ORIGINAL ARTICLE. Abstract. Introduction

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1 ORIGINAL ARTICLE Long-term Pegylated Interferon Monotherapy Following 72 Weeks of Pegylated Interferon and Ribavirin in Hepatitis C Virus Genotype-1-infected Slow Responders Shinya Watanabe 1, Yoshimasa Kobayashi 1, Kazuhito Kawata 1, Hidenao Noritake 1, Takeshi Chida 1, Masamichi Nagasawa 2, Fujito Kageyama 3,KinyaKawamura 3, Yuzo Sasada 4 and Takafumi Suda 1 Abstract Objective Slow responders to pegylated interferon (Peg-IFN) and ribavirin (RBV) among patients infected with hepatitis C virus (HCV) genotype 1 may benefit from an extended treatment course. The aim of this study was to determine the efficacy of persistent negative serum HCV RNA over 96 weeks during long-term Peg-IFN monotherapy following 72 weeks of combination therapy. Methods A total of 46 HCV genotype 1-infected slow responders were treated for 72 weeks with Peg-IFN and RBV combination therapy alone (n=25) or additional long-term biweekly treatment with 90 μg of Peg- IFN-α2a (n=21). The criterion for the completion of long-term Peg-IFN monotherapy was defined as the attainment of constantly negative HCV RNA in the serum over 96 weeks during IFN treatment. Results The patients with sustained negative serum HCV RNA during 96 weeks of IFN treatment had a higher rate of sustained virological response (SVR) than those without (81 vs. 40%, p=0.012). A multivariate analysis identified sustained negativity of serum HCV RNA over 96 weeks of IFN treatment to be a predictive factor for SVR. Conclusion In the present study, sustained negative serum HCV RNA over 96 weeks during long-term Peg- IFN monotherapy following 72 weeks of combination therapy of Peg-IFN and RBV resulted in beneficial virological outcomes among HCV genotype 1-infected slow responders. Key words: extended treatment, pegylated interferon, ribavirin, hepatitis C genotype-1, slow responder (Intern Med 54: , 2015) () Introduction The standard treatment for patients with chronic hepatitis C virus (HCV) genotype 1 is dual therapy with pegylated interferon (Peg-IFN) and ribavirin (RBV), which has been shown to produce a sustained virological response (SVR) in only 40-50% of cases after 48 weeks of treatment (1-3). These unsatisfactory therapeutic outcomes led to the development of direct-acting antivirals (DAAs), including boceprevir, telaprevir, simeprevir and sofosbuvir (4, 5). Triple therapy with either of these DAAs in combination with Peg- IFN and RBV has been found to significantly improve SVR rates and shorten the duration of therapy (6). However, a percentage of the infected population is not eligible for treatment with this new therapy due to drug toxicities, drugdrug interactions, the induction of long-term viral resistance and economic burdens (7, 8). Therefore, it is important to explore more effective dual therapy strategies with Peg-IFN and RBV in these patients. Division of Hepatology, Department of Internal Medicine 2, Hamamatsu University School of Medicine, Japan, Division of Gastroenterology, Seirei Hamamatsu General Hospital, Japan, Division of Gastroenterology, Hamamatsu Medical Center, Japan and Division of Gastroenterology, Iwata City Hospital, Japan Received for publication February 18, 2014; Accepted for publication June 30, 2014 Correspondence to Dr. Yoshimasa Kobayashi, yoshi@hama-med.ac.jp 273

2 Several clinical trials have investigated the efficacy of prolonged treatment with Peg-IFN and RBV in an attempt to improve the rate of SVR in patients with chronic HCV genotype 1 (9-16). The findings of these studies indicate that extending the treatment time from 48 to 72 weeks significantly reduces the rate of viral relapse in patients with a slow on-treatment virological response, defined as a 2-log decrease in the viral load from baseline to week 12, followed by the subsequent loss of serum HCV RNA before week 24 (9, 11, 13-16). However, optimal methods for delivering Peg-IFN and RBV therapy in HCV genotype 1 slow responders have not yet been established. A previous study reported the beneficial virological effects of a sustained negative HCV RNA titer over 96 or more weeks during long-term IFN treatment in patients with chronic HCV genotype 1 (17). The present study was conducted to determine the efficacy of achieving persistent negative HCV RNA over 96 weeks with long-term Peg-IFN monotherapy after 72 weeks of combination therapy in HCV genotype 1 slow responders. Ethics Materials and Methods All patients provided their written informed consent prior to participating in this study. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki (6th revision, 2008), as reflected in a priori approval from our institution s Human Research Committee. Patients This retrospective study was conducted at Hamamatsu University School of Medicine, University Hospital (Hamamatsu, Japan), and its affiliated hospitals. Data were collected from 46 consecutive patients with chronic HCV genotype 1 infection who received 72 weeks of combined therapy with Peg-IFN and RBV between 2005 and The serum HCV RNA level was >100,000 IU/mL at baseline in all patients. Serum HCV RNA became undetectable weeks after the start of therapy and remained undetectable after the 72-week treatment period. Thirty-seven patients underwent liver biopsies prior to treatment. The stage of hepatic fibrosis was scored using standard criteria proposed by Desmet (18). Treatment The patients received 180 μg of Peg-IFN-α2a or 1.5 μg/ kg of Peg-IFN-α2b subcutaneously each week at the physician s discretion and were administered a weight-adjusted dose of RBV (600 mg for <60 kg, 800 mg for kg and 1,000 mg for >80 kg daily), the recommended dosage in Japan. Twenty-one patients in the extended treatment group received continuous treatment with 90 μg of Peg-IFN-α-2a biweekly after the 72-week combination treatment at the physician s discretion. The criterion for the completion of long-term Peg-IFN monotherapy was the attainment of continuous negative serum HCV RNA over 96 weeks during IFN-based therapy, including the initial treatment with Peg- IFN and RBV. Twenty-five patients in the non-extended treatment group did not receive any additional IFN-based therapy for six months after the initial combination therapy. SVR was defined as an undetectable serum HCV RNA titer 24 weeks after the completion of treatment, whereas relapse was defined as the reappearance of serum HCV RNA following the discontinuation of therapy and breakthrough was defined as the reappearance of HCV RNA in the serum while still under therapy. Laboratory tests Blood samples were obtained before, during, and after therapy for hematological, blood chemistry and HCV RNA analyses. The sequences of the HCV core region were determined using direct sequencing after amplification via reverse-transcription-polymerase chain reaction (PCR), as previously reported (19). The presence of genetic polymorphisms in tagged SNPs located near the interleukin 28B (IL 28B) gene (rs ) was determined using allele-specific PCR (20). Statistical analysis PASW was used for the statistical analysis (SPSS, Chicago, USA). The data were evaluated using the Mann- Whitney U test, chi-square independence test, Fisher s exact probability test and a multinomial logistic regression analysis. p values of <0.05 were considered to indicate statistical significance. Patient characteristics Results No significant differences were observed in demographic, clinical, biochemical, virological or histological characteristics at baseline between the extended and non-extended groups (Table 1). Moreover, no significant differences were noted in the mean serum HCV RNA levels between the two groups after 12 weeks of therapy. The time at which the patients first achieved an undetectable HCV RNA titer during the 72-week combination therapy did not differ significantly between the two groups. In addition, the two groups showed identical rates of adherence to the initial Peg-IFN and RBV combination therapy. The total treatment duration was weeks in the extended group, and weeks in the patients with continuously negative serum HCV RNA during the 96 weeks of extended treatment. Safety and tolerability of prolonged Peg-IFN monotherapy following 72-week combination therapy In the extended group, three patients discontinued the IFN treatment six, 18 and 20 weeks after the completion of the 72-week combination therapy due to adverse events, includ- 274

3 Table 1. Clinicopathological Characteristics of HCV Genotype 1-infected Slow Responders who Received Long-term Peg-IFN Monotherapy after 72 Weeks of Peg-IFN and RBV Combination Therapy (Extended Group) and 72-week Combination Therapy Alone (Non-extended Group) Extended group n = 21 Non-extended group n = 25 p value Pre-treatment Gender (male/female) 12/9 16/9 N.S. Age (years) 57 (46 67) 62 (27 71) N.S. Body mass index 22.5 ( ) 22.1 ( ) N.S. Naïve/re-treatment 9/12 8/17 N.S. ALT (IU/L) 36 (20 77) 41 (19 123) N.S. GGT (IU/L) 28 (10 102) 36 (11 889) N.S. Platelets ( 10 4 /mm 3 ) 13.1 ( ) 15.8 ( ) N.S. AFP (ng/ml) 3.0 (1 43.0) 4.0 ( ) N.S. HCV RNA (log IU/mL) 6.7 ( ) 6.5 ( ) N.S. HCV core amino acid 70 (wild type/mutant) 17/1 10/6 <0.05 HCV core amino acid 91 (wild type/mutant) 13/5 12/4 N.S. Hepatic fibrosis (F0-1/F2-4) 10/7 11/9 N.S. IL28B rs genotype (TT/non-TT) 15/5 16/7 N.S. On-treatment IFN cumulative exposure (%) 91.5 ± ± 17.0 N.S. RBV cumulative exposure (%) 85.2 ± ± 19.2 N.S. Loss of serum HCV RNA (week) 18 (16 30) 17 (13 44) N.S. Median (range), Mean ± standard deviation, #Calculated by Mann Whitney U test, Calculated by 2 test for independence. AFP: alpha-fetoprotein, ALT: alanine aminotransferase, GGT: gamma-glutamyltransferase, HCV: hepatitis C virus, IFN: interferon, N.S.: not significant, RBV: ribavirin ing thrombocytopenia, skin rashes and arthralgia. These adverse events disappeared within one month after the cessation of treatment. In addition, two (10%) patients discontinued treatment 26 and 27 weeks after the completion of the 72-week combination therapy due to viral breakthrough. Virological outcomes of the patients The rate of SVR was significantly higher in the extended treatment group than in the non-extended treatment group (71 vs. 40%, p=0.033; Figure A). The difference in the SVR rate between these two groups was related to the significant difference observed in the relapse rate between the nonextended and extended groups (60 vs.14%, p=0.003). A comparative analysis of the patients with and without sustained negative serum HCV RNA over 96 weeks during IFN treatment showed that the former had a higher SVR rate than the latter (81 vs. 40%, p=0.012) (Figure B). As shown in Table 2, the patients who first became HCV RNAnegative weeks after the initial combination treatment had a higher SVR rate than those who first became HCV RNA-negative at weeks among the subjects with a sustained negative serum HCV RNA titer over 96 weeks during IFN treatment [100 (9/9) vs. 57% (4/7), p=0.0293]. However, the time at which serum HCV RNA first became undetectable was not associated with SVR in the nonextended group. Meanwhile, among the patients who became HCV RNA-negative at weeks, the subjects in the 96-week HCV RNA-negative group had a higher SVR rate than those in the non-extended group [100 (9/9) vs. 46% (6/13), p=0.0077], whereas the patients who became HCV RNA-negative at weeks did not have significantly different SVR rates between the two groups. In addition, among the patients with an intended RBV dose of <80% during the initial combination therapy, the 96-week HCV RNA-negative group had a higher SVR rate than the non-extended group [100 (7/7) vs. 30% (3/10), p=0.0039]. In contrast, the 96-week HCV RNA-negative and nonextended groups had similar SVR rates among the patients with an intended RBV dose of >80% during the initial combination therapy [67 (6/9) vs. 47% (7/15), p=0.3411] (Table 3). In addition, no correlations were observed between the IL28B genotype or amino acid substitutions in the HCV core region and SVR among the patients with or without a sustained negative serum HCV RNA titer over 96 weeks during IFN treatment. Predictive factors for SVR Pre- and during- treatment predictive factors for SVR were assessed using a multivariate analysis; the selected factors included gender, age, body mass index, history of IFN treatment, the ALT, gamma-glutamyl transpeptidase and alpha-fetoprotein levels, platelet count, HCV RNA titer, amino acid substitution in the HCV core region, degree of hepatic fibrosis, IL28 genotype, IFN cumulative exposure, RBV cumulative exposure and time to undetectable HCV RNA. As shown in Table 4, the multivariate analysis showed 275

4 A B SVR Rates (%) Extended Treatment Non-Extended Treatment 0 (+) (-) Sustained negativity of HCV RNA over 96 weeks Figure. Virological effects of the long-term pegylated interferon monotherapy after 72 weeks of combination therapy with pegylated interferon and ribavirin in HCV genotype 1-infected slow responders. (A) The bar graphs show the rate of a sustained virological response in the patients receiving long-term treatment with 90 μg of pegylated interferon-α2a biweekly after 72 weeks of combination therapy (extended treatment group: n=21) or the administration of 72 weeks of combination therapy alone (non-extended treatment group: n=25). *p < 0.05 determined using the Chi-square test of independence. (B) The bar graphs show the rate of a sustained virological response in the patients with a persistently undetectable HCV RNA titer in the serum for 96 weeks treated with (n=16) or without (n=30) interferon therapy. * p < 0.05 determined using the Chi-square test of independence. Table 2. SVR Rates Based on Time to Negative Serum HCV RNA in Slow Responders Having Persistent Negative Serum HCV RNA over 96 Weeks during Long-term Peg-IFN Monotherapy after 72 Weeks of Peg-IFN and RBV Combination Therapy or in Those Having 72-week Combination Therapy Alone SVR rates (%) Long-term IFN treatment 72-week treatment Time to undetectable for persistent negative n=25 serum HCV RNA HCV RNA over 96 weeks p value n= weeks 100 (9/9) 46 (6/13) weeks 57 (4/7) 33 (4/12) N.S Calculated by Chi-square independence test N.S.: not significant, Peg-IFN: pegylated interferon, RBV: ribavirin, SVR: sustained virological response that two parameters correlated with SVR: sustained negativity of serum HCV RNA over 96 weeks during the IFN treatment and the time at which serum HCV RNA first became undetectable. Discussion Treatment with DAAs against HCV genotype 1 can achieve very high cure rates when combined with pegylated interferon-α and ribavirin and show promising clinical results when administered in all-oral combinations. However, concerns regarding drug toxicity, drug-drug interactions, naturally occurring or treatment-induced viral resistance mutations and medical costs may prevent some patients from receiving DAA therapy. Therefore, it is necessary to explore the optimal use of Peg-IFN and RBV combination therapy in these patients. The concept of response-guided duration therapy (i.e., adjusting the treatment duration according to the HCV viral load) has been widely investigated with respect to improving the rate of SVR with dual therapy (21). The results for genotype 1 slow responders encourage the continuation of treatment for 72 weeks. However, the virological outcomes of 72-week combination treatment remain unsatisfactory. In the present study, an extended ther- 276

5 Table 3. SVR Rates Based on Cumulative RBV Exposure in Slow Responders Having Persistent Negative Serum HCV RNA over 96 Weeks during Long-term PegIFN Monotherapy after 72 Weeks of PegIFN and RBV Combination Therapy or in Those Having 72-week Combination Therapy Alone SVR rates (%) Long-term IFN treatment for 72-week treatment Cumulative RBV persistent negative HCV RNA n = 25 exposure over 96 weeks pvalue n = 16 80% 100 (7/7) 30 (3/10) > 80% 67 (6/9) 47 (7/15) Calculated by Chi-square independence test Peg-IFN: pegylated interferon, RBV: ribavirin, SVR: sustained virological response Table 4. Predictive Factors for SVR Factor Time to undetectable serum HCV RNA (13-19 weeks/20-48 weeks) Sustained negativity of HCV RNA over 96 weeks (yes/no) CI: confidence interval Odds ratio (95% CI) ( ) ( ) p value apy regimen was designed to ensure that slow responders became serum HCV RNA-negative over 96 weeks using prolonged Peg-IFN monotherapy following 72 weeks of combination therapy with Peg-IFN and RBV. Consequently, a retrospective comparative analysis of the patients treated with and without extended therapy among 46 slow responders infected with HCV genotype 1 showed the following findings: (1) the SVR rate was higher in the extended treatment group than in the non-extended group; (2) sustained negativity of serum HCV RNA over 96 weeks during IFN treatment was predictive of SVR; and (3) extended treatment for long-lasting negativity of serum HCV RNA produced a higher SVR rate than non-extended treatment in the patients who exhibited HCV RNA disappearance at weeks or reduced RBV adherence during the initial combination treatment. We examined slow responders who received 72 weeks of combination therapy with Peg-IFN and RBV. Slow responders are potential candidates for treatment intensification, and several previous trials have reported the virological benefits of prolonged 72-week combination therapy in such patients (9, 11, 13-16). In addition, a recent pooled analysis of slow responders found that 33% of the patients who received 72-week therapy achieved SVR, whereas only 27% of those who received 48 weeks of therapy did so (p=0.02), with relapse rates in the 72- and 48-week treatment groups of 32% and 51% (p=0.007), respectively (22). The present study showed a relapse rate of 60% with 72-week treatment. This higher relapse rate may be explained by differences in patient population, sample size and drug adherence. Our study utilized Peg-IFN monotherapy rather than dual therapy with Peg-IFN and RBV as an extended treatment following the initial 72-week treatment regimen due to concerns regarding potential adverse events associated with the long-term administration of RBV, although RBV is known to reduce viral relapse in combination with Peg-IFN. As a result, favorable safety and tolerance were observed with long-term biweekly half-dose Peg-IFN-α2a monotherapy following the 72-week combination treatment; the type and incidence of adverse events observed in this trial did not differ from that reported in other studies. If ribavirin or fulldose Peg-IFN had been included in the extended treatment, the intensified treatment may have suppressed viral breakthrough and improved the clinical outcomes, albeit with a higher rate of adverse events. In this study, we confirmed and extended previous findings showing that prolonged IFN monotherapy enhances therapeutic effects by lowering the rate of relapse (17, 23-25). In one previous report, HCV genotype 1- infected patients maintaining negative serum HCV RNA over 96 or more weeks during conventional IFN monotherapy consisting of units three times per week achieved a higher SVR rate and lower relapse rate than those treated with 24-week therapy (17). In addition, in a study of conventional IFN monotherapy consisting of units 2-3 times weekly for 96 weeks following the administration of Peg-IFN and RBV combination therapy, slow responders were shown to recieve greater virological benefits than patients with an early viral response to HCV genotype 1 infection (25). The present study showed that persistent negativity of serum HCV RNA over 96 weeks under prolonged monotherapy with 90 μg of Peg-IFN-α2a biweekly following 72-week combination therapy consisting of Peg-IFN and RBV provides better virological outcomes in slow responders infected with HCV genotype 1 than 72-week combination therapy alone. In addition, long-term negativity of serum HCV RNA during extended treatment resulted in better virological outcomes in patients who first became HCV RNA-negative at weeks after the initial combination treatment and those who received an intended RBV dose of <80% for the 72-week combination treatment. These results suggest that this treatment strategy may be considered in slow responders with reduced RBV exposure and/or HCV 277

6 RNA disappearance at weeks during the initial combination treatment. Furthermore, we found that neither the IL28B genotype nor amino acid substitutions in the HCV core region were associated with SVR in the slow responders treated with or without additional long-term Peg-IFN monotherapy after the 72-week dual therapy consisting of Peg-IFN and RBV. The IL28B genotype was originally reported to be a host marker predicting null responders to dual therapy (20), and the presence of amino acid substitutions in the HCV core region has been identified to be a predictive virological factor for a non-virological response to dual therapy (19). However, the patients enrolled in our study were slow responders, not null responders. Therefore, the IL28B genotype and presence of amino acid substitutions in the HCV core region appear to be of no importance for the likelihood of achieving SVR in patients who exhibit a virological response during therapy. The limitations of the present study include its retrospective nature and the small number of patients. However, the present extended regimen may be helpful for treating slow responders with multiple DAA-resistant variants in the near future. In addition, our results may lead to the development of similar prolonged IFN monotherapies for use following new combination therapies comprising DAA(s), Peg-IFN and RBV in order to improve the rate of SVR among patients with a late virological response during the initial combination therapy. In conclusion, extended treatment with long-term biweekly half-dose Peg-IFN-α2a monotherapy following 72- week combination treatment with Peg-IFN and RBV may be used to reduce the rate of relapse and increase the rate of SVR in HCV genotype 1-infected patients with a slow virological response to the initial combination treatment beyond that achieved with 72-week combination treatment alone. 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