NS3 protease polymorphism and natural resistance to protease inhibitors in French patients infected with HCV genotypes 1-5.

Background: Resistant HCV populations may pre-exist in patients before NS3 protease inhibitor therapy and would likely be selected under specific antiviral pressure. The higher prevalence and lower rate of response to treatment associated with HCV genotype 1 infections has led to drug discovery efforts being focused primarily on enzymes produced by this genotype. Protease inhibitors may also be useful for non-genotype-1-infected patients, notably for non-responders.

Methods: We investigated the prevalence of dominant resistance mutations and polymorphism in 298 HCV protease-inhibitor-naive patients infected with HCV genotypes 1, 2, 3, 4 or 5. Genotype-specific NS3 primers were designed to amplify and sequence the NS3 protease gene.

Results: None of the 233 analysed sequences contained major telaprevir (TVR) or boceprevir (BOC) resistance mutations (R155K/T/M, A156S/V/T and V170A). Some substitutions (V36L, T54S, Q80K/R, D168Q and V170T) linked to low or moderate decreases in HCV sensitivity to protease inhibitors were prevalent according to genotype (between 2% and 100%). Other than genotype signature mutations at positions 36, 80 and 168, the most frequent substitution was T54S (4 genotype 1 and 2 genotype 4 sequences). All genotype 2-5 sequences had the non-genotype-1 signature V36L mutation known to confer low-level resistance to both TVR and BOC.

Conclusions: We have developed an HCV protease NS3 inhibitor resistance genotyping tool suitable for use with HCV genotypes 1-5. Polymorphism data is valuable for interpreting genotypic resistance profiles in cases of failure of anti-HCV NS3 protease treatment.