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.
  
  
  METHODS
  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.
authors: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, , Bethesda, Maryland, USA.
authors: Yaron
authors: Y
authors: Rotman
authors: Mazen
authors: M
authors: Noureddin
authors: Jordan J
authors: JJ
authors: Feld
authors: Jeremie
authors: J
authors: Guedj
authors: Michael
authors: M
authors: Witthaus
authors: Hwalih
authors: H
authors: Han
authors: Yoon J
authors: YJ
authors: Park
authors: Su-Hyung
authors: SH
authors: Park
authors: Theo
authors: T
authors: Heller
authors: Marc G
authors: MG
authors: Ghany
authors: Edward
authors: E
authors: Doo
authors: Christopher
authors: C
authors: Koh
authors: Adil
authors: A
authors: Abdalla
authors: Naveen
authors: N
authors: Gara
authors: Souvik
authors: S
authors: Sarkar
authors: Emmanuel
authors: E
authors: Thomas
authors: Golo
authors: G
authors: Ahlenstiel
authors: Birgit
authors: B
authors: Edlich
authors: Rachel
authors: R
authors: Titerence
authors: Leah
authors: L
authors: Hogdal
authors: Barbara
authors: B
authors: Rehermann
authors: Harel
authors: H
authors: Dahari
authors: Alan S
authors: AS
authors: Perelson
authors: Jay H
authors: JH
authors: Hoofnagle
authors: T Jake
authors: TJ
authors: Liang
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D020869:Gene Expression Profiling; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011092:Polyethylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012254:Ribavirin / Q000494:pharmacology* / Q000627:therapeutic use; D059467:Transcriptome / Q000187:drug effects*; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a
keywords: Hepatitis C; Interferon-Alpha
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