Genotypic and Phenotypic Analyses of Hepatitis C Virus from Patients Treated with JTK-853 in a Three-Day Monotherapy
| Autor: | Kunihiro Hirahara, Gabriela Turcanu, Toru Noguchi, Barbara Gerhardt, Yukiyo Toyonaga, Sudhakar M. Pai, Kan Yee, Maribel Rodriguez-Torres, Tsutomu Shibata, Naoki Ogura, Izuru Ando |
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| Rok vydání: | 2013 |
| Předmět: |
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 |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 57:436-444 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.01432-12 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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