JUMP-C: a randomized trial of mericitabine plus pegylated interferon alpha-2a/ribavirin for 24 weeks in treatment-naïve HCV genotype 1/4 patients.

UNLABELLED: Mericitabine is a selective nucleoside analog inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase, with activity across all HCV genotypes. Treatment-naïve patients infected with HCV genotype 1 or 4 were randomized to 24 weeks of double-blind treatment with either mericitabine 1,000 mg (N = 81) or placebo (N = 85) twice-daily (BID) in combination with pegylated interferon alpha-2a (Peg-IFNα-2a)/ribavirin (RBV). Patients randomized to mericitabine with HCV RNA <15 IU/mL from week 4 to 22 (extended rapid virologic response; eRVR) stopped all treatment at week 24; all other patients continued Peg-IFNα-2a/RBV to complete 48 weeks of treatment. The primary efficacy endpoint was sustained virologic response (SVR; HCV RNA <15 IU/mL after 24 weeks of treatment-free follow-up). SVR was achieved in 56.8% (95% confidence interval [CI]: 45.9-67.0) of mericitabine-treated patients and 36.5% (95% CI: 27.0-47.1) of placebo-treated patients (Δ = 20.3%; 95% CI 5.5-35.2). SVR rates were higher in mericitabine- than placebo-treated patients when subdivided by IL28B genotype (CC, 77.8% versus 56.0%; non-CC, 44.1% versus 16.2%) and hepatic fibrosis (noncirrhotic, 63.3% versus 41.9%; cirrhotic, 38.1% versus 21.7%). Overall relapse rates were 27.7% and 32.0% in mericitabine- and placebo-treated patients, respectively. No evidence of NS5B S282T-variant virus or phenotypic resistance to mericitabine was observed in the one patient who experienced partial response. No S282T variants were detected in any baseline samples. The safety profile of mericitabine was similar to that of, and fewer patients in the mericitabine than in the placebo group discontinued treatment for safety reasons. CONCLUSION: A 24-week response-guided combination regimen of mericitabine 1,000 mg BID plus Peg-IFNα-2a/RBV is well tolerated and more effective than a standard 48-week course of Peg-IFNα-2a/RBV.

In routine clinical practice, few physicians use early viral kinetics to guide HCV dual therapy treatment decisions.

BACKGROUND & AIMS: PROPHESYS is a large, multinational, non-interventional prospective cohort study of chronic hepatitis C patients treated with peginterferon alfa/ribavirin. This subanalysis assesses rates of premature treatment discontinuation stratified by on-treatment virological response (VR). METHODS: This PROPHESYS subanalysis is restricted to treatment-naive, hepatitis C virus (HCV) genotype (G)1/2/3 mono-infected patients who received peginterferon alfa-2a (40KD)/ribavirin with intended treatment duration of 48 (G1) or 24 weeks (G2/3). Early virological responses were classified into four mutually exclusive categories [rapid VR (RVR), complete early VR (cEVR), partial EVR (pEVR), no RVR/EVR], using standard criteria. RESULTS: The likelihood for shortening treatment owing to good efficacy was highest among patients with an RVR and HCV RNA≤400 000 IU/ml (G1 10.0%; G2/3 5.8%) whereas for poor efficacy, it was highest in G1 non-RVR/EVR patients with HCV RNA>400 000 IU/ml (56.6%). Factors significantly associated with early treatment discontinuation as a result of good efficacy in G1 patients included RVR vs. no RVR/EVR and, at baseline, lower HCV RNA, lower FIB-4 score, HCV infection via injection drug use. For G2/3 patients, factors included lower baseline HCV RNA and G2 vs. G3 infection. Most patients started with the recommended peginterferon alfa-2a dose, but a high proportion received a higher-than-recommended ribavirin dose. CONCLUSIONS: Despite international guidelines, few physicians used early viral kinetics to abbreviate treatment. Therefore, relatively few patients with an RVR and low baseline HCV RNA abbreviated treatment. In addition, there were deviations in ribavirin starting doses, suggesting that physicians tailor treatment according to local guidelines or previous experience.

Albinterferon Alfa-2b was not inferior to pegylated interferon-α in a randomized trial of patients with chronic hepatitis C virus genotype 1.

BACKGROUND & AIMS: The current standard of care for patients with chronic hepatitis C virus (HCV) genotype 1 is once-weekly pegylated interferon-α (Peg-IFNα) plus daily ribavirin for 48 weeks. We evaluated the efficacy/safety of albinterferon alfa-2b (albIFN), a novel, long-acting, genetic fusion polypeptide of albumin and IFNα-2b. METHODS: In the phase 3 ACHIEVE-1 trial, 1331 patients were assigned equally to 3 open-label, 48-week treatment groups: Peg-IFNα-2a 180 µg every week, or albIFN 900 or 1200 µg every 2 weeks administered subcutaneously, with weight-based oral ribavirin 1000-1200 mg/day. During the study, the data monitoring committee recommended dose modification for all patients receiving albIFN 1200 µg to 900 µg because of increased pulmonary adverse events (AEs) in the 1200-µg arms of both ACHIEVE studies. Main outcome measure was sustained virologic response (SVR; undetectable serum HCV RNA at week 72). RESULTS: Intention-to-treat SVR rates were 51.0% (225/441), 48.2% (213/442), and 47.3% (208/440) with Peg-IFNα-2a, and albIFN 900 and 1200 µg, respectively. The primary objective of showing noninferiority of albIFN 900 µg (P < .001) and 1200 µg (P = .003) vs Peg-IFNα-2a for SVR was achieved. Multivariate modeling indicated consistency of treatment effect across subgroups. Serious/severe AE rates were 23.1%, 24.0%, 28.2%; treatment discontinuation rates because of AEs were 4.1%, 10.4%, 10.0%; discontinuation rates because of respiratory AEs were 0%, 0.9%, 1.6%; with Peg-IFNα-2a, and albIFN 900 and 1200 µg, respectively. Hematologic abnormality rates were comparable across the Peg-IFNα-2a and albIFN 900-µg groups. CONCLUSIONS: albIFN 900 µg every 2 weeks showed comparable efficacy, with similar serious/severe AE rates, although with a higher discontinuation rate, vs Peg-IFNα-2a in patients with chronic HCV genotype 1.

Weight loss, leukopenia and thrombocytopenia associated with sustained virologic response to Hepatitis C treatment.

OBJECTIVE: To identify apparent adverse effects of treatment of chronic hepatitis C and their relationship to sustained virologic response (SVR). METHODS: A retrospective study was conducted of all Hepatitis C virus (HCV)-infected patients treated with pegylated interferon and ribavirin in an academic ambulatory infectious disease practice. Clinical and laboratory characteristics were compared between patients with SVR and without SVR. RESULTS: Fifty-four patients completed therapy with the overall SVR rate of 76%. SVR was associated with genotype non-1 (P=0.01), weight loss more than 5 kilograms (P=0.04), end of treatment leukopenia (P=0.02) and thrombocytopenia (P=0.05). In multivariate analysis, SVR was significant associated with HCV genotype non-1 (Adjusted Odd Ratio [AOR] 15.22; CI 1.55 to 149.72; P=0.02), weight loss more than 5 kilograms, (AOR 5.74; CI 1.24 to 26.32; P=0.04), and end of treatment white blood cell count level less than 3 X 10(3) cells/microl (AOR 9.09; CI 1.59 to 52.63; P=0.02). Thrombocytopenia was not significant after adjustment. Other factors including age, gender, ethnicity, injection drug use, viral load, anemia, alanine transaminase level, and liver histology did not reach statistical significance. CONCLUSION: Besides non-1 genotype, SVR was found to be independently associated with weight loss during therapy, and leukopenia at the end of HCV treatment. These correlations suggest continuation of therapy despite adverse effects, may be of benefit.

Efficacy and safety of peginterferon alfa-2a/ribavirin in methadone maintenance patients: randomized comparison of direct observed therapy and self-administration.

BACKGROUND: Adherence to chronic hepatitis C (CHC) treatment may be particularly challenging in methadone maintenance patients. We assessed the safety, tolerability, and efficacy of peginterferon alfa-2a/ribavirin treatment in methadone maintenance patients previously untreated for CHC. METHODS: Patients were randomized 1:1 to direct observed therapy (DOT) or self-administration (SA) of peginterferon alfa-2a. DOT patients were seen weekly at methadone clinics; SA patients were seen less frequently, only at investigative sites. Genotype 1-infected patients were treated for 48 wk with peginterferon alfa-2a (180 microg/wk)/ribavirin (1,000/1,200 mg/day); genotypes 2- and 3-infected patients were treated for 24 wk with peginterferon alfa-2a (180 microg/wk)/ribavirin (800 mg/day). RESULTS: Based on defined efficacy stopping rules, 77% (37/48) completed their targeted length of treatment, and 44% (21/48) achieved sustained virologic response (SVR). Two DOT and 3 SA patients were withdrawn for safety reasons and 6 and 9, respectively, for nonsafety reasons. Over 60% and 50% of each group were >80% compliant with the planned cumulative doses of peginterferon alfa-2a and ribavirin, respectively, and over 60% with overall treatment duration. SVR rates were 54% (13/24) for DOT and 33% (8/24) for SA; 23% (3/13) and 38% (6/16), respectively, for genotype 1 and 91% (10/11) and 25% (2/8), respectively, for genotypes 2 and 3. Stepwise logistic regression analysis, showed that DOT (vs SA; OR 3.27, 95% CI 0.90-11.91, P = 0.073) and Caucasian race (vs Other; OR 13.31, 95% CI 1.42-124.71, P = 0.023) were predictors of SVR. CONCLUSION: Peginterferon alfa-2a/ribavirin can be used safely and successfully in CHC patients receiving methadone maintenance.

Changes in fasting plasma glucose levels with ribavirin and pegylated interferon treatment in normal and impaired glucose tolerant patients with chronic hepatitis C.

BACKGROUND: Patients with Hepatitis C Virus (HCV) infection have increased rates of glucose intolerance, and studies have shown the improvement of fasting plasma glucose (FPG) levels after clearance of HCV infection with standard ribavirin plus pegylated interferon treatment. The purpose of this study was to examine glycemic changes with standard HCV treatment in patients with impaired fasting glucose (IFG) and normal fasting glucose (NFG). METHODS: A retrospective study of FPG changes in HCV patients with IFG and NFG treated with standard HCV therapy was conducted. Baseline characteristics and viral responses were assessed; FPG levels before treatment, at the end of treatment, and more than one-month post treatment were compared. RESULTS: The mean FPG levels increased by 8.68 mg/dl at the end of treatment in the NFG group but decreased by 9.0 mg/dl in the IFG group, a statistically significant difference (P=0.019). The change in FPG levels remained significantly different after adjusting for weight change (P=0.009) and weight changes and initial weight (P=0.039). FPG change from baseline at more than one month after treatment were similar in both groups (P=0.145). The change in FPG levels was not associated with sustained viral response. CONCLUSIONS: In HCV-infected patients, standard ribavirin plus pegylated interferon treatment reduced FPG levels in patients with IFG and increased FPG levels in NFG individuals; independent of initial weight, weight change, or viral response. Standard HCV treatment modulates fasting plasma glucose levels which supports the need for a prospective study to determine the clinical significance of this finding.