Current therapy for hepatitis C: pegylated interferon and ribavirin

Clin Liver Dis 7 (2003) 149 161 Current therapy for hepatitis C: pegylated interferon and ribavirin John G. McHutchison, MD a, Michael W. Fried, MD b, * a Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC 27710, USA b Division of Digestive Diseases, University of North Carolina at Chapel Hill, Room 708, Chapel Hill CB #7080, 1111 Bioinfomatics Building, Chapel Hill, NC 27599-7080, USA Recent data have suggested that pegylation of interferon produces novel compounds with improved efficacy when compared with standard interferon preparations for treating chronic hepatitis C. The pharmacokinetic properties of these agents, peginterferon alfa-2a (PEGASYS) and peginterferon alfa-2b (PEG- INTRON), are reviewed elsewhere in this issue. This article focuses on recent results of clinical trials of these agents that have set new standards of care for treating chronic hepatitis C. Peginterferon alfa-2a Peginterferon alfa-2a monotherapy Peginterferon alfa-2a has demonstrated superiority over standard interferon alfa-2a for treating chronic hepatitis C. Zeuzem et al randomized 531 patients with chronic hepatitis C to two treatment arms with either peginterferon alfa-2a 180mg once per week for 48 weeks or standard interferon alfa-2a 6 mu three times weekly followed by 3 MU three times weekly for an additional 36 weeks [1]. Sustained virological response in the peginterferon treatment group was significantly greater than in the group treated with standard interferon (39% versus 19%, P = 0.001). Using multiple regression logistical analysis, several Dr. McHutchison has received research support from Schering Plough and Roche and is a member of the speakers bureau for both companies. Dr McHutchison has also acted as a consultant and advisor for Schering Plough. Dr. Fried is funded in part by RO-1 HL64817-01. Dr. Fried receives research support from Hoffman-LaRoche and Schering. * Corresponding author. Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC 27710, USA. 1089-3261/03/$ see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S1089-3261(02)00077-6

150 J.G. McHutchison, M.W. Fried / Clin Liver Dis 7 (2003) 149 161 pretreatment variables were associated with increased likelihood of response to peginterferon alfa-2a monotherapy. Thus, non-1 genotype, age younger than 40 years, absence of significant fibrosis, lower body surface area, and low levels of hepatitis C virus (HCV) RNA (< 2 million copies/ml) were among the variables associated independently with sustained virological response, similar to predictive factors reported from other studies. Serum alanine transferase (ALT) activity quotient (> 3 upper limit of normal) was also associated with increased response [1]. The improved efficacy of peginterferon over standard interferon was achieved without a significant increase in toxicity. Adverse events were typical for those expected from interferon-based regimens and were similar between the two treatment arms. Self-reported depression was less in patients treated with peginterferon alfa-2a than those treated with standard interferon alfa-2a (16% versus 23%), a theme that would be repeated with peginterferon alfa-2a combination therapy. Peginterferon alfa-2a and cirrhosis Patients with hepatitis C who have developed bridging fibrosis or cirrhosis are, arguably, those with the greatest need for immediate and effective antiviral therapy to prevent further progression and to minimize their chances for future hepatic decompensation. When interferon monotherapy proved disappointing in this patient population, the presence of cirrhosis was considered a relative contraindication to therapy. Interest in treating this population was revived, however, when the combination of standard interferon alfa-2b and ribavirin demonstrated reasonable efficacy in a post hoc analysis of patients with significant fibrosis who had been included in the trial [2]. Heathcote et al [3] reported the results of a randomized phase II clinical trial specifically designed to evaluate the response to peginterferon alfa-2a prospectively in a large cohort of patients with advanced fibrosis. Two hundred seventyone patients with bridging fibrosis or cirrhosis were randomized to receive peginterferon alfa-2a 90 mg or 180 mg once per week or standard interferon alfa-2a 3 mu three times weekly for 48 weeks. Sustained virological response was achieved in 30% of those treated with the higher dose of peginterferon alfa-2a, compared with only 8% of those treated with standard interferon alfa-2a ( P = 0.001). Pretreatment characteristics associated with virological response were similar to the earlier trials; increased response was seen in those with non-1 genotype and lower viral levels. Patients underwent liver biopsy before and 6 months after completing treatment. Histologic response (a decrease of Histologic Activity Index of 2 points) was significantly greater in the peginterferon alfa-2a treatment group compared with the standard interferon group (54% versus 31%, P = 0.02). The greatest degree of histological response was found in those with sustained virological response, regardless of treatment group, although 35% of those without a sustained virological response still had a histological response after treatment with the higher dose of peginterferon [3].

J.G. McHutchison, M.W. Fried / Clin Liver Dis 7 (2003) 149 161 151 Peginterferon alfa-2a and ribavirin The previous discussion described several clinical trials that demonstrated the improved efficacy of peginterferon alfa-2a over unmodified interferon. It was logical to assume that the beneficial effects on sustained virological response that occur when standard interferon is combined with ribavirin would be enhanced further when peginterferon is administered in combination with ribavirin. Fried et al recently reported the results of a large registration trial of over 1100 subjects with chronic hepatitis C who were randomized to receive peginterferon alfa-2a 180 mg weekly alone, or in combination with ribavirin 1000 mg to 1200 mg daily for 48 weeks [4] (Tables 1 3). These regimens were compared with treatment with standard interferon alfa-2b and ribavirin. The study groups were matched well; approximately 66% of the patients were genotype 1, and most had high levels of viremia (>2 million copies/ml). Patients treated with peginterferon alfa-2a plus ribavirin achieved a significantly higher sustained virological response (56%) than those treated with interferon alfa-2b plus ribavirin Table 1 Sustained virological response as a function of pretreatment characteristics Variable Peginterferon alpha-2a + ribavirin (n = 453) Interferon alpha-2b + ribavirin (n = 444) Peginterferon alpha-2a + placebo (n = 224) HCV genotype All patients 56% a 44% 29% Genotype 1 46% b 36% 21% Genotypes 2, 3 76% c 61% 45% Genotype 4 77% d 36% 44% Baseline HCV RNA 2 10 6 copies/ml 62% e 52% 46% >2 10 6 copies/ml 53% f 41% 22% HCV genotype and baseline HCV RNA Genotype 1 2 10 6 copies/ml 56% 43% 39% >2 10 6 copies/ml 41% 33% 13% Genotypes 2 and 3 2 10 6 copies/ml 81% 65% 58% >2 10 6 copies/ml 74% 58% 40% Histological diagnosis Cirrhosis 43% 33% 21% a P < 0.001, peginterferon alpha-2a + ribavirin versus interferon alpha-2b + ribavirin. b P = 0.01, peginterferon alpha-2a + ribavirin versus interferon alpha-2b + ribavirin. c P = 0.005, peginterferon alpha-2a + ribavirin versus interferon alpha-2b + ribavirin. d No P value calculated because of to small sample size. e P = 0.04, peginterferon alpha-2a + ribavirin versus interferon alpha-2b + ribavirin. f P = 0.003, peginterferon alpha-2a + ribavirin versus interferon alpha-2b + ribavirin. Adapted from Fried MW, Shiffman ML, Reddy KR, et al. Combination of peginterferon alpha-2a plus ribavirin in patients with chronic hepatitis C virus infection. N Engl J Med 2002;347:975 82.

152 J.G. McHutchison, M.W. Fried / Clin Liver Dis 7 (2003) 149 161 Table 2 Frequency of discontinuations and dose modifications for peginterferon alpha-2a and ribavirin compared to standard interferon alpha-2b and ribavirin Peginterferon alpha-2a and ribavirin Interferon alpha-2b and ribavirin Discontinuation (total) 10% 11% Adverse event 7% 10% Laboratory abnormality 3% 1% Dose modifications Peginterferon Ribavirin Interferon Ribavirin Adverse event 11% 22% 11% 21% Anemia 1% 22% 3% 19% Neutropenia 20% 1% 5% < 1% Thrombocytopenia 4% < 1% < 1% < 1% (44%) or peginterferon alfa-2a plus placebo (29%; all P < 0.001) (Table 1). Patients with HCV genotype 1 also had increased sustained response with peginterferon combination therapy than with standard interferon and ribavirin (46% versus 36%, P = 0.01). Sustained virological response was achieved in 76% of patients with genotype 2 or 3 with peginterferon alfa-2a plus ribavirin, compared with 61% of those treated with standard interferon alfa-2b and ribavirin. Of note, a greater proportion of participants with combined viral characteristics associated with resistance to therapy, HCV genotype 1, and high levels of viremia (>2 million copies/ml) had sustained virological response with peginterferon alfa-2a and ribavirin than with standard interferon and ribavirin (41% versus 33%). Responses also were improved in cirrhotic patients when treated with the Table 3 Frequency of adverse events of peginterferon alpha-2a and ribavirin compared with standard interferon alpha-2b and ribavirin Peginterferon alpha-2a and ribavirin Interferon alpha-2b and ribavirin Fatigue 54% 55% Headache 47% 52% Pyrexia 43% 56% Myalgia 42% 50% Rigors 24% 35% Insomnia 37% 39% Nausea 29% 33% Alopecia 28% 34% Irritability 24% 28% Arthralgia 27% 25% Anorexia 21% 22% Dermatitis 21% 18% Depression 22% 30% Adverse events in bold print indicate lower frequencies for peginterferon alpha-2a and ribavirin compared with standard interferon and ribavirin (> 5% difference).

J.G. McHutchison, M.W. Fried / Clin Liver Dis 7 (2003) 149 161 153 peginterferon and ribavirin (43% versus 33%) (Table 1). Three factors were found to be associated independently with sustained virological response: HCV non-1 genotype (odds ratio, 3.25; confidence interval, 2.09 5.12; P < 0.001), age younger than 40 years (odds ratio, 2.6; confidence interval, 1.72 3.95; P < 0.001), and body weight less than 75 kg (odds ratio, 1.9; confidence interval, 1.27 2.89; P = 0.002) [4]. Early virological response and adherence Data from trials of standard interferon and ribavirin have indicated that the absence of response to treatment by 24 weeks of therapy is highly predictive of treatment failure, as judged by sustained virological response. In the most recent trial of peginterferon alfa-2a and ribavirin, retrospective analyses yielded some important information that has significant implications for the management of patients with this new agent. Early virological response was defined as loss of HCV RNA or a decrease of HCV RNA by at least two log-folds of HCV RNA compared with baseline values (ie, a decrease from 10 6 to 10 4 copies). By week 12 of therapy, 86% of patients treated with peginterferon alfa-2a plus ribavirin had achieved early virological response. Of these, 65% subsequently achieved sustained virological response (Fig. 1). In contrast, among the 14% of patients without early virological response by week 12, only 3% went on to sustained virological response, resulting in a negative predictive value of 97% [4,5]. Thus, in the absence of an early virological response, discontinuation of therapy should be considered, because the likelihood of sustained response is negligible. These decisions must be individualized, however, and evaluated within the context of the recognized variability of HCV RNA assays. To refine the predictability of treatment response further, Ferenci et al [5] analyzed sustained response according to degree of adherence, or compliance, Fig. 1. Predictive value of early virological response to peginterferon alfa-2a and ribavirin combination therapy. (From Fried MW, Shiffman ML, Reddy KR, et al. Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection. N Engl J Med 2002;347: 975 82; with permission.)

154 J.G. McHutchison, M.W. Fried / Clin Liver Dis 7 (2003) 149 161 with the treatment regimen. Among patients treated with peginterferon alfa-2a combination therapy who achieved an early virological response, subsequent sustained virological response occurred in 75% of those who had maintained close adherence to the prescribed treatment regimen. In those with lesser degrees of adherence, only 48% achieved sustained virological response. Dose reduction after early virological response did not reduce substantially sustained virological response, whereas a marked reduction in sustained response was seen with premature discontinuation of treatment [5]. Thus, clinicians should make every effort to maintain patients on treatment when early virological response has been achieved and when there are no safety concerns that would preclude continued therapy. Duration of therapy Preliminary results of a prospective trial that evaluated the impact of duration of therapy and ribavirin dosage have been reported recently. In the trial by Hadziyannis et al [6], patients were stratified by genotype and randomized to receive therapy for 24 or 48 weeks duration with peginterferon alfa-2a 180 mg per week and ribavirin at doses of 800 mg/day or 1000 mg to 1200 mg/day (the latter according to body weight). The overall sustained response rate for patients treated with a regimen similar to that reported in the previous trial (peginterferon alfa-2a and ribavirin for 48 weeks) was 61%. Patients with genotype 1 benefited from the longer course of therapy using the higher doses of ribavirin (sustained response, 51%). Patients with combined unfavorable treatment characteristics, genotype 1 and high viral load, had a sustained response rate of 46% with this regimen. As anticipated, patients with genotypes 2 or 3 had similar sustained response rates with 24 or 48 weeks of therapy. Patients treated for 24 weeks with the lowest dose of ribavirin (800 mg/day) had similar, excellent response rates when compared with the higher doses of ribavirin [6]. Thus, peginterferon alfa-2a and ribavirin 800 mg/day for 24 weeks is an optimal therapy for patients with genotypes 2 or 3. Safety of peginterferon alfa-2a and ribavirin Combination therapy with peginterferon alfa-2a and ribavirin achieved a favorable side effect profile compared with the control arm of interferon alfa-2b and ribavirin [4,7]. The rate of premature withdrawal from therapy for laboratory abnormalities or adverse events was similar in the two treatment arms (10% versus 11%, respectively). Laboratory abnormalities such as neutropenia, anemia, and thrombocytopenia were the most frequent reasons for dose reduction. The frequency of dose reduction for neutropenia was greater in the peginterferon combination arm (20% versus 5%). Despite the increased rate of dose reductions, laboratory abnormalities were a rare cause of early

J.G. McHutchison, M.W. Fried / Clin Liver Dis 7 (2003) 149 161 155 withdrawal (peginterferon and ribavirin, 3% versus standard interferon and ribavirin, 1%). The adverse events associated with peginterferon combination therapy were compared with those reported with standard interferon and ribavirin treatment. The types of adverse events were those generally associated with combination therapy for hepatitis C, and no new classes of adverse events were observed [7]. Most adverse events associated with peginterferon alfa-2a and ribavirin were of similar frequency or substantially less frequent than those reported for standard interferon alfa-2b and ribavirin. In particular, influenza-like symptoms (fever, myalgia, and rigors) and depression occurred less frequently in the peginterferon alfa-2a and ribavirin treatment group [4,7]. Peginterferon alfa-2b Peginterferon alfa-2b monotherapy A phase III trial reported by Lindsay et al [8] indicated that peginterferon alfa-2b administered as a single agent for 48 weeks doubles the sustained virologic response rate to approximately 23% to 25% compared with standard interferon alfa-2b monotherapy. It was not effective for most patients with HCV genotype 1, however, and relapse rates after 1 year of peginterferon alfa-2b monotherapy remained high (40% to 50%) [8]. Peginterferon alfa-2b also was shown to be tolerated well, with a similar adverse effect profile compared with its standard counterpart. Peginterferon alfa-2b and ribavirin As noted previously, the addition of ribavirin in combination with peginterferon alfa-2b was likely to enhance the sustained response rates for the treatment of chronic hepatitis C. Manns et al [9] recently reported the results of a phase III randomized trial assessing the safety and efficacy of peginterferon alfa-2b combined with ribavirin for initial treatment of patients with chronic hepatitis C [4]. In this study, 1530 patients with compensated chronic HCV infection and elevated liver tests were randomized to receive one of three treatment regimens: (1) peginterferon alfa-2b 1.5 ug/kg/week plus ribavirin 800 mg/day for 48 weeks, (2) peginterferon alfa-2b 1.5 mg/kg/week plus ribavirin 1000 mg to 1200 mg/day for 4 weeks followed by peginterferon alfa-2b 0.5 ug/kg/week plus ribavirin 1000 mg to 1200 mg/day for an additional 44 weeks, or (3) standard interferon alfa-2b 3 mu subcutaneously three times weekly plus ribavirin 1000 mg to 1200 mg/day for 48 weeks. The doses of peginterferon alfa-2b were adjusted for the patient s weight and were chosen according to the most efficacious doses that led to early viral clearance in prior studies. Eight hundred milligrams of ribavirin was combined with the higher dose of pegylated interferon because of concern that when combined this

156 J.G. McHutchison, M.W. Fried / Clin Liver Dis 7 (2003) 149 161 regimen may result in a greater degree of anemia. The groups were matched according to their baseline demographics: male (65%), mean age 43 years, pretreatment HCV RNA less than 2 10 6 (68%), cirrhosis (10%), HCV genotype 1 (68%), and the proportion with high viral load (68%). The sustained virologic response rates for the three treatment groups are shown in Table 4 by intention to treat analysis and indicate a significantly higher sustained virologic response rates for patients receiving the higher dose peginterferon alfa-2b and ribavirin combination. Sustained response rates also were increased for patients with genotype 1 (42% versus 33%) compared with standard interferon and ribavirin [9]. Additionally, more than 90% of patients who achieved a sustained virologic response also had normal ALT values at the end of the follow-up period. As in prior HCV treatment trials, histologic inflammation improved in all treatment groups and was most evident in those who achieved a sustained response. Forty-four percent of nonresponder patients also had some improvement in histologic inflammation (Fig. 2). In this peginterferon alfa-2b/ribavirin trial as in prior interferon/ribavirin trials, a secondary analysis identified body weight as an independent predictor of sustained response [9]. Thus, a retrospective categorical analysis also indicated that the sustained response rate was related significantly to the dose of ribavirin on a milligram per kilogram basis (the optimal dose of ribavirin for this combination was identified as 13 mg ± 2 mg/kg). This effect was independent of HCV genotype. Patients who received the higher dose peginterferon in combination with more than 10.6 mg/kg of ribavirin (equivalent to 800 mg/day Table 4 Virologic sustained response rates for peginterferon alpha-2b and ribavirin Sustained virologic response rate (number responding/total treated) PegIFN 1 5 mg/kg + R (n = 511) PegIFN 1.5/0.5 5 mg/kg + R (n = 514) IFN 3 MIU + R (n = 505) End of follow-up (SVR): 54% 47% 47% all patients a SVR by genotype 1 b 42% 34% 33% 2/3 82% 80% 79% 4/5/6 50% 33% 38% SVR by baseline HCV > 2 M 42% 42% 42% 2 M 78% 59% 56% SVR by degree of fibrosis No/minimal fibrosis 57% 51% 49% Bridging fibrosis/cirrhosis 44% 43% 41% Abbreviations: IFN, interferon alpha-2b; MIU, million international unit; PegIFN, peginterferon alpha-2b; R, ribavirin; SVR, sustained virologic response calculated as the number of patients responding who had undetectable HCV RNA 24 weeks after completion of therapy per the total number treated in each group. a P = 0.01 (1.5/R versus I/R); P = 0.73 (0.5/R versus I/R) using logistic regression. b P = 0.01 (1.5/R versus I/R) by Fisher s exact test.

J.G. McHutchison, M.W. Fried / Clin Liver Dis 7 (2003) 149 161 157 Fig. 2. Sustained response as a function of ribavirin dose in milligrams per kilogram and dose of peginterferon alfa-2b. This logistic regression analysis indicates that the doses of peginterferon ( P = 0.002) and ribavirin ( P = 0.015) predict sustained response. (Adapted from Manns MP, Mc- Hutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis: a randomized trial. Lancet 2001;358:958 65; with permission.) for a 75 kg patient) had an enhanced sustained response rate (61%). These response rates are illustrated in Table 5. Predicting response and early stopping rules Pretreatment factors associated with a greater likelihood of achieving a sustained response include genotype 2 or 3 infection, lower viral burden, the absence of significant fibrosis, young age, and female gender [9]. Although these factors provide an estimate of the chances of achieving a response, they are generally unhelpful in accurately identifying patients who will respond to Table 5 Sustained virologic response rates by pretreatment variables and according to ribavirin dosage PegIFN 1 5 mg/kg + R (n = 511) PegIFN 1.5/0.5 5 mg/kg + R (n = 514) IFN 3 MIU + R (n = 505) All patients 54% 47% 47% Ribavirin dose 10.6 mg/kg 50% 41% 27% Ribavirin dose >10.6 mg/kg 61% 48% 47% Genotype 1 42% 34% 33% Ribavirin dose 10.6 mg/kg 38% 25% 20% Ribavirin dose >10.6 mg/kg 48% 34% 34% Response rates for each treatment group are shown as a percentage according to each pre-treatment variable. For each variable, response rates are also shown according to whether the patients in each subgroup received >10 6 mg/kg or 10 6 mg/kg ribavirin. Abbreviations: IFN, interferon alpha-2b; MIU, million international unit; PegIFN, peginterferon alpha-2b; R, ribavirin; SVR, sustained virologic response. Adapted from Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001; 358:958 65.

158 J.G. McHutchison, M.W. Fried / Clin Liver Dis 7 (2003) 149 161 therapy. The ideal test to predict response should be able to identify all nonresponder patients early during therapy, so they may cease therapy and thus avoid the morbidity and expense of prolonged therapy, while continuing treatment in those who eventually will achieve sustained response. Preliminary analyses from the phase III peginterferon alfa-2b/ribavirin trial indicate that 100% of patients receiving peginterferon and ribavirin who fail to achieve a 2 log (100-fold) reduction in serum HCV RNA by week 12 of therapy will be eventual nonresponders [10]. In addition, those individuals who achieve a 2-log reduction by this time point have an 80% chance of achieving a sustained response. Although these rules most accurately predict nonresponse, a number of caveats should be considered when using these data clinically. First, they do not take into account the potential histologic benefits observed in nonresponder patients [11], and second, the limitations of these quantitative HCV RNA assays in terms of their variability and precision may confound interpretation of viral load changes during therapy [12]. Thus, these early stopping rules must be used cautiously, and if doubt exists, the clinician should consider retesting and giving the patient the benefit of the doubt before considering ceasing therapy in the situation where an eventual nonresponse is highly likely. Adherence and its effect on response rates with peginterferon alfa-2b and ribavirin Dosing of peginterferon alfa-2b and ribavirin requires a modestly complex regimen of injections, daily oral medication, and frequent office visits and blood tests to monitor safety. As a result, not all patients complete treatment. A retrospective analysis of the effect of adherence or compliance on sustained response rates in the setting of peginterferon alfa-2b and ribavirin recently was completed [13]. In this trial, overall, 63% of patients who received at least 80% of expected doses of peginterferon alfa-2b 1.5 mg/kg and ribavirin 800 mg/day for at least 80% of the recommended duration of therapy achieved an SVR (compared with 54% overall). With 80 plus 80 plus 80 adherence to the regimen of peginterferon (1.5 mg/kg) and ribavirin (>10.6 mg/kg), the response rate increased from 61% overall to 72%. The impact of adherence to therapy was most significant in patients with genotype I infection; the SVR rate was 63% among adherent patients compared with 34% among nonadherent patients according to these 80% criteria. Thus, patients who can be maintained on at least 80% of their peginterferon dose and at least 80% of their ribavirin dose may have an enhanced SVR rate. Nearly 75% of patients with 80 plus 80 plus 80 adherence to a prescribed regimen of at least 1.5 ug/kg peginterferon alfa-2b and more than 10.6 mg/kg ribavirin for 48 weeks can achieve an SVR. Patients infected with HCV genotype 1 the most difficult to treat stand to benefit the most from adherence, especially in the first 12 to 24 weeks of therapy, when a determination as to who is most likely to achieve an eventual sustained response can be evaluated.

J.G. McHutchison, M.W. Fried / Clin Liver Dis 7 (2003) 149 161 159 Effect of therapy on fibrosis progression rates The effect of pegylated interferon alfa-2b and ribavirin (and other treatment regimens) on fibrosis progression was evaluated recently in a pooled study of 3010 patients from four trials [11]. In this cohort, treatment reduced the rate of fibrosis progression compared with that observed prior to therapy, and this was most evident for patients treated with peginterferon alfa-2b and ribavirin. Fiftytwo percent of patients who were treated with the high-dose peginterferon and ribavirin (>10.6 mg/kg) regimen had reversal of cirrhosis on their subsequent post-treatment biopsy. Although controversial, the results of this study provide substantial evidence that effective treatment associated with sustained virologic eradication can be linked to improvement in the severity of liver fibrosis (see the article in this issue by Bedossa for more detailed information). Cost effectiveness of peginterferon alfa-2b and ribavirin antiviral therapy The short- and long-term benefits of antiviral therapy have allowed economic and cost-effective analysis of antiviral treatment [14]. Results of these studies indicate that antiviral therapy with interferon (standard or pegylated) plus ribavirin is cost-effective and economically feasible when compared with other accepted medical practices (such as screening for hypertension, colorectal cancer, or mammography). In addition, patients who have sustained viral eradication have improvement in their health-related quality of life. Safety of peginterferon alfa-2b and ribavirin The adverse event profile of peginterferon alfa-2b and ribavirin was similar to adverse events observed with interferon alfa-2b and ribavirin. Discontinuations caused by adverse events were observed in 13% (interferon and ribavirin group), 13% (low dose peginterferon and ribaviron group), and 14% (higher dose peginterferon and ribavirin) of patients respectively. Additionally, dose modifications were reported in 34%, (interferon and ribavirin group) 36%, (low dose peginterferon and ribavirin) and 42% (higher dose peginterferon and ribavirin) of the patients in these three treatment groups. Adverse events during therapy were similar in the three groups, and no new adverse events were noted in the groups receiving either dose of peginterferon alfa-2b. The rate of flu-like symptoms was higher in the high-dose peginterferon group (not surprising, because more interferon was being administered), and injection-site reactions were more common but were generally mild and did not limit the course of treatment. Anemia was not observed more frequently or to a greater degree in patients who received the higher dose peginterferon, but neutropenia was observed more frequently in those receiving the higher does of peginterferon. Fewer than 1% of patients required discontinuation of therapy for neutropenia, however. A separate safety analysis of those patients who received more than 10.6 mg/kg of ribavirin

160 J.G. McHutchison, M.W. Fried / Clin Liver Dis 7 (2003) 149 161 indicated that asthenia, weight loss, nausea, and alopecia were observed more commonly but were not dose-limiting, and the degree of anemia, or need to cease therapy, was not increased in this subgroup of patients. Summary The combinations of peginterferon alfa-2a or peginterferon alfa-2b with ribavirin lead to significant improvement in sustained virological response when compared with standard interferon and ribavirin therapy. These newer agents represent the most effective treatments available for the initial therapy of patients with chronic hepatitis C. A review of the clinical trials to date suggests certain similarities and differences between the two preparations. For both regimens, however, it is apparent that information concerning the predictability of response and the importance of adherence to the treatment regimens will be of great value in the therapeutic management of chronic hepatitis C. Although viral load and genotype, gender, age, and absence of fibrosis have been shown consistently to be important predictors of response, identification of additional host immune and genetic factors involved in determining outcome of antiviral therapy are necessary. References [1] Zeuzem S, Heathcote JE, Martin N, Nieforth K, Modi M. Peginterferon alfa-2a (40 kda) monotherapy: a novel agent for chronic hepatitis C therapy. Expert Opin Investig Drugs 2001; 10:2201 13. [2] 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;339:1485 92. [3] 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;343:1673 80. [4] Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL. et al. Combination of peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C virus infection. N Engl J Med 2002;347:975 82. [5] 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. Hepatology 2001;34:351A. [6] Hadziyannis SJ, Cheinquer H, Morgan T, Diago M, Jensen DM, Sette H, 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 examing effect of duration of treatment and RBV dose [abstract]. Hepatology 2002;36:536. [7] Fried MW. Side effects of therapy for hepatitis C and their management. Hepatology, in press. [8] 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 alfa-2b as initial treatment for chronic hepatitis C. Hepatology 2001;34:395 403. [9] 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. [10] Wong JB, Davis GL, McHutchison JG, Manns MP, Albrecht JK. Clinical implications of testing

J.G. McHutchison, M.W. Fried / Clin Liver Dis 7 (2003) 149 161 161 viral response during peginterferon alfa-2b and ribavirin treatment for chronic hepatitis C [abstract]. Hepatology, in press. [11] 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. [12] 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. [13] 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. [14] Wong JB, McHutchison J, Manns M, Davis GL, Albrecht J. Effect of treatment management algorithms on peginterferon alfa-2b costs for chronic hepatitis C [abstract]. Hepatology, in press.