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

Authors: 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.; Hogdal, L.; Rehermann, B.; Dahari, H; Perelson, A. S.; Hoofnagle, J. H.; Liang, T. J.
Article Title: 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-IFNalpha-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% (p0.001). 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: Adult; Female; Humans; Middle Aged; Prospective Studies; Male; Treatment Outcome; Gene Expression Profiling; Oligonucleotide Array Sequence Analysis; Viral Load/drug effects; Hepatitis C; Drug Administration Schedule; Drug Therapy, Combination; Biological Markers/metabolism; Antiviral Agents/pharmacology/therapeutic use; Interferon-alpha/pharmacology/therapeutic use; Polyethylene Glycols/pharmacology/therapeutic use; Recombinant Proteins/pharmacology/therapeutic use; Hepatitis C, Chronic/drug therapy/genetics/virology; Interferon Regulatory Factors/genetics/metabolism; Liver/drug effects/metabolism/virology; Ribavirin/pharmacology/therapeutic use; Transcriptome/drug effects; Interferon-Alpha
Journal Title: Gut
Volume: 63
Issue: 1
ISSN: 1468-3288; 0017-5749
Publisher: Unknown  
Journal Place: England
Date Published: 2014
Start Page: 161
End Page: 169
Language: eng
Notes: LR: 20150325; ClinicalTrials.gov/NCT00718172; GEO/GSE38663; GR: P01 AI071195/AI/NIAID NIH HHS/United States; GR: P20 GM103452/GM/NIGMS NIH HHS/United States; GR: R01 AI028433/AI/NIAID NIH HHS/United States; GR: R01 AI078881/AI/NIAID NIH HHS/United States; GR: R01 OD011095/OD/NIH HHS/United States; GR: R34 HL109334/HL/NHLBI NIH HHS/United States; GR: R37 AI028433/AI/NIAID NIH HHS/United States; GR: Z99 DK999999/Intramural NIH HHS/United States; GR: ZIA DK075046-01/Intramural NIH HHS/United States; JID: 2985108R; 0 (Antiviral Agents); 0 (Biological Markers); 0 (Interferon Regulatory Factors); 0 (Interferon-alpha); 0 (Polyethylene Glycols); 0 (Recombinant Proteins); 0 (peginterferon alfa-2a); 49717AWG6K (Ribavirin); CIN: Gut. 2014 Jan;63(1):3-4. PMID: 23661602; NIHMS476815; OID: NLM: NIHMS476815; OID: NLM: PMC3778097; OTO: NOTNLM; 2013/02/08 [aheadofprint]; ppublish