NUCLEOTIDE-SEQUENCE VARIATIONS IN THE INTERNAL RIBOSOME ENTRY SITE OFHEPATITIS-C VIRUS-1B - NO ASSOCIATION WITH EFFICACY OF INTERFERON THERAPY OR SERUM HCV-RNA LEVELS

The extreme 5'-proximal sequences of the hepatitis C virus (HCV) genom e including the S'untranslated region (5'UTR) and the first 30 nucleot ides of the core region are highly conserved, and serve as an internal ribosome entry site (IRES) that initiates the cap-independent transla tion of HCV polyprotein. Mutations in the IRES sequence have been show n to cause changes in the efficiency of protein translation in vitro. However, the significance of genetic variations in the IRES is not ful ly known in clinical settings. Pretreatment sera of 25 patients with H CV-lb infection who were treated with interferon were amplified by pol ymerase chain reaction (PCR), and the IRES sequence was directly seque nced. Correlation of interferon responses or other clinical features w ith IRES sequence variability was studied. Eleven of 25 patients were sustained responders (SR) of interferon treatment (negative serum HCV RNA and normal alanine transaminase levels for 6 months after the end of interferon treatment), and the other 14 patients were nonresponders ([NR], defined as any patient with positive serum HCV RNA within 6 mo nths after the end of interferon therapy). In each patient, one to fou r nucleotide substitutions were found compared with the consensus sequ ence of HCV-lb genotype. There were no differences in the number of nu cleotide substitutions between either SR and NR (mean, 1.8 in SR, 2.1 in NR; P = .30), and no specific variations associated with SR or NR w ere observed. Although NR had significantly higher serum levels of pre treatment HCV RNA than SR (median, 16 vs. <0.5 Meq/mL; P = .02), there was no correlation between the HCV-RNA level and the number of nucleo tide substitutions in the IRES (mean, 1.9 nucleotide substitutions in 12 patients with HCV RNA (0.5 Meq/mt vs. 2.1 nucleotide substitutions in 13 patients with HCV RNA >0.5 Meq/mL; P = .61). Sequence variabilit y of the IRES has no influence on interferon efficacy or serum HCV-RNA concentrations in patients with chronic HCV-lb infection.