Variants in Interferon-á Pathway Genes and Response to Treatment of Chronic Hepa

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Variants in Interferon-á Pathway Genes and Response to Treatment of

Chronic Hepatitis C

Reported by Jules Levin

DDW, May 17-22, 2008, San Diego, CA

R O'Brien1, Tania M Welzel1, Herbert L Bonkovsky2, T

Chung3, Deepa Naishadham4, C 5, Chanock1,

R 6

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-á 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-á 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-á 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-á pathway may

have an effect on responses to antiviral therapy of chronic hepatitis

C.