Single nucleotide polymorphism upstream of interleukin 28B associated with phase 1 and phase 2 of early viral kinetics in patients infected with HCV genotype 1

Abstract

Background & Aims We studied the relationship between IL28B gene-related SNP rs12979860 and early viral kinetics (day 0–28) during peginterferon and ribavirin treatment, in 173 African Americans (AA) and 188 Caucasian Americans (CA) with HCV genotype 1. Methods We studied the relationship between IL28B 16 gene-related SNP rs12979860 and early viral kinetics (day 0–28) 17 during peginterferon and ribavirin treatment, in 171 African 18 Americans (AA) and 188 Caucasian Americans (CA) with HCV 19 genotype 1. Results Compared to non-C/C genotypes, C/C was associated with greater declines in serum HCV RNA during phase 1 (day 0–2), phase 2 (day 7–28), and day 0–28 and higher response (undetected HCV RNA) rates at weeks 4 and 12 in AA and CA. A static phase and increases in HCV RNA from day 2 to 7 were more common in patients with non-C/C genotypes. C/C was also associated with higher week 24, 48, and 72 response rates in CA (p <0.01) but not in AA. At baseline, SNP genotype was the only independent predictor of phase 1; SNP genotype and phase 1 were independent predictors of phase 2 (p<0.001). There were no racial differences in HCV RNA declines during phase 1, day 2–7, phase 2, and day 0–28 with the same SNP genotype. AA with C/C and C/T genotypes had lower week 24, 48, and 72 (SVR) rates than did CA (p = 0.03). SNP C/C predicted higher SVR rates in AA and CA with high baseline HCV RNA (≥ 600,000 IU/ml), and in CA with ≥ 1 log10 IU/ml decrease in HCV RNA from day 0 to 28. Conclusions SNP rs12979860 is strongly associated with both phase 1 and phase 2 HCV RNA kinetics in AA and CA with HCV genotype 1.

Optimum Ribavirin Exposure Overcomes Racial Disparity in Efficacy of Peginterferon and Ribavirin Treatment for Hepatitis C Genotype 1

“…Yet, week 4, 12, 24, 48, and 72 (SVR) response rates were lower in AA (4). Similar to an earlier study of 361 VIRAHEP-C study participants (188 CA and 173 AA), CA with the SNP C/C genotype had higher WK24VR (C/C: 93%; C/T: 70%; T/T: 50%; P = 0.005) and SVR (C/C: 71 %; C/T: 52 %; T/T: 37 %; P = 0.05) rates than CA patients with non-C/C genotypes (6). Neither WK24VR (C/C: 78 %; C/T: 60 %; T/T: 47 %; P = 0.13) nor SVR (C/C: 44 %; C/T: 40 %; T/T: 32 %; P = 0.5) differed by SNP genotype in AA (6).…”

“…Genomic DNA samples (68 AA and 66 CA) were analyzed for SNP rs12979860 at the University of Maryland and Duke University using the TaqMan SNP Genotyping Assays (Applied Biosystems) (6,21). Replicate genotyping in 8 % of the samples was >98 % concordant.…”

“…Sixty-four patients per group provided 80 % power to detect a 20 % difference in ribavirin AUC between AA and CA with the 40 % interpatient variability observed. The effect of SNP rs12979860 genotype on virologic response was evaluated under the additive genetic model, with the genotype variable coded as the number of C alleles (6). Logistic regression analysis was used to investigate the associations among baseline variables, ribavirin plasma exposure and virologic response.…”

“…Compared with Caucasian Americans (CA), SVR is significantly lower in African Americans (AA) with HCV genotype 1 infections (19–28 % vs. 52 %) (3,4). However, the racial disparity in response is manifested 1–2 days after treatment initiation as a weaker decline in serum HCV RNA in AA (5,6). A single-nucleotide polymorphism (SNP) near the interleukin-28B (IL28B) gene locus on chromosome 19q13.3 explains up to 50 % of the racial disparity in SVR (7).…”

“…The current study investigated the relationship between ribavirin drug exposure (AUC) from week 1 to 24 and week 24 (WK24VR) and 72 (SVR) responses in AA and CA patients with HCV genotype 1 who were more than 90 % adherent to both peginterferon and ribavirin in the VIRAHEP-C. Also, we defined the significance of ribavirin exposure to treatment outcomes in relation to IL28B gene-related SNP rs12979860 and early HCV RNA kinetics (day 0–28) (6,7). …”