Development and persistence of DAA resistance associated mutations in patients failing HCV treatment

•HCV NS3 resistance-associated mutations was investigated in treated patients.•Sanger sequencing was performed on HCV virus from inhibitor treatment-patients.•Overall 16.4% had a detectable RAV in the NS3 region.•Persistence of drug-resistant variants were detected in the patients.•Resistance testing during DAA treatment should be taken into consideration.

BackgroundDirect-acting antiviral agents (DAAs) combined with pegylated-interferon (PegIFN) and ribavirin (RBV) are still a standard treatment in patients with genotype 1HCV infection. However, virologic response could be impaired by baseline or early selection of resistant HCV strains.ObjectivesThe aim of this study was to determine the onset and persistence of resistance-associated mutations (RAMs) in the NS3 and NS5B genes of DAA-naïve patients failing treatment.Study designDirect sequencing of HCV NS3 was performed in 49 DAA-naïve patients with HCV genotype 1 infection.ResultsEight out of 23 patients (34.7%) failed PegIFN/RBV/telaprevir during the 12-weeks of therapy. Treatment failure was associated with the development of RAMs at amino-acids 36,54,80 and 155 of the HCV protease in 6/8 patients (75%). Among patients treated with PegIFN/RBV/boceprevir treatment, 4/18 (22.2%) failed therapy. Of these, 2 (50%) carried virus strains which developed a RAM at amino-acids 54 and 155. Among HCV strains with RAMs, 7 belonged to genotype 1a and 1 to 1b. Finally, in 6/10 (60%) patients, drug-resistant variants could still be detected for up to 3–7 months after stopping therapy.ConclusionsA higher rate (p = 0.49) of treatment failure was observed in patients receiving telaprevir- compared to the boceprevir-based combination. In addition, compared with genotype 1b, genotype 1a was associated with higher rates (p = 0.01) of treatment failure due to virus resistant strains.Resistance testing at baseline and during DAA treatment should be taken into consideration when treating patients with new HCV combination therapies.