November 20, 2013

Antimicrob Agents Chemother. 2013 Nov 11. [Epub ahead of print]

Berger KL, Triki I, Cartier M, Marquis M, Massariol MJ, Böcher WO, Datsenko Y, Steinmann G, Scherer J, Stern JO, Kukolj G.

Boehringer Ingelheim Canada Ltd. R&D, Laval, QC, Canada.

Abstract

A challenge to the treatment of chronic hepatitis C with direct acting antivirals is the emergence of hepatitis C virus (HCV) drug-resistant variants. HCV with pre-existing polymorphisms that are associated with resistance to NS3/4A protease inhibitors have been detected in patients with chronic hepatitis C. We performed a comprehensive pooled analysis from phase 1b and phase 2 clinical studies of the HCV protease inhibitor faldaprevir to assess the population frequency of baseline protease inhibitor resistance-associated NS3 polymorphisms and their impact on response to faldaprevir treatment. A total of 980 baseline NS3 sequences were obtained (543 genotype 1b; 437 genotype 1a). Substitutions associated with faldaprevir resistance (at amino acid positions 155 and 168) were rare (< 1% of sequences) and did not compromise treatment response: in a phase 2 study in treatment-naïve patients, six patients had faldaprevir resistance-associated polymorphisms at baseline, of whom five completed faldaprevir-based treatment and all five achieved a sustained virologic response (SVR24). Among 13 clinically relevant amino acid positions associated with HCV protease resistance, the greatest heterogeneity was seen at NS3 codons 132 and 170 in genotype 1b and the most common baseline substitution in genotype 1a was Q80K (99/437 [23%]). The presence of the Q80K variant did not reduce response rates to faldaprevir-based treatment. Across the three phase 2 studies there was no significant difference in SVR24 rates between patients with genotype 1a Q80K HCV and those without Q80K HCV, whether treatment-experienced (17% vs 26%; P = 0.47) or treatment-naïve (62% vs 66%; P = 0.72).

PMID: 24217701 [PubMed - as supplied by publisher]

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