Very early prediction of response to HCV treatment with PEG‐IFN‐alfa‐2a and ribavirin in HIV/HCV‐coinfected patients

Summary. The objective of this study was to find very early viral kinetic markers to predict nonresponse to hepatitis C virus (HCV) therapy in a group of human immunodeficiency virus (HIV)/HCV‐coinfected patients. Twenty‐six patients (15 HCV genotype‐1 and 11 genotype‐3) were treated with a 48‐week regimen of peginterferon‐alfa‐2a (PEG‐IFN) (180 μg/week) and weight‐based ribavirin (11 mg/kg/day). Samples were collected at baseline; 4, 8, 12, 18, 24, 30, 36 and 42 h; days 2, 3, 4, 7, 8, 15, 22, 29, 43 and 57 then weekly and monthly. Five patients discontinued treatment. Seven patients (27%) achieved a sustained virological response (SVR). Nadir HCV RNA levels were observed 1.6 ± 0.3 days after initiation of therapy, followed by a 0.3‐ to 12.9‐fold viral rebound until the administration of the second dose of PEG‐IFN, which were not associated with SVR or HCV genotype. A viral decline <1.19 log for genotype‐1 and <0.97 log for genotype‐3, 2 days after starting therapy, had a negative predictive value (NPV) of 100% for SVR. The day 2 virological response had a similar positive predictive value for SVR as a rapid virological response at week 4. In addition, a second‐phase viral decline slope (i.e., measured from day 2 to 29) <0.3 log/week had a NPV = 100% for SVR. We conclude that first‐phase viral decline at day 2 and second‐phase viral decline slope (<0.3 log/week) are excellent predictors of nonresponse. Further studies are needed to validate these viral kinetic parameters as early on‐treatment prognosticators of nonresponse in patients with HCV and HIV.     

Prolonged treatment with pegylated interferon α 2b plus ribavirin improves sustained virological response in chronic hepatitis C genotype 1 patients with late response in a clinical real‐life setting in Japan

Aim: This study was conducted to clarify the factors related to sustained virological response (SVR) to pegylated interferon α 2b (PEG‐IFN) plus ribavirin (RBV) combination therapy administered for 48 weeks in patients with chronic hepatitis C virus (CHCV) and to evaluate the usefulness of prolonged treatment in patients with late virological response (LVR). Methods: Of 2257 patients registered at 68 institutions, those with genotype 1 and high viral load were selected to participate in two studies. Study 1 (standard 48‐week group, n = 1480) investigated SVR‐determining factors in patients who received the treatment for ≤52 weeks, whereas study 2 compared SVR rates between patients with LVR who received treatment for either 36–52 weeks (48‐week group, n = 223) or 60–76 weeks (72‐week group, n = 73). Results: In study 1, SVR rate was 44.9%; that in male subjects (50.4%) was significantly (P < 0.0001) higher than in female subjects (36.4%). SVR rate significantly (P < 0.0001) decreased with 10‐year age increments in both sexes. Multivariate logistic regression analysis revealed that age, F score, platelet count, and HCV load were SVR‐related factors. In study 2, SVR rate in the 72‐week group (67.1%) was significantly (P = 0.0020) higher than in the 48‐week group (46.2%). Conclusions: Patients with CHCV genotype 1 infection should be treated with PEG‐IFN plus ribavirin combination therapy as early as possible, and 72 weeks' treatment is recommended in patients with LVR regardless of age.     

Two week induction of interferon‐beta followed by pegylated interferon alpha‐2b and ribavirin for chronic infection with hepatitis C

Objectives: To elucidate the efficacy of interferon (IFN)‐beta induction therapy followed by pegylated IFN alpha and ribavirin for chronic infection with hepatitis C virus (HCV). Methods: Patients chronically infected with HCV genotype 1, high titer were enrolled. Twice daily bolus injections of 3 million units IFN‐beta were administered for 14 days. Thereafter, weekly injection of pegylated IFN alpha 2b and daily intake of ribavirin were followed. Therapy duration was adjusted according to the response to the therapy. When time to an undetectable HCV‐RNA was 1, 2, 4, 8, and 12 weeks, total duration of therapy was 12, 24, 36, 48 and 60 weeks, respectively. Patients who failed to achieve an undetectable HCV‐RNA within 12 weeks discontinued therapy on 12 week. Results: Among the 101 patients treated, 56 (55.4%) achieved sustained virological response (SVR). SVR rate for each treatment duration was 10/10 for 12 weeks, 12/14 for 24 weeks, 18/19 for 36 weeks, 15/26 for 48 weeks, 1/4 for 60 weeks and 0/28 for patients who discontinued therapy at 12 weeks. Mean time to an undetectable HCV‐RNA was 35.5 ± 2.7 days. Mean therapy duration was 27.3 ± 1.4 weeks. Using a cut off value of 21.5 fmol/L of HCV core‐antigen in the first week, SVR could be predicted by sensitivity of 0.91 and specificity of 0.78. Conclusion: IFN‐beta induction therapy resulted in acceptable SVR rates despite short therapy duration. Steep reduction of HCV by IFN‐beta enables us to predict SVR in the first week of therapy.     

Favorable factors for re-treatment with pegylated interferon α2a plus ribavirin in patients with high viral loads of genotype 1 hepatitis C virus

Aim: Effect of re‐treatment for pegylated interferon (PEG‐IFN) plus ribavirin was not fully evaluated. We examined the effects of re‐treatment with PEG‐IFN plus ribavirin in patients with high viral loads of genotype 1 hepatitis C virus who failed to achieve a sustained virological response (SVR) with combination therapy. Methods: We examined 38 patients who were re‐treated with PEG‐IFN α2a plus ribavirin for more than 60 weeks, among whom 14 were non‐responders and 24 were relapsers after previous treatment with PEG‐IFN α2b plus ribavirin. IL28B genotyping was done in 21 patients. Results: The overall SVR rate was 34%. Analysis of baseline characteristics showed that the relapsers had a significantly higher SVR rate than the non‐responders (50.0%, 12/24 vs. 7.1%, 1/14, respectively, P = 0.012) The SVR rates of re‐treated patients who had turned hepatitis C virus (HCV) RNA‐negative at weeks 8, 12, 24, and 48 of the previous therapy were 67% (4/6), 67% (4/6), 29% (2/7), and 25% (1/4), respectively. Re‐treatment achieved an SVR in five of 12 patients with IL28B major alleles and three of nine patients with IL28B minor alleles. During the re‐treatment, patients with complete viral suppression at week‐12 achieved a significantly higher SVR rate (P = 0.001). Conclusions: Re‐treatment with PEG‐IFN α2a plus ribavirin therapy is effective in patients who relapse after a course of PEG‐IFN α2b plus ribavirin therapy. Re‐treatment is a particularly useful option for patients who achieve early viral clearance during previous therapy.     

Enhanced efficacy of pegylated interferon alpha‐2a over pegylated interferon and ribavirin in chronic hepatitis C genotype 4A randomized trial and quality of life analysis

Aim: The therapy of chronic hepatitis C genotype 4 (HCV‐4) has not been optimized yet. This randomized, prospective, parallel‐group clinical trial compared the efficacy and safety of pegylated interferon α‐2a (PEG‐IFN α‐2a) plus ribavirin and PEG‐IFN α‐2b plus ribavirin and assessed the health‐related quality of life (HRQOL) in patients with chronic HCV‐4. Methods: Eligible patients with proven chronic HCV‐4 were randomized to receive either a weekly dose of PEG‐IFN α‐2a (180 μg) or PEG‐IFN α‐2b (1.5 μg/kg) and a daily dose of ribavirin (1000–1200 mg) for 48 weeks with 24 weeks post‐treatment follow‐up. The primary end point was sustained virological response (SVR) defined by undetectable HCV RNA 24 weeks after treatment. The Short form‐36 Health Survey version 2 (SF‐36v2) and the Chronic Liver Disease questionnaires (CLDQ) were assessed before, during and after therapy. Results: The overall SVR rate of the entire cohort was 59.9%. The SVR rates were significantly higher in patients treated with PEG‐IFN α‐2a and ribavirin (Group A; n=109) compared with those treated with PEG‐IFN α‐2b and ribavirin (Group B; n=108, 70.6 vs. 54.6%, respectively; P=0.017). The relapse rates were 5.1% for PEG‐IFN α‐2a and 15.7% for PEG‐IFN α‐2b (P=0.0019). The SF‐36v2 and CLDQ were low during therapy and improved significantly after therapy successful therapy. Conclusion: Pegylated interferon α‐2a plus ribavirin was significantly more effective than PEG‐IFN α‐2b and ribavirin therapy in the treatment of chronic HCV‐4 patients. The tolerability and adverse events were comparable between the two regimens. The HRQOL improved significantly after successful PEG‐IFN α‐2a plus ribavirin therapy.     

Adjuvant epoetin‐β with peginterferon‐α and ribavirin in Japanese ribavirin‐intolerant relapsed patients with chronic hepatitis C genotype 2

Erythropoietin is widely used in the USA and some other Western countries to maintain doses of ribavirin during peginterferon/ribavirin‐based treatment for chronic hepatitis C virus (HCV) infection. However, the impact of erythropoietin on sustained virological response (SVR) is unclear. Here, we report the cases of three Japanese ribavirin‐intolerant relapsed patients with HCV genotype 2 who achieved SVR from retreatment by adding erythropoietin. Three women aged 50, 64 and 68 years with chronic HCV genotype 2 received retreatment with peginterferon‐α and ribavirin. During their prior therapy, HCV RNA became negative according to real‐time polymerase chain reaction at weeks 4–8 in all three patients; however, the total dose of ribavirin was 18.1–30.6% lower than the planned dose, and HCV RNA relapsed post‐treatment. At present, epoetin‐β 24 000 IU was introduced at weeks 2 or 3 of dual‐combination therapy, resulting in a less than 4.2% reduction in the total dose of ribavirin. HCV RNA became negative at weeks 4–8, and all patients achieved SVR. Until the next‐generation antiviral treatments for HCV genotype 2 become available, the addition of erythropoietin to dual therapy can be a treatment of choice for ribavirin‐intolerant relapsed patients.     

Predictive value of on‐treatment response during full‐dose antiviral therapy of patients with hepatitis C virus cirrhosis and portal hypertension

Objective. Therapy with full‐dose pegylated interferon (PEG‐IFN) and weight‐based ribavirin has been evaluated in limited series of patients with hepatitis C virus (HCV) and advanced disease. In this study, we evaluated the efficacy and tolerability of full‐dose antiviral therapy in patients with compensated, fully developed cirrhosis, and assessed the predictive value of on‐treatment virological response. Design and subjects. We studied 85 HCV‐positive cirrhotic patients (82 Child‐Pugh class A; 41 treatment‐naïve) who were treated with PEG‐IFN α‐2_a (1.5 μg kg^?1week^?1) or α‐2_b (180 μg week^?1) and weight‐based ribavirin for 24 (genotype 2–3) or 48 (genotype 1–4) weeks. Forty‐three patients were genotype 1 (51%), and HCV‐RNA was >600 000 IU mL^?1 in 53 patients (62%). Prevalence of portal hypertension and diabetes was 81% and 18% respectively. Results. Sustained virological response (SVR) was obtained in 22 patients (26%). Positive serum HCV‐RNA at week 4 and week 12 of therapy predicted nonresponse (NR) in 85% (52/61) and 100% (38/38) of patients, respectively. Treatment was discontinued due to adverse events in 14 patients (16%). Genotype 1–4 (P = 0.02) and HCV‐RNA >600 000 IU mL^?1 (P = 0.02) were the baseline parameters significantly associated with lack of SVR, whilst positive serum HCV‐RNA at week 12 was the only parameter independently associated with NR (100% negative predictive value). Conclusion. Full‐dose antiviral therapy with PEG‐IFN and ribavirin can be safely carried out even in patients with compensated, fully established cirrhosis and portal hypertension. Selecting patients on the basis of HCV genotype and viral load, and application of on‐treatment stopping rule may help rationalize treatment in patients who are unlikely to obtain SVR.     

Factors affecting efficacy in patients with genotype 2 chronic hepatitis C treated by pegylated interferon alpha‐2b and ribavirin: reducing drug doses has no impact on rapid and sustained virological responses

Summary. Reducing the dose of drug affects treatment efficacy in pegylated interferon (Peg‐IFN) and ribavirin combination therapy for patients with hepatitis C virus (HCV) genotype 1. The aim of this study was to investigate the impact of drug exposure, as well as the baseline factors and the virological response on the treatment efficacy for genotype 2 patients. Two‐hundred and fifty patients with genotype 2 HCV who were to undergo combination therapy for 24 weeks were included in the study, and 213 completed the treatment. Significantly more patients who achieved a rapid virological response (RVR), defined as HCV RNA negativity at week 4, achieved a sustained virological response (SVR) (92%, 122/133) compared with patients who failed to achieve RVR (48%, 38/80) (P < 0.0001). Multivariate logistic‐regression analysis showed that only platelet counts [odds ratio (OR), 1.68; confidence interval (CI), 1.002–1.139] and RVR (OR, 11.251; CI, 5.184–24.419) were independently associated with SVR, with no correlation being found for the mean dose of Peg‐IFN and ribavirin for RVR and SVR. Furthermore, in the stratification analysis of the timing of viral clearance, neither mean dose of Peg‐IFN (P = 0.795) nor ribavirin (P = 0.649) affected SVR in each group. Among the patients with RVR, the lowest dose group of Peg‐IFN (0.77 ± 0.10 μg/kg/week) and ribavirin (6.9 ± 0.90 mg/kg/day) showed 100% and 94% of SVR. Hence, RVR served as an important treatment predictor, and drug exposure had no impact on both SVR and RVR in combination therapy for genotype 2 patients.     

A multicenter survey of re‐treatment with pegylated interferon plus ribavirin combination therapy for patients with chronic hepatitis C in Japan

Aim: This study aimed to clarify the factors associated the efficacy of re‐treatment with pegylated interferon (PEG IFN) plus ribavirin combination therapy for patients with chronic hepatitis C who had failed to respond to previous treatment. Methods: One hundred and forty‐three patients who had previously shown relapse (n = 79), non‐response (n = 34) or intolerance (n = 30) to PEG IFN plus ribavirin were re‐treated with PEG IFN plus ribavirin. Results: Twenty‐five patients with intolerance to previous treatment completed re‐treatment and the sustained virological response (SVR) rates were 55% and 80% for hepatitis C virus (HCV) genotype 1 and 2, respectively. On re‐treatment of the 113 patients who completed the previous treatment, the SVR rates were 48% and 63% for genotype 1 and 2, respectively. Relapse after previous treatment and a low baseline HCV RNA level on re‐treatment were associated with SVR in genotype 1 (P < 0.001). Patients with the interleukin‐28B major genotype responded significantly better and earlier to re‐treatment, but the difference in the SVR rate did not reach a significant level between the major and minor genotypes (P = 0.09). Extended treatment of 72 weeks raised the SVR rate among the patients who attained complete early virological response but not rapid virological response with re‐treatment (72 weeks, 73%, 16/22, vs 48 weeks, 38%, 5/13, P < 0.05). Conclusion: Relapse after previous treatment and a low baseline HCV RNA level have predictive values for a favorable response of PEG IFN plus ribavirin re‐treatment for HCV genotype 1 patients. Re‐treatment for 72 weeks may lead to clinical improvement for genotype 1 patients with complete early virological response and without rapid virological response on re‐treatment.     

Efficacy of pegylated interferon‐α2a monotherapy in Japanese children with chronic hepatitis C

Aim: There is little information available on the efficacy of pegylated interferon (PEG IFN) therapy for children with chronic hepatitis C. The aim of this study was to evaluate the efficacy and tolerability of PEG IFN‐α2a monotherapy for children infected by chronic hepatitis C virus (HCV). Methods: From 2004–2006, we conducted a prospective, open‐label, multicenter study of 22 patients aged 4–18 years, including eight with genotype 1 and 14 with genotype 2. None had previously received IFN. The patients were treated with s.c. PEG IFN‐α2a at a dose of 3 µg/kg once a week for 48 weeks. Rapid virological response (RVR) was defined as: undetectable serum HCV RNA at week 4; early viral response (EVR) as a 2 or more log reduction or undetectable serum HCV RNA at week 12; and sustained viral response (SVR) as undetectable serum HCV RNA at 24 weeks after the cessation of treatment. Results: SVR was achieved in 10 (45%) of the 22 patients (three with genotype 1, seven with genotype 2). Retrospectively, the patients with SVR included five with RVR (one with genotype 1, four with genotype 2) and five with EVR (two with genotype 1, three with genotype 2). PEG IFN‐α2a monotherapy was well tolerated, except in one patient in whom alanine aminotransferase activity flared (>500 IU/L) during treatment. Conclusion: The efficacy of PEG IFN‐α2a monotherapy in children is similar to that for adults, while tolerability seems to be better in children than in adults.     

Cancer preventive effect of pegylated interferon α‐2b plus ribavirin in a real‐life clinical setting in Japan: PERFECT interim analysis

Aim: This study was conducted to clarify the incidence of hepatocellular carcinoma (HCC) and the factors contributing to its occurrence by following chronic hepatitis C patients who received pegylated interferon (PEG‐IFN) α‐2b plus ribavirin (RBV) combination therapy. Methods: Patients who received PEG‐IFN α‐2b and RBV combination therapy with no history of HCC or HCC within 3 months after the start of treatment were observed for the onset of HCC at 67 centers. Results: Sustained virological response (SVR) was observed in 999 (53.5%) of 1865 patients eligible for analysis. During the observation period (median duration: 4 years and 3 months), HCC developed in 59 patients (3.1%). A significant difference was observed in the 5‐year cumulative incidence of HCC between SVR and non‐SVR patients (1.1% vs. 7.1%). Factors contributing to HCC selected in multivariate analysis were therapeutic efficacy, sex, age, alanine aminotransferase (ALT) level at 24 weeks after the end of treatment, and platelet count. Non‐SVR patients with ALT improvement after the end of treatment had a significantly lower 5‐year cumulative incidence of HCC than those without (3.4% vs. 11.0%). HCC developed in 10 patients who achieved SVR, and multivariate analysis indicated that ALT level at 24 weeks after the end of treatment was the only significant factor contributing to HCC. Conclusion: Several known risk factors for HCC contributed to HCC in patients who received PEG‐IFN α‐2b and RBV combination therapy, and ALT abnormality after the end of treatment contributes to the onset of HCC in both non‐SVR and SVR patients.     

Relapse of hepatitis C in a pegylated‐interferon‐α‐2b plus ribavirin‐treated sustained virological responder

A 41‐year‐old woman with chronic hepatitis C was treated with pegylated‐interferon (PEG‐IFN)‐α‐2b plus ribavirin for 24 weeks. She had hepatitis C virus (HCV) genotype 2a (1600 KIU/mL), and her liver histology showed mild inflammation and fibrosis. Four weeks after the start of the therapy, she achieved a rapid virological response (RVR) and then a sustained virological response (SVR). Serum alanine aminotransferase (ALT) levels remained within normal ranges and HCV RNA continued to be negative. However, ALT levels flared with the re‐emergence of HCV RNA in the serum 1.5 years after discontinuation of therapy. HCV RNA obtained from sera before therapy and after relapse shared a 98.6% homology with the E2 region, and phylogenetic analyses indicated that they were the same HCV strain. These results eliminated the possibility of a re‐infection and strongly indicated a late relapse of the disease. Therefore, follow‐up is necessary for chronic hepatitis C patients after SVR, even if they respond well to therapy, including RVR.     

Treatment of hepatitis C virus carriers with persistently normal alanine aminotransferase levels with peginterferon α‐2a and ribavirin: a multicentric study

Background/Aims: To evaluate, in clinical practice, the efficacy and safety of combined antiviral treatment in hepatitis C virus (HCV) carriers with normal alanine aminotransferase (ALT) levels. Methods: Eighty‐eight HCV carriers with persistently normal ALT levels were enrolled. All patients received peginterferon (PEG‐IFN) α‐2a 180 μg once weekly plus ribavirin (RBV) 800 mg/day for 24 weeks (HCV‐2 and ‐3) or 1000–1200 mg/day for 48 weeks (HCV‐1). Results: Rapid virological response (RVR) was seen in 66/88 patients (75%): 19/32 HCV‐1 (59%), 40/46 HCV‐2 (87%) and 7/10 HCV‐3 patients. Younger patients, leaner subjects and patients with non‐1 genotype or lower baseline HCV RNA levels were more likely to achieve an RVR. Sustained virological response (SVR) was seen in 69/88 patients (78%): 20/32 HCV‐1 patients (62%), 41/46 HCV‐2 patients (89%) and 8/10 (80%) HCV‐3 patients. The overall SVR rate was 88% in patients with RVR (58/66) and 50% in those without RVR. Conclusions: The combination of PEG‐IFN α‐2a and RBV produces, in patients with normal ALT, virological response rates that are comparable or even higher than those obtained in patients with elevated ALT levels. Thus, we suggest that in selected cases immediate therapy might be preferred to a ‘wait‐and‐see’ policy.     

Comparison of a 6-month course peginterferon alpha-2b plus ribavirin and interferon alpha-2b plus ribavirin in treating Chinese patients with chronic hepatitis C in Taiwan

Previous studies in Caucasian patients showed treatment of chronic hepatitis C with pegylated interferon/ribavirin was well tolerated, and produced a higher response rate especially in genotype 1 infections. However, it is unknown whether this conclusion can be extrapolated to patients with Chinese ethnic origin. A total of 153 patients with biopsy-proven chronic hepatitis C were randomly assigned to receive either weekly injection of peginterferon alpha-2b 1.5 mcg/kg plus oral ribavirin (1000 or 1200 mg/day, depending on body weight) (PEG group, n = 76) or 3 MU of interferon alpha-2b t.i.w. plus ribavirin (IFN group, n = 77) for 24 weeks. Sustained virological response (SVR) was defined as the sustained disappearance of serum hepatitis C virus (HCV) RNA at 24 weeks after the end of treatment by polymerase chain reaction assay. Baseline demographic, viral and histological characteristics were comparable between the two groups. Using an intent-to-treat analysis, HCV genotype 1 patients showed a significantly higher SVR in patients receiving PEG-IFN rather than IFN (65.8%vs 41.0%, P = 0.019), but no difference was found in genotype non-1 patients (PEG vs IFN: 68.4%vs 86.8%, P = 0.060). Genotype 1 patients (28.6%) in the PEG-IFN group relapsed, as compared with 52.9% in the IFN group (P = 0.040). Multivariate analyses showed early virological response at week 12 of therapy and genotype non-1 were significant predictors to SVR. As compared with the IFN group, patients receiving PEG-IFN had a significantly higher rate of discontinuation, dose reduction, fever, headache, insomnia, leucopenia and thrombocytopenia. In genotype 1 chronic hepatitis C Chinese patient, PEG-IFNalpha2b ribavirin had significantly better SVR and lower relapse rate when compared to IFN/ribavirin. Both regimens can be recommended for genotype non-1 chronic hepatitis C Chinese patients. However, a higher rate of adverse events and discontinuance of therapy were noted in patients treated with PEG-IFNalpha2b ribavirin.     

Advantage of IFN‐β/α2b same‐day administration for ribavirin‐intolerant patients with chronic hepatitis C

Aim: Although interferon (IFN)/ribavirin is the mainstream combination treatment for chronic hepatitis C in patients with a high viral load, ribavirin is problematic for women of childbearing age and patients with anemia. Therefore we needed to establish a new regimen without ribavirin. Methods: We devised a new regimen (same‐day β/α2b) to administer IFN‐β and α2b on the same‐day, and compared it with IFN‐α2b alone and IFN‐α2b plus ribavirin. The cases were 36 patients (26.1%) in whom ribavirin could not be used (young women, anemia, etc.) among 138 patients who underwent IFN treatment after ribavirin release. Results: The percentages of patients withdrawing due to side‐effects were 6.8%, 18.8% and 17.0% in the treatment with same‐day β/α2b, IFN‐α2b alone and IFN‐α2b plus ribavirin groups, respectively. In genotype 1b, the sustained viral response (SVR) was 28.6% (4/14), 13.6% (3/22) and 25.0% (8/32) with a high viral load, and 91.7% (11/12), 27.3% (3/11) and 57.1% (4/7) with a low viral load for the respective groups. According to a study on viral half‐life during the early phase of IFN therapy, there was no difference among the regimens of same‐day IFN‐β/α2b, β alone, α2b alone and twice‐daily treatment with IFN‐β. Same‐day β/α2b treatment showed a significantly higher SVR rate in moving type patients with a genotype 1b/high viral load. Conclusions: Same‐day β/α2b treatment resulted in few cases where therapy was discontinued and showed a high SVR rate. This regimen is especially appropriate in cases where ribavirin has been deemed unsuitable.     

Impact of ribavirin priming on viral kinetics and treatment response in chronic hepatitis C genotype 1 infection

Ribavirin amplifies the interferon‐alpha (IFN) signalling cascade. As ribavirin needs 4 weeks to reach steady state, ribavirin priming may optimize hepatic IFN sensitivity before starting a pegylated (PEG)‐IFN/ribavirin combination therapy. This study investigated potential benefits of ribavirin priming prior to PEG‐IFN2a/ribavirin combination therapy on viral kinetics, on‐treatment and sustained virological response (SVR) in chronic hepatitis C virus (HCV) genotype 1 infection. Sixty‐eight treatment naive patients were randomized 2:2:1 to ribavirin (ribavirin arm) or placebo (placebo arm) or PEG‐IFN2a (PEG‐IFN2a arm) for 6 weeks prior to 12 weeks of PEG‐IFN2a/ribavirin combination therapy within a double‐blind, placebo‐controlled trial. Then, standard PEG‐IFN2a/ribavirin combination therapy according to the German guidelines was continued under the responsibility of the investigators. Ribavirin was given according to body weight and PEG‐IFN2a at a dose of 180 μg subcutaneously once/week. During ribavirin priming, HCV RNA showed a decline of −0.58 log₁₀ IU/mL (P < 0.001) that was unrelated to the IL28B rs12979860 genotype (CC vs CT/TT, P = 0.244). Ribavirin priming did neither increase the PEG‐IFN2a‐induced first‐ or second‐phase viral decline (P values >0.100) nor on‐treatment response or SVR (HCV RNA undetectable at week 12 of combination therapy: ribavirin arm 56%, placebo arm 38%, PEG‐IFN2a arm 50%; SVR: ribavirin arm 41%, placebo arm 54%, PEG‐IFN2a arm 50%; P values >0.300). In conclusion, ribavirin monotherapy showed a significant antiviral activity that was not influenced by the IL28B genotype. Ribavirin priming prior to PEG‐IFN2a/ribavirin combination therapy did neither increase the first‐ or second‐phase viral decline nor on‐treatment response or SVR.     

Multicenter Study of Pegylated Interferon α‐2a Monotherapy for Hepatitis C Virus‐Infected Patients on Hemodialysis: REACH Study

Many studies have reported poor vital prognosis in hepatitis C virus (HCV)‐infected dialysis patients. The rate of HCV‐infected dialysis patients in Japan is as high as 9.8%, and antiviral therapy is believed to be important for improving vital prognosis. We conducted a multicenter study to examine the administration method for pegylated interferon α‐2a (PEG‐IFNα‐2a) monotherapy in HCV‐infected dialysis. We studied 56 patients: 14 with low viral loads (HCV RNA < 5.0 log IU/mL) were treated with 90 μg PEG‐IFNα‐2a weekly, 42 with high viral loads (HCV RNA ≥ 5.0 log IU/mL) were treated with 135 μg PEG‐IFNα‐2a weekly. We examined the sustained virological response (SVR), factors affecting the SVR, and treatment safety. The overall SVR rate was 39% (22/56); that for genotype 1, genotype 2, low viral loads, and high viral loads was 29%, 67%, 93%, and 21%, respectively. From receiver operating characteristic (ROC) analysis, the HCV RNA cutoff values likely to achieve SVR for genotypes 1 and 2 were <5.7 log IU/mL (SVR rate: 64% 9/14) and <6.5 log IU/mL (SVR rate: 88% 7/8), respectively. If there was HCV RNA negativation at 4 weeks (rapid virological response), the SVR rate was 94% (16/17), whereas it was 6% (1/16) if there was HCV RNA positivity at 24 weeks. The rate of treatment discontinuation from adverse events or aggravated complications was 25% (14/56). High SVR rates can potentially be achieved with PEG‐IFN monotherapy by identifying the target patients, based on virus type and viral load before initiating treatment and by modifying therapy during treatment according to responsiveness.     

Effectiveness of triple therapy with simeprevir for chronic hepatitis C genotype 1b patients with prior telaprevir failure

Favourable efficacy and safety profiles for simeprevir in combination with pegylated interferon alpha (PEG‐IFNα) and ribavirin (triple therapy) have been shown in clinical trials. This study was carried out to evaluate the effectiveness of simeprevir‐based triple therapy for patients with prior telaprevir treatment failure. This multicentre, observational cohort consisted of 345 consecutive Japanese patients infected with HCV genotype 1b, including 20 who had experienced telaprevir‐based triple therapy. Amino acid substitutions in the NS3/4A region were identified by direct sequencing at the time of relapse or breakthrough in treatment with telaprevir and at the initiation of treatment with simeprevir. Patients were stratified according to prior response to PEG‐IFNα and ribavirin. Of the 20 patients with telaprevir treatment failure, 10 (50.0%) achieved sustained virological response at week 12 after the end of treatment (SVR12). For patients treatment naïve [3/4 (75.0%)] or with prior relapse [1/1 (100%)] or partial response [5/6 (83.3%)] to PEG‐IFNα and ribavirin, almost all achieved SVR12, mainly because of the improvement of treatment adherence, especially to direct‐acting antiviral agent and ribavirin. However, of the nine patients with prior null response to PEG‐IFNα and ribavirin, only one (11.1%) achieved SVR12, despite all having received an adequate treatment dosage, and five (55.6%) achieved rapid virological response. The treatment outcome of simeprevir‐based triple therapy for HCV genotype 1b patients with prior telaprevir failure depended on the prior response to PEG‐IFNα and ribavirin. For patients with prior null response to PEG‐IFNα and ribavirin, retreatment with simeprevir‐based triple therapy is not a useful option.     

Triple therapy of initial high-dose interferon with ribavirin and amantadine for patients with chronic hepatitis C

Aims: We previously reported the potential effect of combination therapy of an initial high‐dose interferon (IFN) and amantadine on the eradication of HCV‐RNA in patients with chronic hepatitis C. The additive effects of amantadine on interferon and ribavirin combination therapy remain controversial. In this study we investigated the efficacy of initial high‐dose IFN with ribavirin and amantadine on the virological response in patients with chronic hepatitis C with a high viral load of genotype 1b. Methods: Twenty‐two patients with high viral loads of genotype 1b hepatitis C virus were enrolled in this pilot study. Patients were administered IFN‐beta for four weeks and then IFN‐alpha2b for 22 weeks with daily oral administration of ribavirin and amantadine. Results: A sustained virological response (SVR) was shown in 31.8% (seven of 22 patients). With the naïve patients, the SVR rate was 21.4% (three of 14 patients). In patients who could not eradicate HCV‐RNA by previous IFN monotherapy, the SVR rate was 50% (four of eight patients). Conclusion: Triple therapy with an initial high dose of IFN with ribavirin and amantadine may be effective, especially for chronic hepatitis C IFN‐retreatment patients with a high viral load of genotype 1b.     

Efficacy of reduction therapy of natural human β-interferon and ribavirin in elderly patients with chronic hepatitis C, genotype 1b and high viral load

Aim: To evaluate the efficacy of reduction therapy of natural human interferon (IFN)‐β and ribavirin in elderly patients with hepatitis C virus (HCV) genotype 1b and high viral load who had complications of anemia, low bodyweight (<50 kg), diabetes mellitus and/or hypertension. Methods: Inclusion criteria were age of 65 years or older, HCV genotype 1b, and serum HCV RNA level of 5.0 logIU/mL or higher. A total of 23 subjects with hemoglobin level of less than 13 g/dL, low bodyweight, diabetes mellitus and/or hypertension were enrolled in this study (reduction‐dose group). IFN‐β was administrated i.v. at a dose of 6 million units daily for 4 weeks initially, followed by three times a week for 44 weeks. Ribavirin was given daily for 48 weeks at a decreased dose of one tablet per day compared to the ordinary dose described based on bodyweight. As a control, another 22 patients without anemia, low bodyweight and/or complications treated with the standard dose of ribavirin (standard‐dose group) were enrolled. Results: Patients' rates with further dose reduction or discontinuation of treatment was 26.1% (6/23) in the reduction‐dose group and 77.3% (17/22) in the standard‐dose group. The sustained virological response (SVR) was 39.1% (9/23) in the reduction‐dose group and 27.3% (6/22) in the standard‐dose group (P = 0.404). Based on genetic variations near the IL28B gene (rs8099917), SVR was 44.1% (15/34) in patients with TT and 0% (0/11) in patients with TG (P = 0.008). Conclusion: The reduction therapy of IFN‐β and ribavirin in elderly HCV patients with genotype 1b, high viral load, IL28B gene (rs8099917) of TT who had complications of anemia, low bodyweight, diabetes mellitus and/or hypertension is one possible selection of treatment.