Albinterferon Alfa-2b was not inferior to pegylated interferon-α in a randomized trial of patients with chronic hepatitis C virus genotype 2 or 3.

BACKGROUND & AIMS: A phase 3 active-controlled study was conducted to assess the efficacy/safety of albinterferon alfa-2b (albIFN), a novel, long-acting, genetic fusion polypeptide of recombinant human albumin and interferon alfa-2b, in patients with chronic hepatitis C virus (HCV) genotype 2/3. METHODS: In all, 933 patients were randomized to open-label subcutaneous treatment with pegylated interferon-alfa-2a (Peg-IFNalfa-2a) 180 µg/wk, or albIFN 900 or 1200 µg every 2 weeks for 24 weeks, each administered with oral ribavirin 800 mg/day. The primary end point of the study was sustained virologic response (SVR) (HCV-RNA level, <15 IU/mL at week 48). During the study, the data monitoring committee recommended dose modification for all patients receiving albIFN 1200 µg to 900 µg, impacting 38% of this treatment arm. RESULTS: By intention-to-treat analysis, SVR rates were 84.8% (95% confidence interval, 80.4%-88.6%), 79.8% (95% confidence interval, 74.9%-84.1%), and 80.0% (95% confidence interval, 75.1%-84.3%) with Peg-IFNalfa-2a, and albIFN 900 and 1200 µg, respectively. The primary hypothesis of noninferiority of SVR was established for albIFN 900 µg (P = .009) and 1200 µg (P = .006). Independent positive predictors of SVR by multivariate regression analysis were pretreatment HCV-RNA level less than 400,000 IU/mL, age younger than 45 years, body mass index less than 30 kg/m(2), genotype 2, normal γ-glutamyl transpeptidase and increased alanine aminotransferase levels at baseline, fibrosis stage F0-F2, no steatosis, and Asian geographic region (Peg-IFNalfa-2a only). The 3 treatment groups showed similar rates of serious (7%-8%) and severe (13%-16%) adverse events, and discontinuations owing to adverse events (3.6%-5.5%). CONCLUSION: Albinterferon alfa-2b 900 µg every 2 weeks provides an alternative efficacious treatment option in patients with chronic HCV genotype 2 or 3.

Pegylated interferon alpha therapy in acute hepatitis C: relation to hepatitis C virus-specific T cell response kinetics.

Pegylated interferon alpha (PEG IFN-alpha) improves sustained virological response rates in chronic hepatitis C, but neither its role in acute hepatitis C nor the biologic basis for its action has been defined. This prospective study assessed the efficacy of PEG IFN-alpha treatment in acute hepatitis C in relation to the kinetics of hepatitis C virus (HCV)-specific CD4(+) T cell responses during therapy and follow-up. Forty subjects with proven acute hepatitis C who received either PEG IFN-alpha plus ribavirin (n = 20) or PEG IFN-alpha monotherapy (n = 20) for 24 weeks in addition to 14 untreated subjects with acute hepatitis C were prospectively followed. Serum HCV RNA, HCV-specific CD4(+) T cell responses, and cytokine production were measured before and during therapy and at follow-up and correlated to the outcome. The sustained virological response rate was 85% with PEG IFN-alpha/ribavirin combination and 80% with PEG IFN-alpha monotherapy. Five untreated subjects had spontaneous recovery. The frequency, magnitude, and breadth of HCV-specific CD4(+) T helper 1 responses were significantly higher in treated subjects compared with untreated subjects with self-limited disease or subjects with chronic evolution. The CD4(+) T cell responses were maintained in subjects with sustained virological responses and self-limited disease but fluctuated in those who developed chronic infection. In conclusion, PEG IFN-alpha therapy in acute hepatitis induces high rates of sustained virological response and prevents choronicity, probably through efficient early stimulation of multispecific HCV-specific CD4(+) T helper 1 responses.

Kinetics of intrahepatic hepatitis C virus (HCV)-specific CD4+ T cell responses in HCV and Schistosoma mansoni coinfection: relation to progression of liver fibrosis.

The kinetics of intrahepatic hepatitis C virus (HCV)-specific CD4(+) T cell responses and their role in progression of fibrosis have not previously been characterized. Subjects with HCV/Schistosoma mansoni coinfection have a more rapid progression of HCV liver fibrosis than do those with HCV infection alone. The present prospective longitudinal study compared the liver histology, HCV-specific intrahepatic and peripheral CD4(+) T cell proliferative responses, and cytokines (enzyme-linked immunospot) in 48 subjects with unresolved acute HCV infection with or without S. mansoni coinfection, at 6-10 months after acute infection and at the end of follow-up (96+/-8.7 months), and the findings were correlated to the rate of progression of fibrosis per year. Coinfected subjects had significant worsening of fibrosis, compared with subjects with HCV infection alone. At baseline, subjects with HCV infection alone had stronger multispecific intrahepatic HCV-specific CD4(+) T helper 1 responses than did coinfected subjects, who had either no responses or weak, narrowly focused responses, and, over time, these T cell responses were maintained only in the liver. The rate of progression of fibrosis and virus load inversely correlated with intrahepatic HCV-specific CD4(+) T cell response. The present prospective analysis indicates that enhancement of progression of liver fibrosis is associated with failure to develop early, multispecific, HCV-specific CD4(+) Th1 responses, suggesting that novel therapeutic approaches inducing strong cellular immune responses might limit subsequent liver damage in individuals with chronic hepatitis C.

Peginterferon alone or with ribavirin enhances HCV-specific CD4 T-helper 1 responses in patients with chronic hepatitis C.

BACKGROUND & AIMS: Pegylated interferons (IFNs) with or without ribavirin were shown in several studies to improve sustained virologic response compared with standard IFN alpha-2 therapy. This study investigated if the greater efficacy of pegylated IFNs might be related to modulation of immunologic responses. METHODS: Hepatitis C virus (HCV)-specific CD4+ T-cell responses and cytokine production to various HCV proteins (Elispot assay) in peripheral blood were prospectively assessed in 42 patients receiving IFN alpha-2a monotherapy, peginterferon (PEG IFN) alpha-2a monotherapy, or PEG IFN alpha-2a plus ribavirin and correlated to the outcome of therapy. RESULTS: The sustained virologic response rate was significantly higher in the PEG IFN groups (42% in PEG IFN alpha-2a monotherapy and 57% in PEG IFN alpha-2a/ribavirin combination) than in the standard IFN alpha-2a group (14%). The sustained response was 48% in HCV genotype 1 patients treated with PEG IFN alpha-2a/ribavirin therapy. Pretreatment HCV-specific CD4+ responses were either weak or absent. PEG IFN alone or combined with ribavirin induced significant increase in the frequency, strength, and breadth of HCV-specific CD4+ T-cell responses with type 1 predominance; whereas interferon alpha-2a monotherapy was associated with lower, fluctuating, short-lived responses. Sustained responders maintained multispecific HCV-specific CD4+ T-cell responses with enhanced IFN-gamma production. Relapsers and partial responders initially displayed significant HCV-specific CD4+ T-cell responses that waned or were lost. CONCLUSIONS: The efficacy of PEG IFN alpha-2a alone or in combination with ribavirin in inducing high rates of sustained virologic response may be owing to the higher efficacy of PEG IFN in induction and maintenance of significant multispecific HCV-specific CD4+ T-helper 1 responses.