title: Hepatitis C virus variants with decreased sensitivity to direct-acting antivirals (DAAs) were rarely observed in DAA-naive patients prior to treatment.
abstract: The prevalence of naturally occurring hepatitis C virus (HCV) variants that are less sensitive to direct-acting antiviral (DAA) inhibitors has not been fully characterized. We used population sequence analysis to assess the frequency of such variants in plasma samples from 3,447 DAA-naive patients with genotype 1 HCV. In general, HCV variants with lower-level resistance (3- to 25-fold increased 50% inhibitor concentration [IC(50)]) to telaprevir were observed as the dominant species in 0 to 3% of patients, depending on the specific variant, whereas higher-level resistant variants (>25-fold-increased IC(50)) were not observed. Specific variants resistant to NS5A inhibitors were predominant in up to 6% of patients. Most variants resistant to nucleo(s/t)ide active-site NS5B polymerase inhibitors were not observed, whereas variants resistant to non-nucleoside allosteric inhibitors were observed in up to 18% of patients. The presence of DAA-resistant variants in NS5A, NS5B, or NS3 (including telaprevir-resistant variants), in baseline samples of treatment-naive patients receiving a telaprevir-based regimen in phase 3 studies did not affect the sustained viral response (SVR). Treatment-naive patients with viral populations containing the telaprevir-resistant variants NS3 V36M, T54S, or R155K at baseline achieved a 74% SVR rate, whereas patients with no resistant variants detected prior to treatment achieved a 76% SVR rate. The effect of specific resistant variant frequency on response to various DAA treatments in different patient populations, including interferon nonresponders, should be further studied.
authors.affiliation: Vertex Pharmaceuticals, Inc., Department of Infectious Diseases, Cambridge, Massachusetts, USA.
authors.forename: Doug J
authors.initials: DJ
authors.lastname: Bartels
authors.forename: James C
authors.initials: JC
authors.lastname: Sullivan
authors.forename: Eileen Z
authors.initials: EZ
authors.lastname: Zhang
authors.forename: Ann M
authors.initials: AM
authors.lastname: Tigges
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Dorrian
authors.forename: Sandra
authors.initials: S
authors.lastname: De Meyer
authors.forename: Darin
authors.initials: D
authors.lastname: Takemoto
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Dondero
authors.forename: Ann D
authors.initials: AD
authors.lastname: Kwong
authors.forename: Gaston
authors.initials: G
authors.lastname: Picchio
authors.forename: Tara L
authors.initials: TL
authors.lastname: Kieffer
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage* / Q000494:pharmacology; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000302:isolation & purification*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010949:Plasma / Q000821:virology; D012367:RNA, Viral / Q000235:genetics; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase