852 A MUTATIONAL ANALYSIS OF THE INTERNAL RIBOSOME ENTRY SITE IN HEPATITIS C VIRUS IN PATIENTS TREATED WITH PEGYLATED INTERFERON WITH RIBAVIRIN

Abstract

Background and Aims: It has recently been reported that the internal ribosome entry site (IRES) is closely associated with the replication of the hepatitis C virus (HCV) RNA. On the other hand, the HCVRNA kinetics is an important predictive factor for the outcome of antiviral therapy. To investigate the potential mechanisms of resistance, especially regarding the HCVRNA kinetics, we analyzed the mutation of the IRES in chronic hepatitis C (CH-C) patients treated by pegylated interferon (Peg-IFN) with ribavirin (RBV). Methods: 31 CH-C patients demonstrating genotype 1b with a high viral load (more than 100 KIU/ml) were studied. They were divided into two groups. The 12w (+) group included 15 patients, whose HCVRNA were positive at 12 weeks after the start of therapy. In contrast, the 12w (−) group included 16 patients whose HCVRNA were negative at 12 weeks. HCVRNA was extracted from the serum just before therapy in both groups, and the IRES region was sequenced. Three clones were analyzed in each patient. Five patients in the 12w (+) group were further analyzed in the serum at 12 weeks. Results: At week 0, the total number of mutations from each clone in the IRES (domain II/III) in the 12w (+) group was 19/9, in contrast to 14/35 in the 12w (−) group (P = 0.0008). Namely, in the 12w (+) group, most of the mutations were observed in domain II. On the other hand, in the 12w (−) group, the mutations were concentrated in domain III. No other clinical factors were statistically significant. Furthermore, in comparison of the findings at week 0 and week 12 in 5 patients within the 12w (+) group, the number of mutations in domain II/III was 9/4 in week 0, in contrast to 8/1 in week 12. Namely, the mutations of domain III decreased. Conclusions: The mutations of the IRES were found to be related to the HCVRNA kinetics, in particular, mutations in domain II seem to be associated with the resistance of Peg-IFN with RBV therapy.