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

Gut, 2014/1;63(1):161-9.

Rotman Y[1], Noureddin M, Feld JJ, Guedj J, Witthaus M, Han H, Park YJ, Park SH, Heller T, Ghany MG, Doo E, Koh C, Abdalla A, Gara N, Sarkar S, Thomas E, Ahlenstiel G, Edlich B, Titerence R, Hogdal L, Rehermann B, Dahari H, Perelson AS, Hoofnagle JH, Liang TJ

Affiliations

PMID: 23396509DOI: 10.1136/gutjnl-2012-303852

Impact factor: 31.793

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.

Keywords: Hepatitis C; Interferon-Alpha

MeSH terms
Adult; Antiviral Agents; Biomarkers; Drug Administration Schedule; Drug Therapy, Combination; Female; Gene Expression Profiling; Hepatitis C, Chronic; Humans; Interferon Regulatory Factors; Interferon-alpha; Liver; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Polyethylene Glycols; Prospective Studies; Recombinant Proteins; Ribavirin; Transcriptome; Treatment Outcome; Viral Load
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