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

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 IFN-responsiveness in HCV-infected liver.

• Authors: 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 Hogdal, Barbara Rehermann, Harel Dahari, Alan S Perelson, Jay H Hoofnagle, T Jake Liang
• Journal: Gut (Gut) Vol. 63 Issue 1 Pg. 161-9 (Jan 2014) ISSN: 1468-3288 [Electronic] England
• PMID: 23396509 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Biomarkers
• Interferon Regulatory Factors
• Interferon-alpha
• Recombinant Proteins
• Polyethylene Glycols
• Ribavirin
• peginterferon alfa-2a

Topics

• Adult
• Antiviral Agents (pharmacology, therapeutic use)
• Biomarkers (metabolism)
• Drug Administration Schedule
• Drug Therapy, Combination
• Female
• Gene Expression Profiling
• Hepatitis C, Chronic (drug therapy, genetics, virology)
• Humans
• Interferon Regulatory Factors (genetics, metabolism)
• Interferon-alpha (pharmacology, therapeutic use)
• Liver (drug effects, metabolism, virology)
• Male
• Middle Aged
• Oligonucleotide Array Sequence Analysis
• Polyethylene Glycols (pharmacology, therapeutic use)
• Prospective Studies
• Recombinant Proteins (pharmacology, therapeutic use)
• Ribavirin (pharmacology, therapeutic use)
• Transcriptome (drug effects)
• Treatment Outcome
• Viral Load (drug effects)