Polymorphism Associated With Good Antiviral Response But Also Depression in HCV

Nancy A. Melville

November 03, 2010

November 3, 2010 (San Antonio, Texas) — Researchers say they have identified a genetic polymorphism in the promoter region of interferon alpha/beta receptor 1 (IFNAR1), which increases the risk for major depression in patients with hepatitis C virus (HCV) being treated with pegylated interferon and ribavirin.

The study involved 170 treatment-naive patients with HCV infection who were genotyped for polymorphism –408 in the promoter regions of IFNAR1 (C/C C/T T/T) and treated with pegylated interferon and ribavirin. The results indicate that those carrying the C/C allele had a greater risk of developing major depression, but also had an increased likelihood of HCV viral clearance.

Previous research has shown that as much as 20% to 30% of hepatitis C patients receiving antiviral treatment experience major depression, which can result in dose reductions and a shorter duration of treatment. The need to identify patients at risk is therefore exceptionally pressing, according to the study's lead author, Muhamad Aly Rifai, MD, from the Lehigh Valley Health Network in Bethlehem, Pennsylvania.

"The identification of patients with this polymorphism may be useful in helping us determine who is at a greater risk of depression and tailor preventive treatment strategies to prevent discontinuation or adverse effects during their treatment," Dr. Rifai told attendees here at the American College of Gastroenterology 2010 Annual Scientific Meeting and Postgraduate Course.

In addition to genotyping, patients were assessed using the Center for Epidemiological Studies Depression Scale. Patients completed visual analog self-report questionnaires before HCV antiviral treatment, and at weeks 0, 2, 4, 6, 8, 12, 16, 20, and 24 of treatment. Kaplan–Meier analyses were used to compare the incidence of major depression between different genetic profiles.

As is consistent with previous research, the results indicated that 28% of patients receiving the antiviral treatment developed major depression (47 of 170).

According to the Mantel–Cox rank test, the C/C allele was associated with an increased rate of developing major depression (P < .05) and an increased rate of HCV viral clearance (P = .0081).

Dr. Rifai noted that previous research has also suggested an improved HCV clearance rate with the C/C allele. "There have been multiple reports from Japanese researchers that this allele is associated with an improved likelihood of HCV viral clearance; however, the numbers were low."

The C/T and T/T alleles, meanwhile, appeared protective regarding the risk of developing major depression (P = .012).

The differences in the genetic groups were significant in a Cox regression analysis that was adjusted for age, sex, response to interferon alpha treatment, viral genotype, and previous psychiatric history (χ2, 8.02; df, 1; P = .005).

"The findings suggest that incorporating genomic predictors in a treatment strategy may help guide the process of determining whether or not to initiate antiviral treatment in patients with hepatitis C," Dr. Rifai said.

The risk of depression among hepatitis C patients using antiviral medications represents a substantial concern for physicians, and the findings could represent valuable information to help address that concern, said session moderator Paul Pockros, MD, head of the Division of Gastroenterology/Hepatology and director of the Scripps Clinic Liver Research Consortium at The Scripps Clinic in La Jolla, California.

"The presentation was provocative because treatment-related depression is extremely common and is probably the single biggest reason patients fear [pegylated interferon and ribavirin] therapy and are poorly adherent to treatment," said Dr. Pockros.

"If this test were validated, it would offer another genomic pretreatment test that would be useful, just as [interleukin] 28B testing, and likely ITPA deficiency testing, will be."

The study received no funding. Dr. Rifai has disclosed no relevant financial relationships. Dr. Pockros reports being a consultant, speaker, and/or on the advisory board for Genentech, Vertex, Merck, Gilead, BMS, Abbott, Phenomix, Tibotec, Pharmasset, Pfizer, Conatus, 3RT, Novartis, J&J, Achillion, and Regulus; and receiving grants or contracts from Genentech, Vertex, Gilead, BMS, Abbott, Quest, Conatus, Tibotec, Pfizer, Globeimmune, Debio, Novartis, and Mochida.

American College of Gastroenterology (ACG) 2010 Annual Scientific Meeting and Postgraduate Course: Abstract 32. Presented October 19, 2010.

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