title: Genotypic and phenotypic analyses of hepatitis C virus from patients treated with JTK-853 in a three-day monotherapy.
abstract: JTK-853, a palm site-binding NS5B nonnucleoside polymerase inhibitor, shows antiviral activity in vitro and in hepatitis C virus (HCV)-infected patients. Here, we report the results of genotypic and phenotypic analyses of resistant variants in 24 HCV genotype 1-infected patients who received JTK-853 (800, 1,200, or 1,600 mg twice daily or 1,200 mg three times daily) in a 3-day monotherapy. Viral resistance in NS5B was investigated using HCV RNA isolated from serum specimens from the patients. At the end of treatment (EOT) with JTK-853, the amino acid substitutions M414T (methionine [M] in position 414 at baseline was replaced with threonine [T] at EOT), C445R (cysteine [C] in position 445 at baseline was replaced with arginine [R] at EOT), Y448C/H (tyrosine [Y] in position 448 at baseline was replaced with cysteine [C] or histidine [H] at EOT), and L466F (leucine [L] in position 466 at baseline was replaced with phenylalanine [F] at EOT), which are known to be typical resistant variants of nonnucleoside polymerase inhibitors, were observed in a clonal sequencing analysis. These substitutions were also selected by a treatment with JTK-853 in vitro, and the 50% effective concentration of JTK-853 in the M414T-, C445F-, Y448H-, and L466V-harboring replicons attenuated the susceptibility by 44-, 5-, 6-, and 21-fold, respectively, compared with that in the wild-type replicon (Con1). These findings suggest that amino acid substitutions of M414T, C445R, Y448C/H, and L466F are thought to be viral resistance mutations in HCV-infected patients receiving JTK-853 in a 3-day monotherapy.
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ogura
authors.forename: Yukiyo
authors.initials: Y
authors.lastname: Toyonaga
authors.forename: Izuru
authors.initials: I
authors.lastname: Ando
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hirahara
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Shibata
authors.forename: Gabriela
authors.initials: G
authors.lastname: Turcanu
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Pai
authors.forename: Kan
authors.initials: K
authors.lastname: Yee
authors.forename: Barbara
authors.initials: B
authors.lastname: Gerhardt
authors.forename: Maribel
authors.initials: M
authors.lastname: Rodriguez-Torres
authors.forename: Toru
authors.initials: T
authors.lastname: Noguchi
mesh_terms: D019943:Amino Acid Substitution; D000596:Amino Acids / Q000235:genetics; D000998:Antiviral Agents / Q000494:pharmacology*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D009154:Mutation; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology*; D010919:Placebos; D012093:Replicon / Q000187:drug effects; D017422:Sequence Analysis, DNA; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000596:Amino Acids; D000998:Antiviral Agents; D010879:Piperazines; D010919:Placebos; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C578010:JTK-853