MUTATIONS IN THE NONSTRUCTURAL PROTEIN 5A GENE AND RESPONSE TO INTERFERON IN PATIENTS WITH CHRONIC HEPATITIS-C VIRUS 1B INFECTION

Background. A region associated with sensitivity to interferon has bee n identified in the nonstructural protein 5A (NS5A) of hepatitis C vir us (HCV) genotype Ib. The region spans amino acid residues 2209 to 224 8 (NS5A2209-2248) Of HCV-J, a strain of HCV-lb whose complete genomic sequence has been identified. We examined whether the NS5A2209-2248 se quence present before therapy could be used as a predictor of the resp onse to interferon therapy in patients with chronic HCV-lb infection. Methods. We retrospectively analyzed 84 patients with chronic HCV-lb i nfection who had received interferon alfa (total dose, 516 million to 880 million units) for six months. Pretreatment serum samples were ana lyzed. The amino acid sequence of NS5A2209-2248 was determined by dire ct sequencing of the HCV genome amplified by the polymerase chain reac tion (PCR) and was compared with the established sequence for HCV-J. R esults. A complete response, as evidenced by the absence of HCV RNA in serum on nested reverse-transcription PCR for six months after therap y, did not occur in any of the 30 patients whose NS5A2209-2248 sequenc es were identical to that of HCV-J (wild type). Five of 38 patients (1 3 percent) with 1 to 3 changes in NS5A2209-2248 (intermediate type) ha d complete responses, as did all 16 patients with 4 to II amino acid s ubstitutions (mutant type), indicating that the mutant type was signif icantly associated with a complete response (P<0.001). Although baseli ne serum HCV RNA levels, as measured by a branched-chain DNA assay, we re lower in patients with the mutant type of NS5A2209-2248 than in tho se with the other types (P<0.001), multivariate analyses revealed that the number of amino acid substitutions in NS5A2209-2248 was the only variable associated with an independent effect on the outcome of inter feron therapy (odds ratio, 5.3; 95 percent confidence interval, 1.6 to 18; P=0.007). Conclusions. In patients with chronic HCV-lb infection, there is a substantial correlation between responses to interferon an d mutations in the NS5A gene.