IL28B genotype effects during early treatment with peginterferon and ribavirin in difficult-to-treat hepatitis C virus infection.
BACKGROUND: Mathematical models of hepatitis C virus (HCV) during therapy may elucidate mechanisms of action for antiviral therapy. In genome-wide association studies, IL28B gene polymorphisms are highly predictive of therapeutic clearance of HCV. METHODS: We collected sera from 20 chronically infected HCV participants at 13 points during the first 28 days of therapy. We assessed the presence of the C allele at single-nucleotide polymorphism rs12979860 using the ABI TaqMan allelic discrimination kit. We estimated dynamic parameters from the entire population using the Neumann model for HCV infection. Statistical methods for repeated nonlinear measures compared model parameters by established predictors of response. RESULTS: The frequencies of IL28B genotypes were 6 (C/C), 11 (C/T), and 3 (T/T). The mean log decline in HCV RNA from 0 to 48 hours was more rapid among C/C genotype participants compared with C/T or T/T genotype participants (1.4 vs 0.7; P = .07), and from 2 days to 14 days (1.6 vs 0.7; P = .04). In the multivariate model, the C/C genotype predicted a steeper second-phase decline when adjusted for race (P = .01). CONCLUSIONS: The presence of the C/C genotype at IL28B rs12979860 exerts its antiviral effect by increasing the infected hepatocyte death rate. This suggests that an immune-mediated mechanism is responsible.
Scott, J; Holte, S; Urban, T; Burgess, C; Coppel, E; Wang, C; Corey, L; McHutchison, J; Goldstein, D
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