title: Evolution of simeprevir-resistant variants in virological non-responders infected with HCV genotype 1b.
abstract: The present study was designed to assess the evolution of simeprevir-resistant variants (amino acid substitutions of aa80, aa155, aa156, and aa168 positions in HCV NS3 region) over time in virological non-responders (patients with positive HCV-RNA during and at end of treatment). The study enrolled 136 patients infected with HCV genotype 1b who received 12-week simeprevir-PEG-IFN-ribavirin therapy, and data of 87 patients were available for analysis. Twelve patients (14%) were considered virological non-responders, including 9 (75%) who showed absolute no-response (HCV RNA: ≥3.0 log IU/ml at 12 weeks after start of therapy). Multivariate analysis of these patients identified lack of response to prior treatment, use of low ribavirin dose, and old age as independent and significant determinants of virological non-response. Using ultra-deep sequencing, de novo variants of D168 were detected in all of 9 absolute non-responders. The majority of these variants emerged within 5 weeks of triple therapy. In comparison, de novo variants of Q80 were detected in only 3 of 9 absolute non-responders and emerged at 6-12 weeks. Variants of Q80 detected at baseline increased during the course of treatment in 5 of 9 absolute non-responders, while no such increase was noted in variants of R155 and/or A156 detected at baseline during the 12-week course. De novo variants of R155 and/or A156 were not detected in this study. The results demonstrated the emergence of simeprevir-resistant variants during the early stage of triple therapy.
authors: Department of Hepatology, Toranomon Hospital, and Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors: Norio
authors: N
authors: Akuta
authors: Fumitaka
authors: F
authors: Suzuki
authors: Hitomi
authors: H
authors: Sezaki
authors: Tetsuya
authors: T
authors: Hosaka
authors: Masahiro
authors: M
authors: Kobayashi
authors: Yoshiyuki
authors: Y
authors: Suzuki
authors: Satoshi
authors: S
authors: Saitoh
authors: Mariko
authors: M
authors: Kobayashi
authors: Kenji
authors: K
authors: Ikeda
authors: Hiromitsu
authors: H
authors: Kumada
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / 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; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D012367:RNA, Viral / Q000235:genetics; D012254:Ribavirin / Q000627:therapeutic use; D017422:Sequence Analysis, DNA; D000069616:Simeprevir; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D017211:Treatment Failure; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D006575:Heterocyclic Compounds, 3-Ring; D016898:Interferon-alpha; D012367:RNA, Viral; D012254:Ribavirin; D000069616:Simeprevir; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
keywords: HCV; absolute non-response; resistant variants; simeprevir; ultra-deep sequence; virological non-response