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Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C
  1. Yaron Rotman1,
  2. Mazen Noureddin1,
  3. Jordan J Feld1,
  4. Jeremie Guedj2,3,
  5. Michael Witthaus1,
  6. Hwalih Han1,
  7. Yoon J Park1,
  8. Su-Hyung Park1,
  9. Theo Heller1,
  10. Marc G Ghany1,
  11. Edward Doo4,
  12. Christopher Koh1,
  13. Adil Abdalla1,
  14. Naveen Gara1,
  15. Souvik Sarkar1,
  16. Emmanuel Thomas1,
  17. Golo Ahlenstiel1,
  18. Birgit Edlich1,
  19. Rachel Titerence1,
  20. Leah Hogdal1,
  21. Barbara Rehermann1,
  22. Harel Dahari2,5,6,
  23. Alan S Perelson2,
  24. Jay H Hoofnagle1,
  25. T Jake Liang1
  1. 1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
  2. 2Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, USA
  3. 3INSERM, UMR 738, F-75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, UMR 738, F-75018 Paris, France
  4. 4Liver Disease Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
  5. 5Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
  6. 6Department of Medicine, Division of Hepatology, Loyola University Chicago, Maywood, Illinois, USA
  1. Correspondence to Dr Yaron Rotman, NIH, NIDDK, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Building 10, Room 9C434, MSC1800, Bethesda, MD 20892-1800, USA; rotmany{at}mail.nih.gov

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.

  • Hepatitis C
  • Interferon-Alpha

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