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

Background: Direct-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. Objectives: The aim of this study was to determine the onset and persistence of resistance-associated mutations (RAMs) in the NS3 and NS5B genes of DAA-naive patients failing treatment. Study design: Direct sequencing of HCV NS3 was performed in 49 DAA-naive patients with HCV genotype 1 infection. Results: Eight 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 618 patients (75%). Among patients treated with PegIFNIRBV/boceprevir treatment, 4118 (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 1 a and Ito lb. Finally, in 6110 (60%) patients, drug-resistant variants could still be detected for up to 3-7 months after stopping therapy. Conclusions: A higher rate (p=0.49) of treatment failure was observed in patients receiving telaprevircompared to the boceprevir-based combination. In addition, compared with genotype 1 b, genotype 1 a 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. (C) 2015 Elsevier B.V. All rights reserved.