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Variants in Interferon-Α Pathway Genes and Response to Treatment of Chronic Hepatitis C
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Reported by Jules Levin
DDW, May 17-22, 2008, San Diego, CA
Thomas R O'Brien1, Tania M Welzel1, Herbert L Bonkovsky2, Raymond T Chung3, Deepa Naishadham4, Elizabeth C Wright5, Stephen Chanock1, Timothy R Morgan6
1. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA, 2. Carolinas Medical Center, Charlotte, NC, USA, 3. Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA, 4. New England Research Institute, Watertown, MA, USA, 5. Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA, 6. Division of Gastroenterology, University of California - Irvine, Irvine, CA, USA
ABSTRACT from program book
Background: Combination treatment with pegInterferon-Α and ribavirin is the current recommended therapy for chronic hepatitis C virus (HCV) infection, but results in a sustained virological response (SVR) in only half of patients. Because genes involved in the Interferon-Α pathway may affect anti-viral responses, the relationship between variants in these genes and SVR was analyzed among participants in the recently completed "Hepatitis C Antiviral Long-Term Treatment against Cirrhosis" (HALT-C) trial.
Methods: Patients in the HALT-C trial had advanced chronic hepatitis C (Ishak fibrosis score >2) and had previously failed to respond to interferon-based treatment. During the 'lead-in phase' of the trial participants were treated with peginterferon alfa-2a and ribavirin. Subjects with no detectable HCV RNA at week 20 remained on treatment through week 48 and were followed until week 72; those who had no detectable HCV RNA at week 72 were considered to have had an SVR. Subjects with detectable HCV RNA at week 20 were considered non-responders. This analysis compared participants with an SVR to non-responders (patients with relapse were excluded from analysis). Host genotyping, using optimized TaqMan assays, was performed for polymorphisms found in 13 genes in the Interferon-Α pathway. The analysis was restricted to European American and African American patients. A priori statistical power was low for African American participants.
Results:
Among European Americans, SVR was associated with genetic polymorphisms in IFNAR2 exon2 (SVR, 26/137 [19%]; non-responders, 52/437 [12%]; OR, 1.73; 95% CI, 1.04-2.91), EIF2AK2 intron 4 (SVR, 95/136 [70%]; non-responders, 257/429 [60%]; OR, 1.55; 95% CI, 1.03-2.35) and the TYK2 promoter region (SVR, 47/138 [34%]; non-responders, 112/439 [26%]; OR, 1.51; 95% CI, 1.00-2.28).
An especially strong relationship between the TYK2 promoter variant and SVR was present among African American patients in that all 10 with SVR carried the TYK2 polymorphism compared to 68 of 120 (57%) African American non-responders (p=0.006).
To exclude genotyping error as an explanation for the results among African American patients, we sequenced the region that includes the TYK2 promoter variant and found that the results were fully concordant. Consistent results were obtained in analyses that controlled for viral genotype, fibrosis stage, and dosage of peginterferon alfa-2a/ribavirin.
Conclusion: Genetic polymorphisms in the Interferon-Α pathway may have an effect on responses to antiviral therapy of chronic hepatitis C.
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