Hepatic SOCS3 expression is strongly associated with non-response to therapy and race in HCV and HCV/HIV infection☆

Received 29 May 2008; received in revised form 11 November 2008; accepted 9 December 2008. published online 17 February 2009.

Background/Aims

The response rates of HCV infection to interferon therapy vary depending on viral and host factors. We hypothesized that key regulators of the IFN signaling pathway are predictive of treatment outcome.

Methods

We measured the expression of signal transducer and activator of transcription 1 (STAT1) and suppressor of cytokine signaling 3 (SOCS3) in pretreatment liver biopsies. Staining quantitation was compared to treatment outcomes.

Results

Forty-nine patients with HCV and 25 patients with HCV/HIV infection treated with peginterferon/ribavirin were analyzed. Pretreatment hepatic SOCS3 expression was higher in non-responders than responders. Genotype 1 responders had similar levels of SOCS3 as genotype 2/3 responders. African Americans (AA) had higher hepatic SOCS3 than non-AA. Pretreatment hepatic SOCS3 was the most powerful independent predictor of sustained virologic response (SVR), even more so than genotype by logistic regression analysis. Failure to achieve SVR and AA race were independently associated with high hepatic SOCS3 levels. The hepatic expression of STAT-1 did not differ between responders and non-responders.

Conclusions

Our data indicate that hepatic SOCS3 is a stronger baseline predictor of antiviral response than viral genotype. Poor response to antiviral therapy in AA may be associated with higher hepatic SOCS3 expression.

Associate Editor: F. Zoulim

Abbreviations: IFN, interferon, RBV, ribavirin, STAT1, signal transducer and activator of transcription 1, SOCS3, suppressor of cytokine signaling 3, HCV, hepatitis C virus, AA, African Americans, PEG-IFN, peginterferon

Keywords: Suppressor of cytokine signaling 3, Hepatitis C virus, HCV/HIV coinfection, Race, Immunohistochemistry, Signal transducer and activator of transcription 1

1 Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA

2 Department of Medicine, Ilsan Paik Hospital, Inje University, Goyang, Republic of Korea

3 Biostatistics Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

4 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Corresponding author. Tel.: +1 617 724 7562; fax: +1 617 643 0446.

☆ Financial support: NIH AI069939, DK078772 (to R.T.C.) and Massachusetts Biomedical Research Corporation Tosteson Postdoctoral Fellowship (to A.W.T.). The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript.

PII: S0168-8278(09)00012-9

doi:10.1016/j.jhep.2008.12.021

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