Replicated association between an IL28B gene variant and a sustained response to pegylated interferon and ribavirin

Abstract

Background & aims: Patients with chronic hepatitis C virus (HCV) infections are treated with pegylated interferon and ribavirin (PEG-IFN/RBV), which is effective in less than 50% of those infected with HCV genotype 1. Genome-wide association studies have linked response to PEG-IFN/RBV with common single nucleotide polymorphisms in the vicinity of interferon (IFN)-lambda genes on chromosome 19. We investigated the association between the polymorphism rs12979860 and treatment response in a diverse cohort of chronic HCV patients.

Methods: A cross-sectional study of 1021 consecutive patients enrolled in the Duke Hepatology Clinic Research Database and Biorepository. We analyzed DNA, clinical and demographic data, along with validated data of the response of 231 subjects to PEG-IFN/RBV. The study included Caucasians (n = 178), African Americans (n = 53), and HCV genotypes 1 (n = 186) and 2/3 (n = 45). The rs12979860 genotype was tested for an association with sustained virologic response, defined as undetectable levels of HCV RNA 24 weeks after treatment ended.

Results: The rs12979860 CC genotype (found in approximately 40% of Caucasians) predicted a sustained virologic response to therapy among Caucasians (odds ratio, 5.79; 95% confidence interval, 2.67-12.57; P = 9.0 x 10(-6)), independent of HCV genotype and other covariates. Rs12979860 CC predicted a sustained response with 78% specificity and 65% sensitivity in patients infected with HCV genotype 1).

Conclusions: rs12979860 genotype is a significant independent predictor of response to PEG-IFN/RBV in patients with chronic HCV infection; tests for this genotype might be used to determine the best course of treatment for patients considering antiviral therapy.

Figure 1. Flow diagram illustrating selection of subjects from the Duke database for analysis

Figure 2. Association between rs12979860 genotype and PEG-IFN/RBV treatment response in Caucasian and African American chronic HCV patients from our cohort

Panel (A) Caucasians; Panel (B) African Americans. Numbers with sustained virologic response out of all with that genotype are shown below each rs12979860 genotype. Chi squared P values for Caucasian are adjusted for age, sex, HCV genotype, treatment history and fibrosis. P values in African Americans are from Fisher’s Exact Test and not adjusted due to small sample sizes.

Figure 3. Effect of rs12979860 genotype on three-level treatment outcome in Caucasian chronic HCV patients treated with PEG-IFN/RBV

Adjusted odds ratios (Adj. OR) and 95% confidence intervals are for rs12979860 CC versus CT/TT genotype comparing sustained virologic responders (SVR) to relapsers, and relapsers to end of treatment non-responders (NR), while controlling for age, sex, HCV genotype, treatment history and fibrosis score. P value shown is for the effect of the rs12979860 CC genotype on three-level treatment response in multinomial regression analysis.

Figure 4. Association between rs12979860 genotype and HCV genotype among 681 Caucasian chronic HCV patients from our cohort

Percent of subjects carrying the rs12979860 CC genotype is shown with 95% confidence intervals. Chi-squared P value for association between HCV genotype (gt1, gt2, gt3) and rs12979860 CC vs CT/TT genotype.