Comprehensive analysis for viral elements and interleukin-28B polymorphisms in response to pegylated interferon plus ribavirin therapy in hepatitis C virus 1B infection


  • Potential conflict of interest: Shinya Maekawa and Taisuke Inoue belong to a donation-funded department that is funded by MSD Co., Ltd., Tokyo, Japan. Nobuyuki Enomoto received research funded by MSD Co., Ltd.,Tokyo, Japan and Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.

  • This study was supported, in part, by a grant-in-aid scientific research fund of the Ministry of Education, Science, Sports, and Culture (grant nos.: 21590836, 21590837, and 23390195) and, in part, by a grant-in-aid from the Ministry of Health, Labor, and Welfare of Japan (grant nos.: H22-kanen-006, H22-kanen-003, and H23-kanen-001).


To comprehensively characterize the contribution of virological factors as well as interleukin-28B (IL28B) single-nucleotide polymorphisms (SNPs) in determining treatment responses in pegylated-interferon plus ribavirin (Peg-IFN/RBV) therapy for chronic hepatitis C virus (HCV)-1b infection, we undertook a retrospective cohort analysis for the pretreatment dominant complete HCV open reading frame (ORF) amino-acid (aa) sequence study in 103 consecutive HCV-1b Japanese patients. The dominant HCV sequences classified by the response were subjected to systematic sliding-window comparison analysis to characterize response-specific viral sequences, along with IL28B SNP analyses (rs8099917). In each comparison of the patients between with and without rapid viral response (RVR), nonearly viral response (nEVR), sustained virological response (SVR), or relapse, the following regions were extracted as most significantly associated with the different responses respectively: nonstructural protein 5A (NS5A) aa.2224-2248 (P = 1.2E-07); core aa.70 (P = 4E-04); NS5A aa.2340-2382 (P = 7.0E-08); and NS5A aa.2360-2377 (P = 1.1E-05). Those NS5A regions nearly coincided with the interferon (IFN) sensitivity-determining region (NS5A aa.2209-2248) and the IFN/RBV resistance-determining region (NS5A aa.2339-2379). In a multivariate analysis, the IL28B SNP (odds ratio [OR] = 16.8; P = 0.009) and NS5A aa.2340-2382 (OR = 13.8; P = 0.0003) were extracted as the two most-significant independent variables contributing to the final outcome. Conclusion: In Peg-IFN/RBV therapy, polymorphisms in IL28B, NS5A aa.2224-2248, core aa.70, and, most important, NS5A aa.2340-2382 have a tremendous influence on treatment response in association with viral kinetics, resulting in significantly different outcomes in chronic HCV-1b infection. (HEPATOLOGY 2012;56:1611–1621)