Gastroenterology

Gastroenterology

Volume 139, Issue 1, July 2010, Pages 154-162.e4
Gastroenterology

Clinical—Liver, Pancreas, and Biliary Tract
Ribavirin Improves Early Responses to Peginterferon Through Improved Interferon Signaling

https://doi.org/10.1053/j.gastro.2010.03.037Get rights and content

Background & Aims

The therapeutic mechanisms of ribavirin for hepatitis C are unclear. Microarray analyses have shown that ribavirin increases induction of interferon-stimulated genes. We evaluated viral kinetics, serum cytokine expression, and viral mutagenesis during early stages of peginterferon therapy with and without ribavirin.

Methods

Fifty patients with chronic hepatitis C virus (HCV) infection genotype 1 were randomly assigned to groups that were given peginterferon α-2a, with or without ribavirin, for 4 weeks; all patients then received an additional 44 weeks of combination therapy. First- and second-phase viral kinetics were evaluated. Serum levels of interferon-γ−inducible protein-10 (IP10), monokine induced by interferon-γ, and monocyte chemoattractant protein 1 were quantified as measures of the interferon-stimulated genes response. NS5A and NS5B were partially sequenced, and mutation rates were calculated.

Results

The first-phase decrease in HCV RNA was similar between groups. Patients who received ribavirin had a more rapid second-phase decrease, compared with patients who did not receive ribavirin—particularly those with an adequate first-phase decrease (0.61 vs 0.35 log10 IU/mL/week; P = .018). At 12 hours, fold induction of serum IP10 was higher in patients given the combination therapy than those given peginterferon only (7.6- vs 3.8-fold; P = .01); however, the difference was greatest in patients with an adequate first-phase decrease in HCV RNA. IP10-induction correlated with first- and second-phase kinetics and with ribavirin serum concentrations on day 3. HCV mutation rates were similar between groups.

Conclusions

Ribavirin improves the kinetics of the early response to therapy in patients with an adequate initial response to peginterferon. Induction of interferon-stimulated cytokines correlates with viral kinetics following ribavirin therapy, suggesting that ribavirin promotes interferon signaling.

Section snippets

Materials and Methods

Treatment-naïve patients infected with HCV genotype 1 evaluated at the Clinical Center of the National Institutes of Health were recruited for study participation. For study inclusion, patients had to be at least 18 years of age with chronic HCV infection and a liver biopsy within 2 years of study entry. Patients with hepatitis B or human immunodeficiency virus coinfection were excluded, as were those with other causes of chronic liver disease or comorbidities precluding interferon therapy. The

Results

Baseline characteristics were similar between the 2 groups (Table 1). Two patients, 1 from each group, were excluded from the analysis. One patient who was initially reported to have genotype 1 infection was found to have genotype 6 infection by sequencing of the NS5B region. The second patient suffered a cerebrovascular accident during the 2nd week of therapy and stopped treatment early, precluding viral kinetic calculations.

Discussion

Despite the major contribution that ribavirin provides in improving treatment outcomes in chronic HCV infection, the mechanism by which it acts has been hard to tease apart. The poor understanding of its mechanism of action has made development of ribavirin analogues difficult. A close examination of early viral kinetics, mutagenesis, and cytokine levels during peginterferon therapy with and without ribavirin offers some clues to understanding the action of this important adjunctive agent.

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    Conflicts of interest This author discloses the following: Dr Feld reports being a member of the advisory board for Roche Canada and Schering-Plough Canada. The remaining authors disclose no conflicts.

    Funding This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases.

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