ANALYSIS OF GENOTYPES AND AMINO-ACID-RESIDUE-2209 TO AMINO-ACID-RESIDUE-2248 OF THE NS5A REGION OF HEPATITIS-C VIRUS IN RELATION TO THE RESPONSE TO INTERFERON-BETA THERAPY

In chronic hepatitis C virus (HCV) infection, genotypes other than gen otype 1b of HCV (HCV-1b) and low serum HCV-RNA levels are known to be associated with favorable outcome of interferon alfa (IFN-alpha) thera py. In addition, we recently reported a close correlation between the number of mutations in amino acid sequences 2209 to 2248 of the nonstr uctual protein 5A gene (NS5A(2209-2248)) of HCV-1b and the response to IFN-alpha. In the present study, we analyzed these viral factors in r elation to the efficacy to IFN-beta, another type I IFN. The pretreatm ent sera of 40 patients treated with IFN-beta intravenously at 6 MU da ily for 42 days were studied. HCV genotypes, serum HCV-RNA levels, and the amino acid sequence of NS5A(2209-2248) in HCV-1b were determined. A sustained complete response to IFN therapy occurred in none of the ten patients with the wild-type HCV-1b who had an NS5A(2209-2248) sequ ence identical to the prototype HCV-1b and in none of the six patients with the intermediate-type HCV-1b that had 1 mutation. In contrast, c omplete responses occurred in the following: 4 of 6 patients with the mutant-type HCV-1b that had five to ten mutations; 6 of 13 patients wi th genotype 2a of HCV (HCV-2a); and 2 of 5 patients with genotype 2b o f HCV (HCV-2b). Among patients with the mutant-type HCV-1b, or genotyp e 2 of HCV (HCV-S) the rate of complete response was significantly hig her (12 of 24 vs. 0 of 16 patients, P < .001) and HCV-RNA levels were significantly lower (4.5 [4.0-6.5] vs. 6 [4.5-6.5] log copies/mL, medi an [range]; P < .001) compared with patients with the wild- or the int ermediate-type HCV-1b. Patients with the mutant-type HCV-1b or HCV-2 w hose HCV-RNA levels were lower than 6 log copies/mL had a complete res ponse rate of 75% (12 of 16 patients) in contrast to 0% (0 of 24 patie nts) of the others (P < .001). These results indicate that the mutant- type HCV-1b or HCV-2 are sensitive to IFN-beta as well as IFN-alpha. I n conclusion, the determination of HCV genotypes, NS5A(2209-2248) of H CV-1b and serum HCV-RNA levels may facilitate the selection of patient s with a high likelihood of response to IFN-beta.