Naturally occurring substitutions conferring resistance to hepatitis C virus polymerase inhibitors in treatment-naive patients infected with genotypes 1–5

Abstract

The hepatitis C virus (HCV) RNA-dependent RNA polymerase, NS5B, is essential for virus RNA replication. It is thus an attractive therapeutic target. Several compound nucleoside analogues, non-nucleoside inhibitors and cyclosporine analogues are being developed to inhibit NS5B activity. However, nucleotide changes in the NS5B gene can confer resistance to them. We investigated the prevalence of known substitutions conferring resistance in HCV polymerase in 124 treatment-naive French patients infected with HCV genotypes 1, 2, 3, 4 or 5 by sequencing the NS5B gene. None of the 124 HCV NS5B sequences analysed contained substitutions conferring resistance to nucleoside analogues; however, NS5B polymerases containing substitutions conferring resistance to non-nucleoside inhibitors were frequent within genotype 1 strains (17%) and very common in non-genotype 1 strains. Similarly, substitutions conferring resistance to cyclosporine analogues were more prevalent within the various genotypes. Naturally occurring substitutions conferring resistance to NS5B inhibitors are common in treatment-naive patients infected with HCV genotype 1, 2, 3, 4 or 5. Their influence on treatment outcome should be assessed.