Pegylated interferons (peginterferons) represent the

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1 Viral Kinetics in Genotype 1 Chronic Hepatitis C Patients During Therapy With 2 Different Doses of Peginterferon Alfa-2b Plus Ribavirin Maria Buti, 1 Francisco Sanchez-Avila, 1 Yoav Lurie, 2 Carlos Stalgis, 3 Auristela Valdés, 1 Maria Martell, 1 and Rafael Esteban 1 Pegylated interferon (peginterferon) alfa-2b plus ribavirin achieves a higher sustained response rate in patients with genotype 1 chronic hepatitis C virus (HCV) than standard combination therapy. This study evaluated HCV kinetics throughout therapy with 2 doses of peginterferon alfa-2b and ribavirin in 55 patients. Twenty-eight patients were randomized to receive a high once-weekly dose of peginterferon alfa-2b (3 g/kg for 1 week, 1.5 g/kg for 3 weeks, and 1.0 g/kg for 44 weeks), and 27 patients were randomized to receive a low dose (0.5 g/kg) for 48 weeks. Both groups also received 800 mg ribavirin daily. Mean baseline HCV RNA load, measured by reverse-transcription polymerase chain reaction, was similar in both groups ( log vs log). The 3- g/kg dose of peginterferon alfa-2b inhibited HCV RNA more significantly than the 0.5- g/kg dose during the first 48 hours ( log vs log; P <.001) and both increased at 72 hours ( log vs log; P not significant [NS]), but the high dose showed a greater reduction at the end of the week ( log vs log). Both doses showed a progressive, slower viral decrease throughout therapy; however, HCV RNA became undetectable faster and in more patients with the high dose (22% vs. 7% at week 4, 56% vs. 44% at week 12, 69% vs. 63% at week 24, and 71% vs. 61.5% at the end of therapy). In conclusion, peginterferon alfa-2b/ribavirin produces an initial rapid decline in HCV RNA levels, followed by a slower, progressive decrease, similar to the biphasic kinetic profile of standard combination therapy. Higher doses of peginterferon alfa-2b also accelerate viral clearance. (HEPATOLOGY 2002;35: ) See Editorial on page 967 Abbreviations: peginterferon, pegylated interferon; HCV, hepatitis C virus; NS, not significant. From the 1 Liver Unit, Hospital General Universitari Vall d Hebron, Barcelona, Spain; 2 Liver Clinic, Gastro Enterology Institute, Kaplan, Israel; and 3 Schering- Plough, Kenilworth, NJ. Received August 15, 2001; accepted January 9, Supported in part by a grant from Schering-Plough. Address reprint requests to: Maria Buti, M.D., Liver Unit, Hospital General Universitari Vall d Hebron, Paseo Valle de Hebron 119, Barcelona Spain. mbuti@hg.vhebron.es; fax: (34) Copyright 2002 by the American Association for the Study of Liver Diseases /02/ $35.00/0 doi: /jhep Pegylated interferons (peginterferons) represent the most recent advance in the treatment of patients with chronic hepatitis C. Peginterferon alfa-2b consists of a conjugate of straight-chain polyethylene glycol (molecular weight, 12,000 daltons) and interferon alfa-2b in a 1:1 ratio. 1,2 The main effects of pegylated proteins are to delay clearance and prolong half-life, which allows for less-frequent dosing and may be associated with increased efficacy. Studies in humans have shown peginterferon to be safe and well tolerated. 1-4 The efficacy of peginterferon alfa-2b given once weekly has been evaluated in a large, multicenter study. This study showed that peginterferon alfa-2b increases the sustained virologic response rate to 25%, compared with the 12% rate observed with standard interferon therapy. 4 Even patients infected with genotype 1, who are least responsive to interferon therapy, experienced an increase in sustained virologic response when treated with peginterferon alfa-2b. 4,5 This response appeared to be dose dependent; 11% of patients with hepatitis C virus (HCV) genotype 1 treated with 0.5 g/kg peginterferon alfa-2b achieved sustained virologic 930

2 HEPATOLOGY, Vol. 35, No. 4, 2002 BUTI ET AL. 931 responses, compared with 14% of those who received 1.5 g/kg peginterferon alfa-2b and 6% of those given standard interferon alfa-2b. 4 Recently, peginterferon alfa-2b plus ribavirin has become the standard therapy for patients with chronic hepatitis C. 6-8 In a pivotal phase III clinical study involving more than 1,500 patients, 1.5 g/kg peginterferon alfa-2b once weekly plus a daily dose of ribavirin greater than 10.6 mg/kg achieved an overall sustained virologic response rate of 61% in previously untreated patients with chronic hepatitis C. Sustained virologic response rates across hepatitis C genotypes ranged from 48% in patients infected with genotype 1 to 88% in patients infected with genotypes 2 or 3. 9 Induction therapy with high daily doses of interferon alfa-2b plus ribavirin is associated with more rapid viral clearance than the standard interferon alfa-2b plus ribavirin regimen, 10 which may be especially important for patients infected with HCV genotype 1. Knowledge of viral kinetics in response to high-dose peginterferon alfa-2b plus ribavirin could be important to design new therapeutic strategies. The current study assessed the kinetics of HCV RNA throughout 48 weeks of therapy with 2 different doses of peginterferon alfa-2b plus ribavirin in untreated patients with chronic hepatitis C caused by HCV genotype 1 infection. The safety and tolerability of the 2 regimens were also assessed. Patients and Methods Patients. Adult patients with chronic hepatitis C were eligible for the study if they were HCV RNA positive, had abnormal alanine transaminase levels, and were infected with HCV genotype 1. Exclusion criteria included decompensated liver disease, hemoglobin level less than 12 g/dl, human immunodeficiency virus infection, cardiovascular disease, previous treatment with interferon and/or ribavirin, and inability to practice contraception. All patients gave written informed consent before treatment, and the protocol was approved by the ethics committees of both participating centers. Study Design. This was a randomized, open-label, active-controlled, parallel-group study performed in 2 centers: one in Israel and the other in Spain. As shown schematically in Fig. 1, patients were randomly assigned to receive 1 of 2 regimens: (1) a high dose of peginterferon alfa-2b (PEG-INTRON; Schering-Plough, Kenilworth, NJ), 3.0 g/kg once weekly for 1 week, followed by 1.5 g/kg once weekly for 3 weeks and then 1.0 g/kg once weekly for 44 weeks plus ribavirin (Rebetol; Schering- Plough) for the entire treatment period or (2) a low dose Fig. 1. Study design for assessing the impact on viral kinetics, safety, and efficacy of 2 different once-weekly (QW) doses of peginterferon (PEG-IFN) alfa-2b plus ribavirin in patients with genotype 1 chronic hepatitis C. of peginterferon alfa-2b, 0.5 g/kg once weekly for 48 weeks, plus ribavirin for the entire treatment period. Ribavirin was administered orally twice daily at a total daily dosage of 800 mg. Subjects were seen as outpatients, and complete blood counts, liver function tests, and HCV RNA analyses were performed at baseline, every 24 hours during the first week of therapy, and then at weeks 2, 3, 4, 6, 8, 12, 24, and 48 of treatment. Tests were performed just before administration of peginterferon alfa-2b. For the virologic studies, frozen stored serum samples ( 80 C) obtained during therapy were analyzed for HCV RNA in a central laboratory using a sensitive, quantitative, real-time reverse-transcription polymerase chain reaction technique with a lower limit of detection of 100 IU/mL. 11 HCV genotyping was performed by line probe assay (INNO-LiPA; Innogenetics, Antwerp, Belgium). Statistical Analysis. All data analyses were conducted using the Statistical Package for Social Sciences (SPSS for Windows, version 9.0). Viral load data was log base 10 transformed. Differences between viral loads and groups were analyzed using Student s t test and the Mann-Whitney rank-sum test for quantitative and qualitative variables, respectively. A P value of less than.05 was considered to be statistically significant. Results Fifty-five patients (22 women and 33 men) with chronic hepatitis C (median age, 42.8 years; range, years) who were HCV RNA seropositive, infected with HCV genotype 1, and had abnormal alanine transaminase levels (mean alanine transaminase level, UI/L; range, UI/L) were included. Of these patients, 28 were randomly assigned to receive the high dose of peginterferon alfa-2b and 27 to receive the low dose. Of the 55 patients, 49 completed the entire treatment (24 in the high-dose group and 25 in the low-dose group).

3 932 BUTI ET AL. HEPATOLOGY, April 2002 Table 1. Baseline Characteristics of Patients According Treatment Group High Dose (n 28) Low Dose (n 27) P Mean age, yr NS Male sex, % Mean weight, kg (range) 80.1 (53-132) 74.6 ( ) NS Cirrhosis, % NS Mean serum alanine transaminase UI/L NS Serum HCV RNA, log10 IU/mL (range) 5.17 ( ) 5.32 ( ) NS Baseline characteristics of patients in the 2 groups are shown in Table 1. All 55 patients underwent a liver biopsy 6 months before therapy, and 4% showed cirrhotic lesions. HCV RNA Kinetics. Mean baseline HCV RNA load was similar in both groups: log in the group who received the high dose of peginterferon alfa-2b vs in the low-dose group (P not significant [NS]). HCV RNA levels greater than 800,000 UI/mL were detected in 29% of the high-dose group and 22% of the low-dose group. HCV RNA kinetic results were analyzed in 3 phases, which corresponded to the different doses of peginterferon alfa-2b in the high-dose group. The first phase encompassed the first week of therapy, the second phase encompassed the second to fourth weeks, and the third phase encompassed the fifth to 48th weeks. HCV RNA Kinetics During the First Week. The 3- g/kg dose of peginterferon alfa-2b significantly inhibited HCV RNA replication during the first 2 days of therapy compared with the 0.5 g/kg dose. At 24 hours, a mean reduction in HCV RNA log of was observed in the 3- g/kg group compared with log in the 0.5- g/kg group (P.0001); at 48 hours, the respective reductions in the 2 groups were log and log (P.001). By 72 hours, HCV RNA levels had increased slightly in both groups ( log and log [P NS]) relative to 48 hours and then stabilized. At 120 hours, HCV RNA levels were with the 3- g/kg dose compared with with the 0.5- g/kg dose (P.001; Fig. 2); at the end of the first week, both groups had HCV RNA levels lower than baseline with a decrease of log in the high-dose group and log in the low-dose group (P NS) (Table 2). HCV RNA kinetics during the first week differed greatly between patients who cleared HCV RNA at week 48 and those who did not. The decrease in HCV RNA levels in logs during the first week was significantly higher in responding patients than in nonresponders (Fig. 3). In Fig. 2. Kinetics of HCV RNA after the first dose of peginterferon alfa-2b. addition, the decrease in HCV RNA levels during the first 48 hours was significantly greater in patients treated with the high dose of interferon alfa-2b than in those treated with the low dose. HCV RNA Kinetics Between Weeks 2 and 4. Between the second and fourth weeks, patients in the highdose group received 1.5 g/kg of peginterferon alfa-2b, whereas patients in the low-dose group continued to receive 0.5 g/kg. During this period, HCV kinetics were very similar in the 2 groups, with decreases of approximately 1 log noted in each group (P NS; Fig. 4). By week 4, 15 of the 27 patients (55.6%) treated with the high dose achieved a 2-log reduction in HCV RNA levels, as opposed to 9 of the 27 patients (33.3%) treated with the low dose (P NS). The 2-log decrease in HCV RNA levels at week 4 had a specificity of 95% and a sensitivity of 53% for predicting HCV RNA clearance at week 48. HCV RNA became negative in 6 patients (21.4%) in the high-dose group and in 2 patients (7.1%) in the low-dose group (P NS). HCV RNA Kinetics Between Weeks 5 and 48. After the fourth week, when the high dose of peginterferon alfa-2b was double the low dose (1 vs. 0.5 g/kg), HCV RNA levels showed a slower, progressive decrease, which occurred in parallel in both groups. Although the decrease was slightly steeper with the high dose of peginterferon Table 2. HCV RNA Decrease in Logs Throughout Therapy Relative to Dose of Peginterferon Alfa-2b Low Dose (n 27) High Dose (n 28) P Baseline NS Day Day NS Week NS Week NS Week NS Week NS

4 HEPATOLOGY, Vol. 35, No. 4, 2002 BUTI ET AL. 933 week 12, 69% vs. 63% at week 24, and 71% vs. 61.5% at the end of therapy) (P NS). Safety and Tolerability. Four patients who received the high dose of peginterferon alfa-2b plus ribavirin and 2 patients who received the low dose discontinued therapy due to adverse events between weeks 3 and 36. Before discontinuation, 1 patient in each group needed a reduction in the dose of peginterferon alfa-2b for neutropenia, and 3 patients required a reduction in the dose of ribavirin for anemia (2 in the high-dose group and 1 in the lowdose group). Fig. 3. HCV RNA decrease in logs during the first week of therapy relative to end-of-treatment response. E, nonresponders (n 16); F, responders (n 33). alfa-2b, this difference did not reach statistical significance at any time point. By week 48, the mean HCV RNA log decrease was log in the high-dose group versus log in the low-dose group (P NS) (Fig. 3). The log decrease between weeks 4 and 48 was log for the high-dose group and log for the low-dose group (P NS). Representative viral kinetic graphs of the individual patients receiving the high dose and low dose of peginterferon alfa-2b plus ribavirin relative to response at the end of treatment are shown in Figs. 5 and 6. The high dose of peginterferon alfa-2b cleared HCV RNA more rapidly and in a higher number of patients. At week 12, HCV RNA became undetectable in 56% of patients receiving the high dose versus 44% of those receiving the low dose; the corresponding percentages at week 24 were 69% and 63%, respectively, and at the end of therapy were 71% and 61.5%. Viral kinetics analysis in the first week relative to HCV RNA clearance at the end of therapy shows no relation between increases in HCV RNA levels at 72 hours and viral response at the end of therapy. Eight patients (16%) presented a HCV RNA rebound of more than 1 log at 72 hours, most in the high-dose group (6 were responders and 2 nonresponders [P NS]). Even analyzing all patients with any increase in HCV RNA levels after 72 hours, no relation was observed between the changes in HCV RNA at this time and the end of treatment response. Biochemical Response. At weeks 4, 12, 24, and 48, a higher proportion of patients achieved normal alanine transaminase levels in the high-dose group than in the low-dose group (22% vs. 7% at week 4, 56% vs. 44% at Discussion Pharmacokinetic studies have shown that the concentration-time profile of peginterferon alfa-2b is marked by rapid absorption, a prolonged concentration peak, and delayed elimination; these pharmacokinetic properties result in measurable serum concentrations up to 144 hours after dose, which permits a once-weekly regimen. 1 In our study, both the high and low doses of peginterferon alfa-2b achieved a dramatic decrease in HCV RNA levels during the first week of therapy in patients with genotype 1, the most treatment-resistant genotype. However, this decrease was more pronounced during the first 48 hours in patients treated with 3 g/kg of peginterferon alfa-2b. This phenomenon in HCV RNA kinetics is well established in patients with genotype 1 who are treated with standard interferon alfa. Different studies have shown a dose-dependent effect on viral load after a single dose of standard interferon, but no information is available about whether this effect occurs during the first week of therapy with peginterferon alfa-2b and ribavirin. Using standard interferon, some investigators have shown 2 phases of HCV decreases during the first week of therapy: (1) a first phase characterized by a dramatic decrease in Fig. 4. Kinetics of HCV RNA throughout therapy and proportion of patients who became HCV RNA negative at different times with the high and low doses of peginterferon alfa-2b plus ribavirin.

5 934 BUTI ET AL. HEPATOLOGY, April 2002 Fig. 5. Hepatitis C viremia throughout treatment in 5 individual patients (A-E) receiving the low dose of peginterferon alfa-2b plus ribavirin; 3 were responders (A-C) and 2 were nonresponders (D and E) to therapy. HCV RNA was measured by quantitative reversetranscription polymerase chain reaction before initiation of treatment and subsequently at 24, 48, 72, 96, and 120 hours and at weeks 1, 4, 8, 12, 24, and 48. HCV RNA levels, which occurs during the first 24 hours and is dose dependent, and (2) a second phase between 24 hours and day 7, during which another dose-dependent decrease in HCV RNA levels is observed These studies using interferon alfa administered 3 times per week analyzed HCV kinetics at some points during the first week but not every 24 hours. Unpublished data with 10 MU of interferon alfa-2b daily during the first week shows a similar pattern to that observed in our study with an HCV RNA rebound after 48 hours (F. C. Bekkering, personal communication, 2001). This rebound seems related to the dose of interferon and is greater with a higher dose. Our study is the first to analyze viral kinetics after combination therapy with peginterferon alfa-2b plus ribavirin in a large number of patients infected with genotype 1. After a single dose of peginterferon alfa-2b, especially using high doses, we observed a very rapid and dramatic decrease in HCV RNA levels during the first 48 hours, similar to that seen after the first injection of standard interferon This initial decrease observed with peginterferon alfa-2b, which was dose dependent, indicated that peginterferon alfa-2b was well absorbed. A second, slower decrease in HCV RNA levels was observed in the ensuing days of the first week. Some patients (16%), mostly in the high-dose group, had a rebound in viral load after the first 2 days of therapy. This rebound is not related to the clearance of HCV RNA at the end of therapy. This also happens with daily interferon therapy, 19 but its importance and significance is unclear. The design of our Fig. 6. Hepatitis C viremia throughout treatment in 5 individual patients (A-E) receiving the high dose of peginterferon alfa-2b plus ribavirin; 2 were responders (A and B) and 3 were nonresponders (C-E) to therapy. HCV RNA was measured by quantitative reverse-transcription polymerase chain reaction before initiation of treatment and subsequently at 24, 48, 72, 96, and 120 hours and at weeks 1, 4, 8, 12, 24, and 48.

6 HEPATOLOGY, Vol. 35, No. 4, 2002 BUTI ET AL. 935 study does not permit the evaluation of this phenomena during the second week, but at this time HCV RNA levels were much lower than at baseline, and this probably explains why the decrease in HCV RNA levels was not so dramatic after the second dose of peginterferon alfa-2b, particularly with the 0.5- g/kg dose. The dosing frequency schedule of peginterferon alfa-2b was analyzed in a pilot study performed by Lurie et al. 20 They compared the effect on HCV RNA level decrease at week 12 with 1.5 g/kg peginterferon alfa-2b administered once weekly or the same dose administered 2 or 3 times per week in patients infected with genotype 1. They showed that patients treated with 1.5 g/kg peginterferon alfa-2b once weekly achieved a higher and more significant reduction in HCV RNA levels at week 12 than those treated with the same dose administered 2 or 3 times per week. This shows no additional benefit to administering peginterferon alfa-2b in 2 or 3 weekly doses. Although no more detailed information about daily HCV kinetics after the first injection exists, it seems improbable that administering peginterferon alfa-2b more frequently would affect HCV RNA level decrease in the first 12 weeks, although it could produce small changes in the first week of therapy when HCV RNA level decrease is higher. In this study, the higher efficacy of peginterferon alfa-2b versus standard interferon is shown. The effect of these different peginterferon alfa-2b schedules on sustained response is not well established; however, if they do not produce important changes in HCV RNA levels during the first 12 weeks of therapy, they are unlikely to modify the end-of-treatment and sustained response. Using a mathematical model, Bekkering et al. estimated early HCV clearance in patients with genotype 1 chronic hepatitis C receiving daily interferon and ribavirin, a pharmacokinetic situation similar to that produced by peginterferon alfa-2b. 19 The model predicted that doses of 5 or 10 MU interferon plus ribavirin theoretically would need to be administered for more than 4 weeks to maximize the number of patients who clear virus by week 12 of therapy. In our study, patients treated with the high dose of peginterferon alfa-2b achieved an earlier clearance of HCV RNA. We propose that this early clearance of the virus could be improved by using high doses of peginterferon alfa-2b for a more prolonged period (e.g., 4 or 6 weeks) as induction therapy. The use of such a regimen could allow a large number of patients to achieve early viral negativity, which theoretically might result in high rates of end-of-treatment response and sustained virologic response. Recently, Zeuzem et al. analyzed viral kinetics in patients with chronic hepatitis C treated with standard interferon or peginterferon alfa-2a. They found that the initial decrease in HCV RNA levels was similar in patients treated with either standard interferon or peginterferon alfa-2a, and our study with peginterferon alfa-2b showed a similar pattern. They showed that the degradation rate of infected cells is dependent on HCV genotype. 21 In patients infected with genotype 1, treatment with peginterferon alfa-2a may reinforce the death rate of infected cells or stabilize the therapeutic effect on viral production, which would explain the better response of these patients to peginterferon alfa-2b. When we designed the current study, no information about the safety and tolerability of a high dose of peginterferon alfa-2b (i.e., 1.5 g/kg) in patients with chronic hepatitis C was available. 4 At that time, a multicenter study evaluating 0.5-, 1.0-, and 1.5- g/kg doses of peginterferon alfa-2b 4 had just been completed and the study using peginterferon alfa-2b plus ribavirin had not yet started. 9 For these reasons, we chose 3 g/kg as the higher dose of peginterferon alfa-2b for our study. Because no information about the safety and tolerability of the 3- g/kg dose was available, we limited the duration of therapy with this dose to 1 week. Similarly, we adjusted the dosage of ribavirin to 800 mg/d because there was no previous experience combining a high dose of peginterferon alfa-2b with ribavirin, and the phase III study of combination therapy with peginterferon alfa-2b plus ribavirin used these doses. Our study showed that the safety and tolerability profile of 3 g/kg peginterferon alfa-2b is similar to that of 1.5 g/kg. Peginterferon alfa-2b produces the typical side effects seen after administration of interferon: flu-like symptoms, asthenia, fever, and changes in laboratory test results. The addition of ribavirin is associated with a decrease in hemoglobin levels. 9 In our study, 6 patients stopped therapy and 4 needed reductions in the dosage of peginterferon alfa-2b and/or ribavirin, a proportion similar to that observed with combination therapy. Recently, in a multicenter trial using peginterferon alfa-2b plus ribavirin in more than 1,500 patients, Manns et al. showed the importance of adjusting the dosage of ribavirin according to the patient s body weight. 9 Using a low 800-mg daily dosage of ribavirin and 1.5 g/kg of peginterferon alfa-2b weekly, these investigators found that sustained virologic response differs depending on body weight. Patients with HCV genotype 1 treated with a dosage of ribavirin less than 10.6 mg/kg/day achieved a sustained response rate of 38% compared with a rate of 48% in those treated with higher dosages of ribavirin. Retrospectively, we analyzed the end-of-treatment response relative to a weight-adjusted dosage of ribavirin and found no difference using more than 10.6 mg/kg of ribavirin. In our study, a large number of patients weighed

7 936 BUTI ET AL. HEPATOLOGY, April 2002 more than 65 kg and thus received a suboptimal dosage of ribavirin; this could have been an important factor affecting sustained virologic response. Although we do not yet have data on sustained response, extrapolating the results of the study by Manns et al. 9 showing that 10% of end-of-treatment responders do not achieve a sustained response, we can predict a sustained response of approximately 60% with the high dose and 50% with the low dose. In addition, to achieve the best response in the future, it will be necessary to select dosages of peginterferon alfa-2b and ribavirin according to the patient s body weight in addition to viral load and genotype. 9,22 In conclusion, the results of our study show that, similar to observations with interferon alfa-2b, the magnitude of the initial decrease in HCV RNA is related to the dose of peginterferon alfa-2b. However, the stability and the progression of decrease in HCV RNA levels is less well known but seems to be less dependent on the dose of peginterferon alfa-2b. Therefore, it would be interesting to explore the role of higher doses of peginterferon alfa-2b in patients most resistant to therapy. References 1. Glue P, Fang JWS, Rouzier-Panis R, Raffanel C, Sabo R, Gupta SK, Salfi M, et al. Pegylated interferon- -2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Clin Pharmacol Ther 2000;68: Talpaz M, Cortes J, O Brien S, Keating M, Giles F, Rose E, Rybak ME, et al. Phase I study of polyethylene glycol (PEG) interferon alpha-2b (Intron A) in CML patients [Abstract]. Blood 1998; 92(Suppl):251A. 3. Glue P, Rouzier-Panis R, Raffanel C, Sabo R,Gupta SK, Salfi M, Jacobs S, et al. A dose-ranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis C. HEPATOLOGY 2000; 32: Lindsay KL, Trepo C, Heintges T, Schiffman M, Gordon S, Hoefs J, Schiff E, 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: Zeuzem S, Feinman SV, Rasenack J, Heathcote EJ, Lai M-Y, Gane E, O Grady J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000;343: McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, et al. for the Hepatitis Interventional Therapy Group. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339: Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, Bain V, et al. for the International Hepatitis Interventional Therapy Group (IHIT). Randomised trial of interferon 2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alfa b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998;352: EASL International Consensus Conference on Hepatitis C: Paris, February Consensus statement. J Hepatol 1999;30: Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, et al. Peginterferon alfa-2b in combination with ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: results of a randomised trial. Lancet 2001;358; Carithers RL Jr, Zeuzem S, Manns MP, McHutchison JG, Perrillo RP, Bailey R, Ling M-H, et al. Multicenter, randomized, controlled trial comparing high dose daily induction interferon plus ribavirin versus standard interferon alfa-2b plus ribavirin [Abstract]. HEPATOLOGY 2000;32:317A. 11. Martell M, Gómez J, Esteban JI, Sauleda S, Quer J, Cabot B, Esteban R, et al. High-throughput real-time reverse transcription- PCR quantitation of hepatitis C virus RNA. J Clin Microbiol 1999;37: Lam NP, Neumann AU, Gretch DR, Wiley TE, Perelson AS, Layden TJ. Dose-dependent acute clearance of Hepatitis C genotype 1 virus with interferon alfa. HEPATOLOGY 1997;26: Zeuzem S, Lee J-H, Franke A, Rüster B, Prümmer O, Herrmann G, Roth WK. Quantification of the initial decline of serum hepatitis C virus RNA and response to interferon alfa. HEPATOLOGY 1998;27: Bekkering FC, Brouwer JT, Leroux-Roels G, Van Vlierberghe H, Elewaut A, Schalm SW. Ultrarapid hepatitis C virus clearance by daily high-dose interferon in non-responders to standard therapy. J Hepatol 1998;28: Zeuzem S, Schmidt JM, Lee JH, Von Wagner M, Teuber G, Roth WK. Hepatitis C dynamics in vivo: effect of ribavirin and interferon alfa on viral turnover. HEPATOLOGY 1998;28: Zeuzem S. Clinical implications of hepatitis C viral kinetics. J Hepatol 1999;31(Suppl 1): Layden TJ. Principles of interferon induction therapy. Am J Med 1999;107:71S-73S. 18. Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, Perelson AS. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon- therapy. Science 1998;282; Bekkering FC, Stalgis C, McHutchison JG, Brouwer JT, Perelson AS. Estimation of early hepatitis C viral clearance in patients receiving daily interferon and ribavirin therapy using a mathematical model. HEPATOLOGY 2001;33; Lurie Y, Dusheiko G, Rouzier-Panis R, Glue P. Assesment of optimal dosing frequency of pegylated interferon alfa-2b (Pegintrom) in chronic hepatitis C [Abstract]. HEPATOLOGY 2000;32: 1138A. 21. Zeuzem S, Herrmann E, Lee J-H, Fricke J, Neumann AU, Modi M, Colucci G, et al. Viral kinetics in patients with chronic hepatitis C treated with standard or peginterferon 2a. Gastroenterology 2001;120: Poynard T, McHutchison J, Goodman Z, Ling AH, Albrecht J, for the ALGOVIRC Project Group. Is a la carte combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C? HEPATOLOGY 2000;31: