieperink E. Influence of psychiatric diagnoses on interferon-a treatment for chronic hepatitis C in a veteran population. Am J Gastroenterol 2001;96:157–64. [53] Pariante CM, Landau S, Carpiniello B. Interferon alfa-induced adverse effects in patients with a psychiatric diagnosis [letter]. N Engl J Med 2002;347:148–9. [54] Goldsmith RJ, Mindrum G, Myaing M. Psychiatric assessment of patients with hepatitis C virus before initiating interferon treatment. Psychiatr Ann 2003;33:369–76. [55] Hauser P, Soler R, Reed S, Kane R, Gulati M, Khosla J, et al. Prophylactic treatment of depression induced by interferon-a. Psychosomatics 2000;41:439–41. [56] Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 2001;344:961–6. [57] Veterans Health Administration. Treatment recommendations for patients with chronic hepatitis C. Version 3.0. Washington (DC): Department of Veterans Affairs; 2002. p. 1–38.

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Future trends in managing hepatitis C John G. McHutchison, MD*, Anouk T. Dev, MD, PhD Division of Gastroenterology and GI/Hepatology Research, Duke Clinical Research Institute, Duke University Medical Center, P.O. Box 17969, Durham, NC 27710, USA

Current standard therapy with pegylated interferon (PEG-IFN) plus ribavirin (RBV) produces a sustained virologic response (SVR) in more than 50% of patients who have chronic hepatitis C [1–3], but such therapy is associated with certain limitations including high cost, morbidity from side effects, and the requirement for prolonged (6–12 months) treatment. In addition, a substantial proportion of patients do not achieve an adequate response and might therefore require further therapy, and patients who have advanced liver disease or contraindications to current therapy have limited treatment options. Further, the growing number of patients who have chronic hepatitis C who are undergoing treatment will contribute to the need for new agents and innovative treatment strategies for those who do not respond to currently available therapy. The search for new therapies will focus on the development of agents that have improved efficacy or tolerability. Desired features of agents for the treatment of hepatitis C virus (HCV) infection include oral bioavailability, a high degree of antiviral efficacy, greater tolerability, minimal or no development of resistance, cost effectiveness, and broad application for most patients [4]. To date, such therapy is not available, and current standard regimens of PEG-IFN plus RBV are likely to remain the mainstay of

Dr. McHutchison has received grants and research support from or has acted as an advisor for Akros Pharma, Amgen, Biomedicines, Bristol-Myers Squibb, Fujisawa, Gilead Sciences, IDUN, Isis Pharmaceuticals, Prometheus Laboratories, Ribozyme Pharmaceuticals, Roche Pharmaceuticals, Sciclone, and Schering-Plough Corporation, and he has consulted for Anadys Pharmaceuticals, Centocor, GlaxoSmithKline, Intermune Pharmaceuticals, Isis Pharmaceuticals, National Genetics Institute, Prometheus Laboratories, Ribozyme Pharmaceuticals, and Schering-Plough Corporation. He is also a member of Speaker’s Bureaus for Intermune Pharmaceuticals, Roche Pharmaceuticals, and Schering-Plough Corporation. * Corresponding author. E-mail address: [email protected] (J.G. McHutchison). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2003.12.001

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Box 1. Anti-hepatitis C virus therapeutics under development Modified interferons (IFNs)/new delivery methods Disposable infusion pumps Controlled-release injectables Oral delivery systems Liposome-based systems Ribavirin analogs Levovirin Viramadine Other immunomodulatory agents Inosine 59-monophosphate dehydrogenase (IMPDH) inhibitors Histamine dihydrochloride Thymosin-a1 Amantadine Molecular-based therapies HCV enzyme inhibitors Antisense oligonucleotides Ribozymes Short interfering RNAs Antifibrotic agents c interferon Vaccines

anti-HCV therapy for the next decade. Many new agents and treatment strategies are currently under intense investigation (Box 1). Enhancement of current therapies Adherence and viral testing Response rates to current treatment regimens might be improved by promoting adherence to anti-HCV therapy. A retrospective analysis of three randomized clinical trials evaluating standard IFNa-2b plus RBV or PEGIFNa-2b plus RBV demonstrated that patients who were maintained on greater than or equal to 80% of their total IFN and RBV doses for greater than or equal to 80% of the expected duration of therapy (80/80/80 adherence) had higher SVR rates compared with patients who received reduced doses (\ 80% of one or both drugs for  80% of the expected duration of therapy) [5]. The benefit was particularly evident among patients who had HCV genotype 1 infection. Among patients who had genotype 1 who

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received PEG-IFNa-2b 1.5 lg/kg weekly plus RBV 800 mg/day for 48 weeks, 51% of patients who had 80/80/80 adherence achieved SVR compared with 34% of patients who received reduced doses (P = 0.011). Statistical modeling demonstrated a progressive positive correlation between SVR rates and adherence. The most frequent reason for nonadherence was treatment-related side effects ([75% of patients) followed by failure to attend scheduled appointments, withdrawal of consent, and nonadherence in the absence of apparent side effects. Strategies to improve adherence to therapy may involve interventions directed at the patient and the support staff, modifications to the treatment regimen, and management of side effects. Potential strategies include the use of medication diaries, electronic monitoring devices, and directly observed therapy for selected patients at high risk of nonadherence [5]. Follow-up telephone calls from support staff and patient education designed to provide feedback regarding viral loads, management of treatment-related side effects [6], and the need for lifestyle changes are likely to be beneficial [5]. Support groups and frequent follow-up clinic visits might also be important. The introduction of PEG-IFNs, with the decreased number of injections compared with standard IFN (weekly versus three times per week), is also likely to be associated with improved adherence [5]. Viral testing early in the course of therapy can be used to predict patients who are more likely to achieve a response and, more accurately, patients who are unlikely to respond. Among patients receiving weekly PEG-IFNa2b 1.5 lg/kg weekly plus RBV 800 mg/day, a greater than or equal to 2-log10 decrease in HCV RNA after 12 weeks of therapy had a negative predictive value of 100%; none of the patients who failed to achieve a greater than or equal to 2-log10 decrease in HCV RNA after 12 weeks subsequently achieved SVR [7]. The effect was evident primarily among patients who had HCV genotype 1; patients who have genotypes 2 and 3 have such a high rate of response that early testing is unlikely to be necessary in most patients. The clinical decision to continue therapy beyond 12 weeks, however, must take into consideration a number of other factors (eg, patient tolerance and possible stabilization of fibrosis progression in patients who have advanced histology). Novel interferons/cytokines and interferon delivery methods Beyond PEG-IFNs there are several novel parenteral IFN and cytokines in early development [4], including PEG-IFNa-con-1; omega IFN; albumin-bound IFN; interleukins (IL)-28A, -28B, and -29; and engineered, second-generation IFNs. Oral agents that can stimulate the production of IFN (eg, ANA245) are also under development. There are also a number of new delivery systems under investigation designed to produce sustained IFN release into the systemic circulation, including disposable infusion pumps, controlled-release injectables (using a polymer matrix) for

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intramuscular or subcutaneous administration, oral delivery systems (eg, polyaminoacid-based systems), and the encapsulation of IFN in liposomes [8]. Ribavirin analogs Although the addition of RBV to IFN-based regimens improves SVR rates, the drug is associated with side effects (particularly anemia) that often require dosage reduction or discontinuation of treatment [1,4,6]. RBV-induced anemia is believed to be caused by the accumulation of the phosphorylated form of RBV in red blood cells (RBCs) [9,10]. RBCs lack the phosphatase activity responsible for converting phosphorylated RBV back to the parent compound, the only form capable of being transported out of the cell [9]. RBV analogs such as levovirin and viramidine, which are designed to produce the efficacy of RBV while avoiding its RBC toxicity, are under investigation [9,10]. Levovirin, the L-enantiomer of RBV, undergoes a different metabolic pathway than the parent compound [9,10]. Levovirin retains the immunomodulatory properties of RBV but, unlike RBV, levovirin is not phosphorylated and does not accumulate in RBCs [9,10], the likely reason for its potentially improved safety profile. In preclinical studies, levovirin was not associated with anemia or genotoxicity [11,12]. In a phase I study in humans, levovirin was safe and well tolerated at the single doses tested (200–1200 mg) with no anemia [13]. Viramidine is a prodrug of RBV that retains the antiviral and immunomodulatory properties of the parent drug but lacks its uptake and toxicity characteristics [10]. Because viramidine does not use the same nucleoside transporter as RBV, it accumulates in RBCs to a much lower degree than RBV [10,14]. Viramidine also is taken up into hepatocytes by a mechanism distinct from that of RBV, with greater affinity for the liver [9]. The difference between the agents in hepatic and RBC uptake results in a much higher liver-to-RBC ratio for viramidine compared with RBV [14]. The liver-targeting properties of viramidine appear to be responsible for the decreased propensity of the drug to cause anemia. In Cynomolgus monkeys there were no observable effects limits for viramidine at doses of greater than 300 mg/kg daily administered for 14 days [14]. In contrast, RBV 100 mg/kg daily for 14 days produced significant decreases in RBC, hematocrit, and hemoglobin counts. Phase II and Phase III studies of viramidine in combination with IFN are ongoing [4]. Inosine 59-monophosphate dehydrogenase inhibitors IMPDH is the rate-limiting enzyme involved in the biosynthesis of guanine [4]. Drugs that inhibit IMPDH have antiproliferative, antiviral, and immunomodulatory effects [8]. Selective IMPDH inhibitors include RBV, mycophenolate, and the investigational agent VX-497. VX-497 is an orally

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bioavailable, small molecule with demonstrated broad in vitro activity against a wide variety of viruses [4]. VX-497 also has inhibitory activity in the HCV replicon system as a single agent and additive activity to that of IFN [15] or IFN/RBV. Fifty-three previously untreated patients who had HCV genotype 1 were randomized to receive IFNa-2b plus VX-497 100 mg or 300 mg orally or placebo orally three times daily for 4 weeks [15]. VX-497 was well tolerated, with no anemia and no additional hematologic toxicity over that seen with IFNa-2b monotherapy. There was a trend toward greater reductions in HCV RNA among patients in the VX-497 100 mg group compared with the placebo group, although the difference did not reach statistical significance. Longer-term studies are currently underway to better determine the anti-HCV efficacy of VX-497/IFNa combinations. Mycophenolate mofetil is also under evaluation in combination with PEGIFNa-2a in patients who relapsed or did not respond to IFN/RBV therapy [16]. A number of other, more potent IMPDH inhibitors are also currently under development.

Other adjuvant immunomodulatory agents Histamine dihydrochloride exhibits various immunomodulatory effects by way of T-cells and natural killer (NK) cells and inhibits phagocyte-derived oxidative stress and inflammation [17]. A randomized trial compared four dosage regimens of histamine dihydrochloride in combination with IFNa-2b in treatment-na€ıve patients [18]. Patients received a fixed 1 mg dose of histamine dihydrochloride in one of four schedules: (1) once a day, three times a week; (2) once a day, five times a week; (3) twice a day, three times a week; or (4) twice a day, five times a week. The SVR rate at the end of the follow-up period (week 72) ranged from 31% to 38% across the dosage groups [18]. Although this was not a placebo-controlled trial, these SVR rates were higher than those typically achieved with standard IFNa monotherapy. Larger phase II studies evaluating histamine dihydrochloride in combination with standard agents (ie, PEG-IFN, RBV) are currently underway. Thymosin-a1 is a synthetic 28-amino acid nonglycosylated peptide derivative of a purified thymosin extract from the thymus gland and other cells. The compound has immunoregulatory activity that includes the promotion of T-cell maturation, increased NK cell activity, and the increased production of IFNc, IL-2, and IL-3 [19]. Small pilot studies evaluating the safety and efficacy of thymosin-a1 in combination with IFNa have suggested that the drug is more effective than IFN monotherapy [20–22] and that the compound might have a role in combination with IFN in patients who do not respond to first-line IFN monotherapy [8]; however, deficiencies in the design of these studies preclude a valid conclusion regarding the efficacy of thymosin-a1. Currently there are two double-blind, multicenter trials underway assessing the efficacy of thymosin-a1 plus PEG-IFNa-2a

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in cirrhotic and noncirrhotic patients who have not responded to IFN monotherapy or IFN/RBV combination therapy [8]. Amantadine is an antiviral agent that has activity against a wide range of viruses, including influenza A [23]. Amantadine appears to interfere with the early stages of viral replication or the uncoating or primary transcription of viral RNA; however, the drug has shown little or no direct inhibition of HCV replication in vitro [4,23]. In patients who had previously untreated chronic hepatitis C, the results of some, but not all, randomized trials evaluating the addition of amantadine to standard IFNa have suggested that the combination therapy modestly improves SVR rates [24]. A metaanalysis of five trials involving 924 treatment-na€ıve patients showed that standard IFNa plus amantadine was associated with a significantly higher SVR rate compared with standard IFNa monotherapy (22.4% versus 16.6%; P \ 0.03) [4]. Data evaluating the efficacy of amantadine in tripletherapy regimens in combination with standard IFNa and RBV are also equivocal. Among 400 patients who had previously untreated disease, amantadine/IFNa/RBV produced SVR in 52% of patients compared with 43% of patients receiving IFNa/RBV, although the difference did not quite reach statistical significance (P = 0.055); no significant difference in response rates between treatment regimens in patients infected with HCV genotype 1 was observed [25]. Because PEG-IFN/RBV therapy produces higher SVR rates, the value of adding amantadine to such regimens in previously untreated patients needs evaluation, and additional randomized trials of triple therapy using PEG-IFN are ongoing [4]. The role of amantadine in combination with IFN and RBV among patients who have failed prior IFN monotherapy or standard IFN/RBV combination therapy has not been clearly established, and further evaluation might be warranted, particularly in combination with PEG-IFN and RBV [24].

Molecular-based therapies Hepatitis C virus enzyme inhibitors HCV is a positive-stranded RNA virus 9.6 kb in length that belongs to the flaviviridae family of viruses [26,27]. The genome is flanked by 59 and 39 untranslated regions, which are required for translation and replication of the viral RNA [4]. The genome encodes a polyprotein of approximately 3000 amino acid residues that is processed posttranslationally by host and viral proteases into 10 structural (core, E1, E2, p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A, NS5B) proteins [4,26,27]. The nonstructural proteins encode several enzymes required for protein processing and replication (eg, proteases, helicases, polymerases), thus providing novel targets for the development of antiviral therapies [26]. Proteins that are potential therapeutic targets for inhibition include NS3 protease, NS3 helicase, NS3 bifunctional protease/helicase, and the NS5B RNA-dependent RNA polymerase,

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whose three-dimensional structures have been determined recently [27]. Because of their specificity many of these enzymes are promising targets for drug therapy. A number of potential inhibitors have been described and some are in the early stages of preclinical and clinical development [4]; however, there are a number of barriers to the development of HCV enzyme inhibitors, including the need to have activity against a broad range of genotypes (6) and subtypes (90) and the potential for the development of viral resistance. It will likely be several years before the clinical potential of any specific HCV enzyme inhibitor is known. Antisense oligonucleotides Antisense oligonucleotides are unmodified or chemically modified single-stranded DNA or RNA molecules designed to prevent the translation of viral RNA [28]. The antisense oligonucleotide specifically binds to a target mRNA, resulting in a hybrid mRNA that is subsequently degraded by the cellular enzyme RNAase H [4,28]. ISIS-14803 is a 20-base antisense oligonucleotide currently under development that is complementary to a highly conserved region of the HCV internal ribosomal entry site (IRES) [29]. ISIS-14803 has been demonstrated to have dose-dependent anti-HCV activity in a number of in vitro and in vivo models [29]. In a phase I/II trial, 28 patients infected with HCV (primarily including patients who had not responded to prior IFN-based therapy) received escalating doses of intravenous or subcutaneous ISIS-14803 [30]. Treatment was generally well tolerated and associated with HCV RNA reductions greater than 1.0 log10; however, some of the responding patients experienced transient and asymptomatic increases in serum alanine aminotransferase (ALT) levels. Current and planned studies are designed to evaluate the long-term efficacy and safety of this agent in a variety of patient populations and combination treatment regimens [29]. Ribozymes Ribozymes are catalytic RNA molecules that act by binding to and cleaving specific sequences of RNA. Although unmodified ribozymes are subject to rapid host nuclease degradation, chemical modifications produce improved stability. Animal studies of a ribozyme targeted at the 59 untranslated region of HCV (RPI.13919) have demonstrated that this agent is distributed to the liver in sufficient amounts to inhibit HCV-IRESluciferase expression after intravenous administration [31]. RPI.13919 has also been shown to produce dose-dependent inhibition of viral replication in vitro, and the effect is potentiated by IFN [4]. Short interfering RNAs Short interfering RNAs are the byproducts of the cleaving of doublestranded RNA, an intermediate in the replication of many viruses. Short

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interfering RNA molecules associate with the RNA-induced silencing complex, a multiprotein complex. Thus, homologous mRNA is targeted for degradation, leading to the selective destruction of nonself double-stranded RNA. HCV-specific short interfering RNAs have recently been demonstrated to block HCV replication and protein expression in vitro by a mechanism that is independent of IFN [32], which suggests that the induction of RNA interference has a potential role as a therapeutic modality in patients who have chronic HCV infection.

Antifibrotic agents The development of hepatic fibrosis is initiated by an injurious stimulus (eg, HCV infection) resulting in a cascade of events that are mediated by a variety of cytokines. Therapeutic approaches aimed at reducing liver inflammation and preventing the development of fibrosis in the absence of viral clearance are important objectives in patients who have chronic hepatitis C, especially patients who are unresponsive to antiviral therapy or who have contraindications to current therapies. Potential antifibrotic therapies include cytokine manipulation and antifibrotic agents. Although several antifibrotic compounds are under development, for the most part these agents have not progressed beyond preclinical evaluation. IFNc has a number of properties (antimicrobial, antiproliferative, and antifibrotic) that suggest that it might have a role in preventing the progression of liver fibrosis. In subgenomic HCV replicon constructs IFNc inhibits protein synthesis and RNA replication [33]. IFNc has also been shown to downregulate transforming growth factor-b and to decrease hepatic stellate cell activation and proliferation [4]. In patients who have idiopathic pulmonary fibrosis who are not responsive to glucocorticoids alone, the combination of IFNc and prednisolone improves markers of pulmonary function [34]. A randomized, double-blind, multicenter phase II trial is currently evaluating the ability of IFNc-1b to improve histologic fibrosis in 450 patients infected with HCV who have severe liver fibrosis or compensated cirrhosis who have failed IFNa therapy [4].

Vaccines The development of a vaccine against HCV has been slow because of substantial barriers including the lack of a small animal model, the high degree of HCV genomic variability, and difficulties with producing high quantities of HCV in tissue culture [35]. Targets for HCV DNA vaccines include envelope glycoproteins (E1 or E2), core antigen, and nonstructural proteins (NS3, NS4, NS5) [36,37]. The development of a novel HCV replicon system might allow for faster progress in HCV vaccine development [35]; however, a clinically available vaccine remains many years away.

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Summary The treatment of chronic hepatitis C remains less than ideal for all patients. Despite the availability of new treatment regimens such as PEG-IFNs plus RBV, which produce significant improvements in SVR rates, there remains a substantial proportion of patients who do not achieve sustained viral clearance. This situation is particularly true for difficult-totreat populations (eg, patients who have HCV genotype 1 infection or cirrhosis). These regimens are also associated with substantial side effects that can lead to nonadherence, dosage reductions, and treatment discontinuation [6]; however, these regimens will continue to be the primary treatments for the next decade. A number of new therapeutic agents and strategies are under development that have the potential to further improve SVR rates. The goal of the new agents and strategies is to increase SVR rates significantly over current therapy and to improve tolerability. It is likely that new regimens will involve the use of multiple-drug combinations to produce improved SVR rates and to diminish or reduce the emergence of viral resistance; however, the addition of new agents to the current anti-HCV regimen will also increase the complexity of treatment. When a third drug is added numerous potential treatment sequences need to be explored to determine the schedule that will produce optimal results. Treatment regimens for chronic hepatitis C will continue to evolve and improve. Expanding knowledge of the molecular biology of HCV has provided the basis for developing a number of novel therapeutic targets. Promising initial results have been demonstrated with several new therapies; however, most of these agents and strategies require considerable further investigation before their potential role in the treatment of chronic hepatitis C can be determined.

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