Hepatic gene expression during treatment with peginterferon ... : Hepatology (original) (raw)

Liver Biology/Pathobiology

Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response

Feld, Jordan J.1; Nanda, Santosh1; Huang, Ying1; Chen, Weiping2; Cam, Maggie2; Pusek, Susan N.3; Schweigler, Lisa M.3; Theodore, Dickens3; Zacks, Steven L.3; Liang, Jake T.1*; Fried, Michael W.3

1_Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD_

2_Microarray Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD_

3_University of North Carolina, Chapel Hill, NC_

*Address reprint requests to: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9B16, 10 Center Drive, MSC 1800, Bethesda MD 20892-1800

Email:[email protected]

Received 17 March 2007; Accepted 2 June 2007

Published online 10 October 2007 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: Hoffmann-La Roche; Grant sponsor: General Clinical Research Center of the University of North Carolina; Grant Number: RR 000046; Grant sponsor: Midcareer Investigator Award in Patient-Oriented Research; Grant Number: DK06614; Grant sponsor: Doris Duke Fellowship (LMS); Grant sponsor: Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health).

Potential conflict of interest: Dr. Fried is a consultant for and received grants from Roche. Dr. Zacks is on the speakers' bureau of Roche.

These authors contributed equally to this study.

fax: 301 402 0491

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.

Abbreviations: ECM, extracellular matrix; HCV, hepatitis C virus; HSC, hepatic stellate cell; IFN, interferon; IRF, interferon regulatory factor; ISG, interferon-stimulated gene; ISRE, interferon-sensitive response element; Mx, myxovirus resistance; OAS, oligoadenylate synthetase; PBMC, peripheral blood mononuclear cell; PCR, polymerase chain reaction; PIAS, protein inhibitor of activated signal transducer and activator of transcription; PP2A, protein phosphatase 2A; PPAR-γ, peroxisome proliferator-activated receptor gamma; RIG-I, retinoic acid–inducible gene I; RR, rapid responder; SOCS, suppressor of cytokine signaling; SR, slow responder; STAT, signal transducer and activator of transcription; SUMO, small ubiquitin-like modifier; SVR, sustained virological response; TGF-β, transforming growth factor beta; TIMP, tissue inhibitor of metallopeptidase; USP, ubiquitin-specific peptidase.