Sustained virological response of patients with hepatitis C virus genotype 2 depends on pegylated interferon compliance

Aim: Patients infected with hepatitis C virus (HCV) genotype 2 are more sensitive to interferon (IFN) therapy than those infected with genotype 1, but 10–20% of patients do not achieve a sustained viral response (SVR) to combination therapy with pegylated (PEG) IFN and ribavirin (RBV). This study examines the prognostic factors associated with SVR in patients infected with HCV genotype 2 treated with PEG IFN and RBV. Methods: We treated 149 patients with chronic hepatitis C caused by HCV genotype 2. The patients received s.c. PEG IFN‐α‐2b (1.5 µg/kg) and a weekly weight‐adjusted dose of RBV (600, 800 and 1000 mg per <60, 60–80 and >80 kg, respectively) for 24 weeks and then prognostic factors associated with the SVR were examined. Results: Among the 149 patients, 138 completed the combination therapy and a sustained viral response was achieved in 71.8% of them. Univariate analysis showed that age, as well as mean RBV and PEG IFN doses were factors affecting the SVR (P = 0.012, =0.021, =0.014). Multivariate analysis identified age and mean PEG IFN dose (P = 0.021, =0.018, respectively) as factors involved in the SVR, but not mean RBV dose. Conclusion: The SVR of patients infected with HCV genotype 2 depended on the dosage of PEG IFN, but not of RBV. Selecting sufficient doses of PEG IFN for combination with RBV is critical for treating such patients.     

Early identification of achieving a sustained virological response in chronic hepatitis C patients without a rapid virological response

Background and Aim: A number of hepatitis C virus (HCV) patients without a rapid virological response (RVR) achieved a sustained virological response (SVR) with peginterferon‐α‐2a/ribavirin. The aim of this study was to identify factors associated with SVR in non‐RVR patients. Methods: Baseline and on‐treatment factors were used to explore the prognostic factors for SVR in 113 HCV genotype‐1 (HCV‐1) and 20 HCV‐2 non‐RVR patients in two randomized trials. Results: The SVR rate in HCV‐1 patients with a complete early virological response (cEVR) and partial early virological response was 91.9% versus 45% (P < 0.001) and 21.4% versus 10% (P = 0.62), respectively, after 48 and 24 weeks of treatment. The SVR rate in HCV‐2 patients with a cEVR was 90.9% versus 57.1% (P = 0.25), respectively, after 24 and 16 weeks of treatment. Multivariate analysis showed that cEVR and standard regimen were independently associated with SVR. Viral kinetic study revealed that HCV viral loads < 10 000 IU/mL at week 4 were the best predictor of cEVR for both HCV‐1 and HCV‐2 non‐RVR patients with the accuracy of 81% and 95%, respectively, and also of SVR with the accuracy of 78% and 92%, respectively, in patients receiving standard of care. The most important independent predictors for cEVR were HCV viral loads < 10⁴ IU/mL at week 4, followed by increased ribavirin dose within 12 weeks of treatment. Conclusions: Achieving a cEVR with standard of care is the most important predictor of SVR in non‐RVR patients. Week 4 viral loads < 10 000 IU/mL could accurately predict cEVR early and following SVR in non‐SVR patients.     

Hepatic steatosis in chronic hepatitis C patients infected with genotype 2 is associated with insulin resistance, hepatic fibrosis and affects cumulative positivity of serum hepatitis C virus RNA in peginterferon and ribavirin combination therapy

Aim: Hepatic steatosis is one of the factors limiting the virological response to interferon‐based antiviral therapy for chronic hepatitis C (CH‐C) patients infected with genotype 1, while contradictory results have been reported for genotype 2. We aimed to clarify the effect of hepatic steatosis on therapeutic outcome and cumulative positivity of serum HCV RNA in CH‐C patients infected with genotype 2 treated by peginterferon (PEG‐IFN)α2b and ribavirin (RBV) combination therapy. Methods: A total of 74 treatment‐naïve non‐cirrhotic CH‐C patients infected with genotype 2 who received PEG‐IFNα2b and RBV according to the standard regimen were divided into hepatic steatosis 0–10% and >10% groups. The clinical backgrounds, sustained virological response (SVR) rates and cumulative positivity of serum HCV RNA were compared between the two groups. Results: Among the 74 patients, 61 (82.4%) had hepatic steatosis 0–10% and 13 (17.6%) had hepatic steatosis >10%. Scores of homeostasis model assessment‐insulin resistance and hepatic fibrosis were higher in patients with hepatic steatosis >10% than hepatic steatosis 0–10% (P = 0.040 and 0.042, respectively). Non‐SVR was more frequent in patients with hepatic steatosis >10% than hepatic steatosis 0–10% (P = 0.003). Cumulative positivity of serum HCV RNA was significantly higher in patients with hepatic steatosis >10% than hepatic steatosis 0–10% (P = 0.004). Conclusions: In CH‐C patients infected with genotype 2 treated by PEG‐IFNα2b and RBV combination therapy, hepatic steatosis >10% was associated with increased insulin resistance, advanced hepatic fibrosis and higher cumulative positivity of serum HCV RNA, which lead to a higher risk of non‐SVR.     

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.     

Pioglitazone improves virological response to peginterferon α‐2b/ribavirin combination therapy in hepatitis C genotype 4 patients with insulin resistance

Background & aim: Insulin resistance (IR) affects sustained virological response (SVR). The use of insulin‐sensitizing agents has been proposed to improve therapy outcome. The safety and efficacy of pioglitazone on insulin sensitivity and SVR in treatment‐naïve patients with chronic hepatitis C (CHC) genotype 4 with IR receiving standard antiviral therapy were evaluated in a randomized‐controlled study. Methods: Ninety‐seven previously untreated patients with CHC and IR [homeostasis model assessment (HOMA>2)] were randomly assigned into two arms; (arm A; n=48) were given pioglitazone 30 mg/day combined with peginterferon (Peg‐IFN)‐α‐2b/ribavirin (RBV) for 48 weeks, and (arm B; n=49) were given standard of care (Peg‐IFN‐α‐2b/RBV for 48 weeks); HOMA index and hepatitis C virus RNA (HCV RNA) levels were measured at baseline, during therapy and follow‐up. Treatment was stopped in patients without an early virological response or those who were HCV RNA positive at 24 weeks. Results: Baseline data of both groups were comparable, with no significant statistical differences. The percentages of rapid virological response (RVR) and SVR were significantly higher in patients given triple therapy compared with standard of care (27.08 vs. 6.1%; P=0.006 and 60.4 vs. 38.7%; P=0.04 respectively); patients in arm A showed a greater decrease in the HOMA index than those in arm B (?1.8 ± 0.3, ?2.1 ± 0.3 vs. ?1.1 ± 0.6, ?1.3 ± 0.7) at week 24 and at the end of follow‐up (P=0.001 at both time points). The triple therapy was well tolerated. Conclusions: A combination of pioglitazone, Peg‐IFN‐α‐2b and ribavirin increased RVR, SVR and decreased IR, compared with patients given Peg‐IFN plus ribavirin without an increase in adverse events.     

A predictive model of response to peginterferon ribavirin in chronic hepatitis C using classification and regression tree analysis

Aim: Early disappearance of serum hepatitis C virus (HCV) RNA is the prerequisite for achieving sustained virological response (SVR) in peg‐interferon (PEG‐IFN) plus ribavirin (RBV) therapy for chronic hepatitis C. This study aimed to develop a decision tree model for the pre‐treatment prediction of response. Methods: Genotype 1b chronic hepatitis C treated with PEG‐IFN alpha‐2b and RBV were studied. Predictive factors of rapid or complete early virological response (RVR/cEVR) were explored in 400 consecutive patients using a recursive partitioning analysis, referred to as classification and regression tree (CART) and validated. Results: CART analysis identified hepatic steatosis (<30%) as the first predictor of response followed by low‐density‐lipoprotein cholesterol (LDL‐C) (≥100 mg/dL), age (<50 and <60 years), blood sugar (<120 mg/dL), and gamma‐glutamyltransferase (GGT) (<40 IU/L) and built decision tree model. The model consisted of seven groups with variable response rates from low (15%) to high (77%). The reproducibility of the model was confirmed by the independent validation group (r² = 0.987). When reconstructed into three groups, the rate of RVR/cEVR was 16% for low probability group, 46% for intermediate probability group and 75% for high probability group. Conclusions: A decision tree model that includes hepatic steatosis, LDL‐C, age, blood sugar, and GGT may be useful for the prediction of response before PEG‐IFN plus RBV therapy, and has the potential to support clinical decisions in selecting patients for therapy and may provide a rationale for treating metabolic factors to improve the efficacy of antiviral therapy.     

HCV-related advanced fibrosis/cirrhosis: randomized controlled trial of pegylated interferon alpha-2a and ribavirin

Summary. In patients with hepatitis C virus (HCV)‐related advanced fibrosis/cirrhosis, 30% of sustained HCV clearance has been reported with pegylated interferon α‐2a (PEG‐IFN) alone, but the efficacy and tolerability of the PEG‐IFN/ribavirin (RBV) combination remain poorly defined. A total of 124 treatment‐naïve patients with biopsy proved HCV‐related advanced fibrosis/cirrhosis (Ishak score F4–F6, Child–Pugh score ≤7) were randomized to 48 weeks of PEG‐IFN (180 μg sc weekly) and standard dose of RBV (1000/1200 mg po daily, STD) or PEG‐IFN (180 μg sc weekly) and low‐dose of RBV (600/800 mg po daily, LOW). Sustained virologic response (SVR) rates with PEG‐IFN/STD RBV (52%) were higher – albeit not significantly – than that with PEG‐IFN/LOW RBV (38%, P = 0.153). In multivariate analysis, genotype 2/3 and a baseline platelet count ≥150 × 10⁹/L were independently associated with SVR. The likelihood of SVR was <7% if viraemia had not declined by ≥2 log or to undetectable levels after 12 weeks. Nine adverse events in the STD RBV and 15 in the LOW RBV group were classified as severe (including two deaths); dose reductions for intolerance were required in 78% and 57% (P = 0.013), and treatment was terminated early in 23% and 27% of patients (P = n.s.). The benefit/risk ratio of treating compensated HCV‐cirrhotics with STD PEG‐IFN/RBV is favourable.     

Peginterferon-Α_2B plus ribavirin is more effective than peginterferon-Α_2A plus ribavirin in menopausal women with chronic hepatitis C

Summary. Under‐enrolment of women to randomized clinical trials, including chronic hepatitis C, has long been recognized. The aim of this study was to identify factors predictive of sustained virological response (SVR) to PEG IFN/Ribavirin antiviral therapy in relation to gender and reproductive status of female patients involved. Seven hundred and forty‐six treatment‐naïve patients (431 men, 315 women) treated with Peg‐IFNα‐2a (180 μg/week) or Peg‐IFNα‐2b (1.5 μg/kg/week) plus ribavirin (800–1400 mg/day) for 24 or 48 weeks were studied between 2006 and 2010. Differences in SVR rate, overall and by gender were assessed after adjustment and propensity score matching. SVR was obtained in 44.2% of Peg‐IFNα‐2a‐treated patients and in 51.2% of Peg‐IFNα‐2b‐treated patients (intention‐to‐treat; P = 0.139). Age, fibrosis stage and genotype 2 and 3 were independently associated with SVR by multivariate analysis. Analysing by gender, the difference in SVR between PEG‐IFNα types was not significant in men but highly significant in women (Peg‐IFNα‐2a:39.1%vs Peg‐IFNα‐2b:54.4%, P = 0.007). This was attributable to a higher SVR rate with Peg‐IFNα‐2b in the difficult postmenopausal population (26.9% Peg‐IFNα‐2a vs 46.0% Peg‐IFNα‐2b, P = 0.040). In women, absence of menopause, genotype 2 hepatitis C virus infection and use of Peg‐IFNα‐2b were independently associated with SVR. In conclusion, predictive factors for SVR are different in men and women. Factors differing between genders are menopause, severe steatosis and peg‐interferon used. The higher SVR rate with Peg‐IFNα‐2b in menopausal women is likely attributable to more favourable pharmacokinetics that allows Peg‐IFNα‐2b to reach visceral fat and oppose the increased cytokine production and enhanced inflammatory status in menopause.     

Efficacy and safety of double filtration plasmapheresis in combination with interferon therapy for chronic hepatitis C

Aim: Efficacy and safety of double filtration plasmapheresis (DFPP) for chronic hepatitis C were prospectively analyzed in Japanese clinical settings. Methods: All patients who received DFPP in combination with interferon (IFN) therapy for chronic hepatitis C were serially recruited at 36 institutions between April 2008 and July 2009 in Japan. Results: A total of 239 patients were analyzed for the safety of DFPP and 206 patients for the efficacy. Of the 206 patients, 181 patients were treated with DFPP in combination with pegylated interferon plus ribavirin (PEG‐IFN/RBV + DFPP). Among the 181 patients, 60 patients (33.1%) were treatment‐naïves, 35 (19.3%) relapsers and 62 (34.3%) non‐responders. Complete early virological response (cEVR) in patients treated with PEG‐IFN/RBV + DFPP was achieved in 57.5% overall, 70.0% in treatment‐naïves, 57.1% in relapsers and 41.9% in non‐responders. In patients with previous PEG‐IFN/RBV therapy, cEVR were found in 63.0% of relapsers and 18.9 % of non‐responders, and cEVR in patients with other than PEG‐IFN/RBV therapy as previous IFN therapy, relapsers and non‐responders was 37.5% and 76.0%, respectively. Adverse events were found in 55 patients (23.0%). Serious adverse events were found in four patients (1.7%) who showed puncture‐site injury. Adverse events were related to female sex, but not related to age, and DFPP could be performed safely. Conclusion: The cEVR results in this study suggest that high rates of sustained virological response can be achieved in retreated and treatment‐naïve patients using DFPP in combination with PEG‐IFN/RBV therapy. Results indicate that this therapy could be safely conducted, even in elderly patients.     

Efficacy of the regimen using twice-daily β-interferon followed by the standard of care for chronic hepatitis C genotype 1b with high viral load

Aim: In patients with refractory genotype 1b chronic hepatitis C with high viral loads, we retrospectively compared the efficacy of standard of care treatment (SOC: combined PEG‐IFN‐α‐2b/ribavirin for 48 weeks) and a regimen in which 2 weeks of SOC induction was replaced by twice‐daily β‐interferon alone (IFN‐β induction therapy). Methods: Seventeen patients received the IFN‐β induction therapy plus SOC (IFN‐β induction group) and 13 patients received SOC alone (SOC group). Results: In the IFN‐β induction group and SOC group, early virological response (EVR) rates were 88.2% and 53.8%, respectively. The end of treatment rates were 100.0% and 92.3%, and sustained virological response (SVR) rates were 70.6% and 53.8%, respectively. By induction with IFN‐β, even in refractory cases, the high virus negative conversion rate in the early treatment phase and actions of pegylated IFN‐α‐2b and ribavirin in the maintenance treatment phase led to an additive effect. In the analysis of contributing factors, only the achievement of EVR was associated with a significant difference in SVR (P = 0.0011). The univariate logistic regression analysis showed that only IFN‐β treatment was associated with a significant difference in EVR (P = 0.0492, odds ratio = 6.248, 95% confidence interval = 1.026–40.252), whereas no significant factors were found in the multivariate analysis due to small samples. Conclusion: IFN‐β induction therapy with higher EVR might be beneficial for protease inhibitor‐refractory chronic hepatitis C patients.     

Efficacy and safety of pegylated interferon alpha‐2a therapy for chronic hepatitis C in HIV‐infected patients with haemophilia

Summary. The objective of this study was to evaluate the efficacy and safety of pegylated interferon (PEG‐IFN) alpha‐2a monotherapy in a cohort of Chinese haemophilic patients co‐infected with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) and undergoing highly active antiretroviral drugs therapy. Twenty‐two (n = 22) patients with CD4 lymphocyte counts over 200 cells μL^?1 were treated with 180 μg of PEG‐IFN alpha‐2a subcutaneously once in a week for 48 weeks. HCV load (HCV RNA), HIV load (HIV RNA) and CD4 lymphocyte counts were measured at baseline and 4, 12, 24, 48 and 72 weeks after initiation of anti‐HCV therapy. Efficacy and safety were analysed according to baseline CD4 status (≥350 cells μL^?1). Significant HCV‐RNA decreases (>1 log₁₀ copies mL^?1) were observed through week 72 after PEG‐INF alpha‐2a monotherapy across both CD4 strata. CD4 status was not associated with treatment outcomes as evaluated using rapid viral response rate (P = 0.655), early viral response rate (P = 0.387), end‐of‐treatment viral response rate (P = 1.000) or sustained viral response rate (SVR, P = 0.674). A sustained virological response was achieved in nine patients (41%), five with genotype 2a (83%) and four with genotype 1b (25%, P = 0.023). SVR was HCV genotype dependent. Eleven patients required a dose reduction in PEG‐IFN alpha‐2a. PEG‐IFN alpha‐2a monotherapy could be considered as a safe and effective option for the treatment of HCV infection in HIV patients with haemophilia, particularly in resource‐limited settings. While higher CD4 lymphocyte counts resulted in greater HCV‐RNA reduction, HCV genotype was a predictor for sustained virological response.     

Efficacy and tolerability of peginterferon alfa‐2a or alfa‐2b plus ribavirin in the daily routine treatment of patients with chronic hepatitis C in Germany: The PRACTICE Study

Summary. In randomized clinical trials, treatment with peginterferon plus ribavirin (RBV) results in a sustained virological response (SVR) in around half of hepatitis C virus genotype 1‐infected and 80% of genotype 2/3‐infected individuals. This study aimed to evaluate efficacy and tolerability of peginterferon alfa‐2a plus RBV compared with peginterferon alfa‐2b plus RBV for the treatment of chronic hepatitis C in routine clinical practice. The intent‐to‐treat cohort consisted of 3414 patients treated with either peginterferon alfa‐2a plus RBV (Group A) or peginterferon alfa‐2b plus RBV (Group B) in 23 centres participating in the large, multicentre, observational PRACTICE study. Collected data included baseline characteristics, treatment regimen, RBV dose and outcome. Rates of early virological response, end of treatment response and SVR were 76.6%, 75.7% and 52.9% in Group A, and 70.2%, 65.6% and 50.5% in Group B, respectively. In patients matched by baseline parameters, 59.9% of patients in Group A and 55.9% in Group B achieved an SVR (P ≤ 0.051). In genotype 1‐infected patients matched by baseline parameters and cumulative RBV dose, SVR rates were 49.6% and 43.7% for Group A and Group B, respectively (P ≤ 0.047); when matched by baseline parameters and RBV starting dose, SVR rates were 49.9% and 44.6%, respectively (P = 0.068). Overall, 21.8% of group A and 29.6% of group B patients discontinued treatment (P ≤ 0.0001). The efficacy and tolerability of peginterferon plus RBV in this large cohort of patients treated in routine daily practice was similar to that in randomized clinical trials. In matched pairs analyses, more patients achieved an SVR with peginterferon alfa‐2a compared with peginterferon alfa‐2b.     

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.     

Response-guided therapy for patients with hepatitis C virus genotype 6 infection: a pilot study

Summary. The optimal duration of treatment with pegylated interferon (PEG‐IFN) plus ribavirin (RBV) in patients with hepatitis C virus (HCV) genotype 6 is unknown. This study was aimed at determining treatment response on the basis of rapid virological response (RVR) of HCV genotype 6 in comparison with genotypes 1 and 3. Sixty‐six treatment naïve patients were treated with PEG‐IFN‐α2a (180 μg/week) plus weight‐based RBV (1000–1200 mg/day). Patients with genotype 1 n = 16) and genotype 3 (n = 16) were treated for a fixed duration of 48 and 24 weeks, respectively. Patients with genotype 6 (n = 34) who achieved RVR were treated for 24 weeks (response‐guided therapy) and the remaining patients were treated for 48 weeks (standard therapy). The mean baseline HCV RNA levels were not statistically different between groups (6.4 ± 0.8, 6.0 ± 1.0 and 6.5 ± 0.8 Log₁₀ IU/mL for genotypes 1, 3 and 6, respectively). Patients with genotypes 1, 3 and 6 achieved RVR in 43.8%, 87.5% and 73.5% of cases, respectively. One patient with genotype 1 and 3 with genotype 6 were considered nonresponders and discontinued therapy. Sustained virological response (SVR) was achieved in 62.5%, 81.3% and 76.5% of patients with genotypes 1, 3 and 6, respectively. The SVR rate in patients with genotype 6 who underwent response‐guided therapy was 88%. This pilot study suggested that the SVR rate of HCV genotype 6 was at an intermediate level between those of genotypes 3 and 1. Treatment with PEG‐IFN plus RBV for 24 weeks may be sufficient for patients with genotype 6 who achieve RVR. Prospective randomized trials are required to evaluate this response‐guided strategy in a larger number of patients with genotype 6.     

Effect of vitamin D supplementation on pegylated interferon/ribavirin therapy for chronic hepatitis C genotype 1b: a randomized controlled trial

Chronic HCV–infected patients tend to have vitamin D deficiency, suggesting that vitamin D supplementation may enhance the efficacy of treatment with pegylated interferon (PEG‐IFN) and ribavirin (RBV). We therefore assessed the effects of vitamin D supplementation on viral response to PEG‐IFN/RBV. Eighty‐four patients with HCV genotype 1b were randomized, 42 to oral vitamin D supplementation (1000 IU/day) and 42 to nonsupplementation (control), from week 8 to the end of PEG‐IFN/RBV therapy. The primary end point was undetectable HCV RNA at week 24 (viral response [VR]). VR rate at week 24 was significantly higher in the vitamin D than in the control group (78.6% vs 54.8% P = 0.037). Adverse events were similar in both groups. When patients were subdivided by IL28B SNP rs8099917 genotype, those with the TT genotype group showed a significantly higher VR rate at week 24 with than without vitamin D supplementation (86.2% vs 63.3% vs P = 0.044). Although patients with the TG/GG genotype, who were relatively resistant to PEG‐IFN treatment, had similar VR rates at week 24 with and without vitamin D supplementation, the decline in viral load from week 8 to week 24 was significantly greater with than without vitamin D supplementation. Multivariate analysis showed that rs8099917 genotype and vitamin D supplementation contributed significantly to VR at week 24. SVR rates were similar in the vitamin D and control groups [64.3% (27/42) vs 50% (21/42), P = 0.19]. Vitamin D supplementation may enhance the effects of PEG‐IFN/RBV in HCV genotype 1b–infected patients.     

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.     

Early prediction of sustained virological response at day 3 of treatment with albinterferon‐α‐2b in patients with genotype 2/3 chronic hepatitis C

Background: Albinterferon‐α‐2b (albIFN) is a long‐acting fusion polypeptide composed of albumin and IFN‐α‐2b. In a phase 2 study of albIFN 1500 μg q2wk or q4wk in patients with genotype 2/3 chronic hepatitis C, albIFN demonstrated sustained virological response (SVR) rates of 62–77% (intent‐to‐treat population). Aims: To assess the association of initial viral kinetics during albIFN therapy with baseline factors and SVR prediction. Methods: In all, 43 patients were treated with albIFN 1500 μg (q2wk/q4wk) plus ribavirin (RBV) 800 mg/day for 24 weeks. Hepatitis C virus (HCV)‐RNA levels were measured by real‐time polymerase chain reaction, insulin resistance by homeostasis model assessment of insulin resistance (HOMA‐IR) and serum albIFN levels by enyzme‐linked immunosorbent assay. Prediction analysis was performed in a per protocol 28‐patient subset who were ≥80% adherent to albIFN/RBV and had HCV‐RNA levels measured at treatment day 3. Results: Day‐3 HCV‐RNA level and first‐phase viral decline as well as second‐phase slope of viral decline were significantly associated with SVR. In adherent patients, 82.1% had a day‐3 viral load <4.2 log₁₀ IU/ml or first‐phase decline >1.25 log₁₀ IU/ml, which was predictive of SVR, both positively (95.7%; sensitivity: 100%) and negatively (100%; specificity: 83.3%). As low first‐phase decline was associated with a high pretreatment HOMA‐IR index (P=0.004) and a low day‐3 serum albIFN level (P=0.01). Conclusions: First‐phase viral decline with albIFN/RBV was predictive of SVR in this study and may be modulated in part by IR.     

Two patients treated with pegylated interferon/ribavirin/telaprevir triple therapy for recurrent hepatitis C after living donor liver transplantation

It is difficult to use protease inhibitors in patients with recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) due to interaction with immunosuppressive drugs. We report our experience with two patients treated with telaprevir (TVR) combined with pegylated interferon/ribavirin (PEG IFN/RBV) for recurrent HCV genotype 1 infection after LT. The first was a 63‐year‐old man with HCV‐related liver cirrhosis, who failed to respond to IFN‐β plus RBV after LT. Treatment was switched to PEG IFN‐α‐2b plus RBV and TVR was started. The donor had TT genotype of interleukin (IL)‐28 single nucleotide polymorphisms (SNP) (rs8099917). The recipient had TT genotype of IL‐28 SNP (rs8099917). Completion of 12‐week triple therapy was followed by PEG IFN‐α‐2b plus RBV for 36 weeks. Finally, he had sustained viral response. The second was a 70‐year‐old woman with HCV‐related liver cirrhosis and hepatocellular carcinoma. She failed to respond to PEG IFN‐α‐2b plus RBV after LT, and was subsequently switched to PEG IFN‐α‐2b/RBV/TVR. Genotype analysis showed TG genotype of IL‐28 SNP for the donor, and TT genotype of IL‐28 SNP for the recipient. Serum HCV RNA titer decreased below the detection limit at 5 weeks. However, triple therapy was withdrawn at 11 weeks due to general fatigue, which resulted in HCV RNA rebound 4 weeks later. Both patients were treated with cyclosporin, starting with a small dose to avoid interactions with TVR. TVR is a potentially suitable agent for LT recipients who do not respond to PEG IFN‐α‐2b plus RBV after LT.     

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.