Emergence of telaprevir-resistant variants detected by ultra-deep sequencing after triple therapy in patients infected with HCV genotype 1

Using ultra‐deep sequencing technology, the present was designed to investigate whether the emergence of telaprevir‐resistant variants (amino acid substitutions of aa36, aa54, aa155, aa156, and aa170 positions in HCV NS3 region) after commencement of triple therapy of telaprevir/peginterferon (PEG‐IFN)/ribavirin could be predicted at baseline in previous non‐responders to dual therapy. Fourteen patients infected with HCV genotype 1 who did not respond to previous PEG‐IFN/ribavirin, received a 24‐week regimen of triple therapy, and were evaluated for appearance of telaprevir‐resistant variants (amino acid substitutions of more than 0.2% among the total coverage) by ultra‐deep sequencing. The sustained virological response rate was 28.6% (4 of 14 patients), which was significantly higher in patients with Arg70 (substitution at core aa70) and partial response (type of previous response to PEG‐IFN/ribavirin) than in other patients. Telaprevir‐resistant variants at baseline were detected in 7.1% (1 of 14 patients) by direct sequencing and in 21.4% (3 of 14 patients) by ultra‐deep sequencing. The appearance of telaprevir‐resistant variants was examined by ultra‐deep sequencing in 10 who did not show sustained virological responders. De novo variants emerged at re‐elevation of viral load, regardless of variant frequencies at baseline (one patient with very high frequency variants [T54S: 99.9%], two patients with very low frequency variants [V36A: 0.2%; and V170A: 0.4%], and seven patients of undetectable variants). It is concluded that it is difficult to predict at baseline the emergence of telaprevir‐resistant variants after commencement of triple therapy in prior non‐responders of HCV genotype 1, even with the use of ultra‐deep sequencing. J. Med. Virol. 85: 1028–1036, 2013. © 2013 Wiley Periodicals, Inc.