Substitutions in interferon sensitivity-determining region and hepatocarcinogenesis after hepatitis C virus eradication

Background and Aim: Amino-acid substitutions in the interferon sensitivity-determining region (ISDR) within the NS5A region are known to be associated with responsiveness to interferon (IFN)-based therapy. Additionally, previous studies reported that the ISDR was related to the development of hepatocellular carcinoma (HCC) in patients infected with hepatitis C virus (HCV). However, the association between substitutions in the ISDR and the development of HCC in patients who achieved sustained virological response (SVR) is unclear. The aim of this study was to clarify the association between amino-acid substitutions in the ISDR and development of HCC after SVR. Methods: One thousand five hundred eighty-eight patients infected with HCV who were treated with IFN-based therapy were enrolled, and 475 patients who achieved SVR and underwent complete virological analysis at pretreatment were investigated. HCV genotypes consisted of 1a (n = 10), 1b (n = 307), 2a (n = 110), 2b (n = 41), and 3a (n = 7), and the ISDR in each genotype was examined by direct sequencing. Results: Nineteen patients developed HCC after SVR. The cumulative incidence of HCC was 2.1% and 15.9% at 5 and 10 years after SVR, respectively. Multivariate analysis indicated older age (≥ 60 years: hazard ratio [HR], 3.23; P = 0.014), higher γ-glutamyl transpeptidase level (≥ 50 IU/L: HR, 8.42; P < 0.001) and ≥ 3 substitutions in the ISDR (HR, 3.24; P = 0.016) as independent factors that were significantly associated with HCC development. Conclusion: Amino-acid substitutions in the ISDR are useful to predict not only IFN responsiveness but also HCC development in patients who achieved SVR by IFN-based therapy.