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

MedStar author(s):
Citation: Gut. 63(1):161-9, 2014 Jan.PMID: 23396509Institution: MedStar Washington Hospital CenterDepartment: Medicine/GastroenterologyForm of publication: Journal ArticleMedline article type(s): Journal Article | Randomized Controlled Trial | Research Support, N.I.H., Intramural | Research Support, Non-U.S. Gov'tSubject headings: *Antiviral Agents/pd [Pharmacology] | *Hepatitis C, Chronic/dt [Drug Therapy] | *Interferon-alpha/pd [Pharmacology] | *Liver/de [Drug Effects] | *Polyethylene Glycols/pd [Pharmacology] | *Ribavirin/pd [Pharmacology] | *Transcriptome/de [Drug Effects] | *Viral Load/de [Drug Effects] | Adult | Antiviral Agents/tu [Therapeutic Use] | Biological Markers/me [Metabolism] | Drug Administration Schedule | Drug Therapy, Combination | Female | Gene Expression Profiling | Hepatitis C, Chronic/ge [Genetics] | Hepatitis C, Chronic/vi [Virology] | Humans | Interferon Regulatory Factors/ge [Genetics] | Interferon Regulatory Factors/me [Metabolism] | Interferon-alpha/tu [Therapeutic Use] | Liver/me [Metabolism] | Liver/vi [Virology] | Male | Middle Aged | Oligonucleotide Array Sequence Analysis | Polyethylene Glycols/tu [Therapeutic Use] | Prospective Studies | Recombinant Proteins/pd [Pharmacology] | Recombinant Proteins/tu [Therapeutic Use] | Ribavirin/tu [Therapeutic Use] | Treatment OutcomeLocal holdings: Available online from MWHC library: 1960 - present, Available in print through MWHC library: 1999 - February 2004ISSN:
  • 0017-5749
Name of journal: GutAbstract: 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.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.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.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.All authors: Abdalla A, Ahlenstiel G, Dahari H, Doo E, Edlich B, Feld JJ, Gara N, Ghany MG, Guedj J, Han H, Heller T, Hogdal L, Hoofnagle JH, Koh C, Liang TJ, Noureddin M, Park SH, Park YJ, Perelson AS, Rehermann B, Rotman Y, Sarkar S, Thomas E, Titerence R, Witthaus MDigital Object Identifier: Date added to catalog: 2014-04-04
Holdings
Item type Current library Collection Call number Status Date due Barcode
Journal Article MedStar Authors Catalog Article Available 23396509

Available online from MWHC library: 1960 - present, Available in print through MWHC library: 1999 - February 2004

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.

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.

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.

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.

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