title: Emergence of telaprevir-resistant variants detected by ultra-deep sequencing after triple therapy in patients infected with HCV genotype 1.
abstract: 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.
authors.affiliation: Department of Hepatology, Toranomon Hospital, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan. akuta-gi@umin.ac.jp
authors.forename: Norio
authors.initials: N
authors.lastname: Akuta
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Suzuki
authors.forename: Yuya
authors.initials: Y
authors.lastname: Seko
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kawamura
authors.forename: Hitomi
authors.initials: H
authors.lastname: Sezaki
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hosaka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Tasuku
authors.initials: T
authors.lastname: Hara
authors.forename: Mariko
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Saitoh
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Arase
authors.forename: Kenji
authors.initials: K
authors.lastname: Ikeda
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kumada
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000627:therapeutic use*; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics*; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D009842:Oligopeptides; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C486464:telaprevir; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a