Mutagenic effects of ribavirin and response to interferon/ribavirin combination therapy in chronic hepatitis C

Background/Aims To elucidate whether ribavirin acts as a mutagen in the clinical setting and to clarify the relationship between ribavirin-induced mutations and virological response to combined therapy. Methods Thirty-four patients with hepatitis C virus (HCV) genotype 1b received ribavirin monotherapy for 4 weeks, followed by a 24-week course of IFN/ribavirin therapy. HCV mutations during a non-treatment observation period and during subsequent ribavirin monotherapy were determined, and the relationship between mutations and response to subsequent IFN/ribavirin therapy was evaluated. Results Serum HCV significantly decreased from 6.90 to 6.56 log10copy/ml in response to ribavirin monotherapy (P<0.0001). Nucleotide mutations in the NS5A and NS5B regions occurred during ribavirin monotherapy at a rate of 2.9×10−2/site/year and 1.3×10−2/site/year, respectively, a significantly higher rate than the mutation rates during the prior non-treatment observation period (0.60×10−2/site/year and 0.24×10−2/site/year, P=0.02, respectively). Mutation rates in the NS5A region were significantly higher in sustained viral responders (SVRs, n=10) than in non-responders (8.8×10−2/site/year vs. 0.38×10−2/site/year, P=0.0005, respectively). In the NS5A region, non-synonymous mutations only occurred in SVRs. Conclusions Ribavirin may act as a mutagen, and mutations occurring during ribavirin therapy correlate with the virological response to subsequent IFN/ribavirin combination therapy.