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Gene Expression Profiles Predict Emergence of Psychiatric Adverse Events in HIV/HCV-Coinfected Patients on Interferon-Based HCV Therapy

Rasimas, Joseph MD, PhD*,†; Katsounas, Antonios MD, PhD‡,§; Raza, Haniya MD*,‖; Murphy, Alison A. BA; Yang, Jun PhD; Lempicki, Richard A. PhD; Osinusi, Anu MD, MPH¶,#; Masur, Henry MD**; Polis, Michael MD; Kottilil, Shyam MD, PhD; Rosenstein, Donald MD*,††

JAIDS Journal of Acquired Immune Deficiency Syndromes: July 1st, 2012 - Volume 60 - Issue 3 - p 273–281
doi: 10.1097/QAI.0b013e31824c17c4
Clinical Science

Background: The efficacy of pegylated interferon-α and ribavirin (pegIFN/RBV) in the treatment of Hepatitis C infection is limited by psychiatric adverse effects (IFN-PE). Our study examined the ability of differential gene expression patterns before therapy to predict emergent IFN-PE among 28 HIV/HCV-coinfected patients treated with pegIFN-α2b/RBV.

Methods: Patients dually infected with HIV and HCV were evaluated at baseline and during treatment by board-certified psychiatrists who classified patients into 2 groups: those who developed IFN-PE and those who did not (IFN-NPE). Gene expression analysis (Affymetrix HG-U133A) was performed using peripheral blood mononuclear cells before and after initiation of treatment. Analysis of Variance, post hoc analysis based on pair-wise comparisons, and functional annotation analysis identified differentially expressed genes within and between groups. Prediction analysis for microarrays was used to test the predictive ability of selected genes.

Results: Twenty-four genes (16 upregulated and 8 downregulated) that were differentially expressed at baseline in patients who subsequently developed IFN-PE compared with the IFN-NPE group showed the ability to predict IFN-PE with an accuracy of 82%. In 16 patients with IFN-PE, 135 genes (117 upregulated; 18 downregulated) were significantly modulated after treatment. Of these, 10 genes have already been shown to be associated with neuropsychiatric illnesses and were significantly modulated only in patients who experienced IFN-PE.

Conclusions: We describe a novel molecular diagnostic biomarker panel to predict emergent IFN-PE in HIV/HCV-coinfected patients undergoing pegIFN/RBV treatment, which may improve the identification of patients at greatest risk for IFN-PE and suggest candidate therapeutic targets for preventing or treating IFN-PE.

Supplemental Digital Content is Available in the Text.

*Office of the Clinical Director, National Institute of Mental Health, National Institutes of Health, Bethesda, MD

Department of Psychiatry, Penn State College of Medicine, Hershey, PA

Laboratory of Immunopathogenesis and Bioinformatics, SAIC-Frederick Inc, NCIFrederick, Frederick, MD

§Department of Gastroenterology and Hepatology, Hufelandstrasse, D-Essen, Germany

Department of Psychiatry and Behavioral Sciences, Children's National Medical Center, Washington, DC

Section of Immunopathogenesis, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD

#Clinical Research Directorate, Clinical Monitoring Research Program, SAIC-Frederick Inc, NCIFrederick, Frederick, MD

**Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD

††Department of Psychiatry, University of North Carolina, Chapel Hill, NC

Correspondence to: Shyam Kottilil, MD, PhD, LIR, National Institute of Allergy and Infectious Diseases, National Institute of Health, Building 10, Room 11N204, 10 Center Drive, Bethesda, MD 20892 (e-mail: skottilil@niaid.nih.gov).

This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. This research was supported in whole or in part by the Intramural Research Program of the NIH (National Institute of Allergy and Infectious Diseases).

Presented in part as one of the Presidential Plenary III talks on Tuesday, November 3, 2009 at the American Association for the Study of Liver Diseases, The Liver Meeting 2009, Boston, MA.

The authors contribution are as follows—R.J., K.S., P.M., and R.D.: study design, protocol writing, patient management, and article preparation. K.A., M.A., Y.J., and L.R.: Laboratory studies, data analysis, and article preparation. R.H., O.A., and M.H.: patient management and article preparation.

The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions this article on the journal's Web site (www.jaids.com).

The authors have no conflicts of interest to disclose.

Received October 13, 2011

Accepted January 19, 2012

© 2012 Lippincott Williams & Wilkins, Inc.