Journal
HEPATOLOGY
Volume 49, Issue 6, Pages 1847-1858Publisher
WILEY
DOI: 10.1002/hep.22877
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Funding
- National Institute of Diabete & Digestive & Kidney Diseases
- National Institute of Allergy and Infectious Diseases (NIAID)
- National Cancer Institute
- National Center for Minority Health and Health Disparities
- National Center for Research Resources
- National Institutes of Health
- Hoffmann-La Roche, Inc.
- NATIONAL CANCER INSTITUTE [ZIABC010791, ZIACP005782] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR000042, M01RR000827, M01RR000633, M01RR006192, M01RR001066, M01RR000043, M01RR000051, M01RR000065] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [N01DK092318, N01DK092320, N01DK092326, ZIADK075009, N01DK092324, N01DK092327, N01DK092328, N01DK092325, N01DK092319, N01DK092322, N01DK092323, N01DK092321] Funding Source: NIH RePORTER
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Combination treatment with pegylated-interferon-alpha (PEG IFN-alpha) and ribavirin, the current recommended therapy for chronic hepatitis C virus (HCV) infection, results in a sustained virological response (SVR) in only about half of patients. Because genes involved in the interferon-alpha pathway may affect antiviral responses, we analyzed the relationship between variants in these genes and SVR among participants in the Hepatitis C Antiviral Long-Term treatment Against Cirrhosis (HALT-C) trial. Patients had advanced chronic hepatitis C that had previously failed to respond to interferon-based treatment. Participants were treated with peginterferonce-alpha 2a and ribavirin during the trial. Subjects with undetectable HCV RNA at week 72 were considered to have had an SVR. Subjects with detectable HCV RNA at week 20 were considered nonresponders. We used TaqMan assays to genotype 56 polymorphisms found in 13 genes in the interferon-alpha pathway. This analysis compares genotypes for participants with an SVR to nonresponders. The primary analysis was restricted to European American participants because a priori statistical power was low among the small number (n = 131) of African American patients. We used logistic regression to control the effect of other variables that are associated with treatment response. Among 581 European American patients, SVR was associated with IFNAR1 IVSI-22G (adjusted odds ratio, 0.57; P = 0.02); IFNAR2 Ex2-33C (adjusted odds ratio, 2.09; P = 0.02);JAK1 IVS22 + 112T (adjusted odds ratio, 1.66; P = 0.04); and ADAR Ex9 + 14A (adjusted odds ratio, 1.67; P = 0.03). For the TYK2-2256A promoter region variant, a borderline association was present among European American participants (OR, 1.51; P = 0.05) and a strong relationship among, African American patients; all 10 with SVR who were genotyped for TYK2-2256 carried the A variant compared with 68 of 120 (57%) nonresponders (P = 0.006). Conclusion. Genetic polymorphisms in the interferon-alpha pathway may affect responses to antiviral therapy of chronic hepatitis C. (HEPATOLOGY 2009;49:1847-1858.)
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