Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response
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Open Access
- 29 October 2007
- journal article
- research article
- Published by Wolters Kluwer Health in Hepatology
- Vol. 46 (5) , 1548-1563
- https://doi.org/10.1002/hep.21853
Abstract
The reasons for hepatitis C treatment failure remain unknown but may be related to different host responses to therapy. In this study, we compared hepatic gene expression in patients prior to and during peginterferon and ribavirin therapy. In the on-treatment group, patients received either ribavirin for 72 hours prior to peginterferon alpha-2a injection or peginterferon alpha-2a for 24 hours, prior to biopsy. The patients were grouped into rapid responders (RRs) with a greater than 2-log drop and slow responders (SRs) with a less than 2-log drop in hepatitis C virus RNA by week 4. Pretreatment biopsy specimens were obtained from a matched control group. The pretreatment patients were grouped as RRs or SRs on the basis of the subsequent treatment response. Gene expression profiling was performed with Affymetrix microarray technology. Known interferon-stimulated genes (ISGs) were induced in treated patients. In the pretreatment group, future SRs had higher pretreatment ISG expression than RRs. On treatment, RRs and SRs had similar absolute ISG expression, but when it was corrected for the baseline expression with the pretreatment group, RRs showed a greater fold change in ISGs, whereas SRs showed a greater change in interferon (IFN)-inhibitory pathways. The patients pretreated with ribavirin had heightened induction of IFN-related genes and down-regulation of genes involved in IFN inhibition and hepatic stellate cell activation. Conclusion: These data suggest that ISG inducibility is important for the treatment response and that ribavirin may improve outcomes by enhancing hepatic gene responses to peginterferon. Collectively, these mechanisms may provide a molecular basis for the improved efficacy of combination therapy.Keywords
Funding Information
- Hoffmann-La Roche
- General Clinical Research Center of the University of North Carolina (RR 000046)
- Midcareer Investigator Award in Patient-Oriented Research (DK06614)
- Doris Duke Fellowship (LMS)
- Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health)
This publication has 31 references indexed in Scilit:
- Changes in Gene Expression during Pegylated Interferon and Ribavirin Therapy of Chronic Hepatitis C Virus Distinguish Responders from Nonresponders to Antiviral TherapyJournal of Virology, 2007
- Regulation of Interferon Regulatory Factor-3 by the Hepatitis C Virus Serine ProteaseScience, 2003
- Ribavirin Treatment Up-Regulates Antiviral Gene Expression via the Interferon-Stimulated Response Element in Respiratory Syncytial Virus-Infected Epithelial CellsJournal of Virology, 2003
- Peginterferon Alfa-2a plus Ribavirin for Chronic Hepatitis C Virus InfectionNew England Journal of Medicine, 2002
- Transcriptional regulation of hepatic stellate cell activationGut, 2002
- Mechanism of action of ribavirin in the combination treatment of chronic HCV infectionHepatology, 2002
- Transcriptional Regulation in Hepatic Stellate CellsSeminars in Liver Disease, 2001
- Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trialPublished by Elsevier ,2001
- Use of real-time gene-specific polymerase chain reaction to measure RNA expression of three family members of rat cytochrome P450 4AJournal of Biochemical and Molecular Toxicology, 2001
- Peginterferon Alfa-2a in Patients with Chronic Hepatitis C and CirrhosisNew England Journal of Medicine, 2000