title: Evolution of simeprevir-resistant variants over time by ultra-deep sequencing in HCV genotype 1b.
abstract: Using ultra-deep sequencing technology, the present study was designed to investigate the evolution of simeprevir-resistant variants (amino acid substitutions of aa80, aa155, aa156, and aa168 positions in HCV NS3 region) over time. In Toranomon Hospital, 18 Japanese patients infected with HCV genotype 1b, received triple therapy of simeprevir/PEG-IFN/ribavirin (DRAGON or CONCERT study). Sustained virological response rate was 67%, and that was significantly higher in patients with IL28B rs8099917 TT than in those with non-TT. Six patients, who did not achieve sustained virological response, were tested for resistant variants by ultra-deep sequencing, at the baseline, at the time of re-elevation of viral loads, and at 96 weeks after the completion of treatment. Twelve of 18 resistant variants, detected at re-elevation of viral load, were de novo resistant variants. Ten of 12 de novo resistant variants become undetectable over time, and that five of seven resistant variants, detected at baseline, persisted over time. In one patient, variants of Q80R at baseline (0.3%) increased at 96-week after the cessation of treatment (10.2%), and de novo resistant variants of D168E (0.3%) also increased at 96-week after the cessation of treatment (9.7%). In conclusion, the present study indicates that the emergence of simeprevir-resistant variants after the start of treatment could not be predicted at baseline, and the majority of de novo resistant variants become undetectable over time. Further large-scale prospective studies should be performed to investigate the clinical utility in detecting simeprevir-resistant variants.
authors.affiliation: Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Akuta
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Suzuki
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: Mariko
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Saitoh
authors.forename: Kenji
authors.initials: K
authors.lastname: Ikeda
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kumada
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology / Q000627:therapeutic use*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D007564:Japan; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000235:genetics*; D012254:Ribavirin / Q000627:therapeutic use; D000069616:Simeprevir; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D017211:Treatment Failure; D019562:Viral Load; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D006575:Heterocyclic Compounds, 3-Ring; D016898:Interferon-alpha; D012367:RNA, Viral; D013449:Sulfonamides; D012254:Ribavirin; D000069616:Simeprevir
keywords: HCV; resistant variants; simeprevir; ultra-deep sequence