Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C

Yaron Rotman, Mazen Noureddin, Jordan J. Feld, Jeremie Guedj, Michael Witthaus, Hwalih Han, Yoon J. Park, Su Hyung Park, Theo Heller, Marc G. Ghany, Edward Doo, Christopher Koh, Adil Abdalla, Naveen Gara, Souvik Sarkar, Emmanuel Thomas, Golo Ahlenstiel, Birgit Edlich, Rachel Titerence, Leah HogdalBarbara Rehermann, Harel Dahari, Alan S. Perelson, Jay H. Hoofnagle, T. Jake Liang

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Objective Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C. Design 70 treatment-naive patients were randomised to 4 weeks of ribavirin (1000-1200 mg/d) or none, followed by PEG-IFNα-2a and ribavirin at standard doses and durations. Patients were also randomised to a liver biopsy 24 h before or 6 h after starting PEG-IFN. Hepatic gene expression was assessed by microarray and interferon-stimulated gene (ISG) expression quantified by nCounter platform. Temporal changes in ISG expression were assessed by qPCR in peripheral-blood mononuclear cells (PBMC) and by serum levels of IP-10. Results After 4 weeks of ribavirin monotherapy, hepatitis C virus (HCV) levels decreased by 0.5±0.5 log10 (p=0.009 vs controls) and ALT by 33% (p<0.001). Ribavirin pretreatment, while modestly augmenting ISG induction by PEG-IFN, did not modify the virological response to subsequent PEG-IFN and ribavirin treatment. However, biochemical, but not virological, response to ribavirin monotherapy predicted response to subsequent combination treatment (rapid virological response, 71% in biochemical responders vs 22% non-responders, p=0.01; early virological response, 100% vs 68%, p=0.03; sustained virological response 83% vs 41%, p=0.053). Ribavirin monotherapy lowered serum IP-10 levels but had no effect on ISG expression in PBMC. Conclusions Ribavirin is a weak antiviral but its clinical effect seems to be mediated by a separate, indirect mechanism, which may act to reset IFNresponsiveness in HCV-infected liver.

Original languageEnglish (US)
Pages (from-to)161-169
Number of pages9
JournalGut
Volume63
Issue number1
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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    Rotman, Y., Noureddin, M., Feld, J. J., Guedj, J., Witthaus, M., Han, H., Park, Y. J., Park, S. H., Heller, T., Ghany, M. G., Doo, E., Koh, C., Abdalla, A., Gara, N., Sarkar, S., Thomas, E., Ahlenstiel, G., Edlich, B., Titerence, R., ... Liang, T. J. (2014). Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C. Gut, 63(1), 161-169. https://doi.org/10.1136/gutjnl-2012-303852