1. Genotypic and Phenotypic Analyses of Hepatitis C Virus from Patients Treated with JTK-853 in a Three-Day Monotherapy
- Author
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Kunihiro Hirahara, Gabriela Turcanu, Toru Noguchi, Barbara Gerhardt, Yukiyo Toyonaga, Sudhakar M. Pai, Kan Yee, Maribel Rodriguez-Torres, Tsutomu Shibata, Naoki Ogura, and Izuru Ando
- Subjects
Genotype ,Arginine ,Hepatitis C virus ,Phenylalanine ,Hepacivirus ,Viral Nonstructural Proteins ,Biology ,medicine.disease_cause ,Antiviral Agents ,Drug Administration Schedule ,Piperazines ,Placebos ,chemistry.chemical_compound ,Double-Blind Method ,Drug Resistance, Viral ,medicine ,Humans ,Pharmacology (medical) ,Amino Acids ,NS5B ,Pharmacology ,chemistry.chemical_classification ,Methionine ,Sequence Analysis, DNA ,Hepatitis C ,Virology ,Amino acid ,Phenotype ,Infectious Diseases ,Amino Acid Substitution ,chemistry ,Mutation ,Replicon ,Leucine - 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.
- Published
- 2013