Analysis of the complete open reading frame of hepatitis C virus in genotype 2a infection reveals critical sites influencing the response to peginterferon and ribavirin therapy

Abstract

A proportion of patients infected with genotype 2a hepatitis C virus (HCV) cannot achieve a sustained virological response (SVR) to pegylated-interferon plus ribavirin therapy (PEG-IFN/RBV) but the reason remains unclear. The present study aimed to clarify the possible correlation between viral sequence variations and final outcome. The pretreatment complete open reading frame (ORF) sequences of genotype 2a HCV were determined by direct sequencing for two independent groups of patients (43 patients as test; group 1 and 35 as validation; group 2), and the correlation with the final outcome was explored. Patients with SVR (n=58) and with non-SVR (n=20) differed significantly in pretreatment HCV RNA level (p=0.002), fibrosis score (p=0.047), and cumulative RBV dosage (p=0.003). By comparison of all amino acid positions in the complete HCV ORFs, threonine at amino acid (aa) 110 in the core region was remarkably frequent in SVR (p=0.01 for group 1, p=0.004 for group 2, and p=5E-05 for combined). A sliding window analysis revealed that the total number of amino acid variations within the NS5A aa 2258-2306 region were significantly high in SVR compared to non-SVR patients (p=0.01 for group 1, p=0.006 for group 2, and p=0.0006 for combined). Multivariate analyses revealed that core aa 110 (p=0.02), NS5A aa 2258-2306 (p=0.03), and cumulative RBV dosage (p=0.02) were identified as independent variables associated with the final outcome. The outcome of PEG-IFN/RBV therapy is significantly influenced by variation in the core and NS5A regions in genotype 2a HCV infection.