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Gut. 2014 Jan;63(1):161-9. doi: 10.1136/gutjnl-2012-303852. Epub 2013 Feb 8.

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

Author information

1
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, , Bethesda, Maryland, USA.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00718172.

KEYWORDS:

Hepatitis C; Interferon-Alpha

PMID:
23396509
PMCID:
PMC3778097
DOI:
10.1136/gutjnl-2012-303852
[Indexed for MEDLINE]
Free PMC Article

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