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

被引：42

作者：

Rotman, Yaron ^{[1
]}

Noureddin, Mazen ^{[1
]}

Feld, Jordan J. ^{[1
]}

Guedj, Jeremie ^{[2
,3
,4
]}

Witthaus, Michael ^{[1
]}

Han, Hwalih ^{[1
]}

Park, Yoon J. ^{[1
]}

Park, Su-Hyung ^{[1
]}

Heller, Theo ^{[1
]}

Ghany, Marc G. ^{[1
]}

Doo, Edward ^{[5
]}

Koh, Christopher ^{[1
]}

Abdalla, Adil ^{[1
]}

Gara, Naveen ^{[1
]}

Sarkar, Souvik ^{[1
]}

Thomas, Emmanuel ^{[1
]}

Ahlenstiel, Golo ^{[1
]}

Edlich, Birgit ^{[1
]}

Titerence, Rachel ^{[1
]}

Hogdal, Leah ^{[1
]}

Rehermann, Barbara ^{[1
]}

Dahari, Harel ^{[2
,6
,7
]}

Perelson, Alan S. ^{[2
]}

Hoofnagle, Jay H. ^{[1
]}

Liang, T. Jake ^{[1
]}

机构：

[1] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA

[2] Los Alamos Natl Lab, Theoret Biol & Biophys Grp, Los Alamos, NM USA

[3] INSERM, UMR 738, F-75018 Paris, France

[4] Univ Paris Diderot, Sorbonne Paris Cite, UMR 738, F-75018 Paris, France

[5] NIDDK, Liver Dis Res Branch, NIH, Bethesda, MD 20892 USA

[6] Univ Illinois, Dept Med, Chicago, IL USA

[7] Loyola Univ Chicago, Dept Med, Div Hepatol, Maywood, IL USA

来源：

GUT | 2014年 / 63卷 / 01期

关键词：

Hepatitis C; Interferon-Alpha; PEGYLATED INTERFERON; COMBINATION THERAPY; VIRUS-INFECTION; PLUS RIBAVIRIN; ALPHA; NONRESPONDERS; PEGINTERFERON; RESPONDERS; INDUCTION; MECHANISM;

D O I：

10.1136/gutjnl-2012-303852

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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 4weeks of ribavirin (1000-1200mg/d) or none, followed by PEG-IFN-2a and ribavirin at standard doses and durations. Patients were also randomised to a liver biopsy 24h before or 6h 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 4weeks of ribavirin monotherapy, hepatitis C virus (HCV) levels decreased by 0.50.5 log(10) (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.

引用

页码：161 / 169

页数：9

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