Antiviral response and resistance analysis of treatment-naïve HCV infected patients receiving multiple doses of the NS3 protease inhibitor GS-9256
| Autor: | Charlotte Hedskog, William E. Delaney, Diana M. Brainard, Michael D. Miller, Jenny C. Yang, Eric Lawitz, Angela Worth, Hongmei Mo |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
Male 0301 basic medicine medicine.medical_specialty Genotype 030106 microbiology Population Hepacivirus Viral Nonstructural Proteins medicine.disease_cause Peptides Cyclic Gastroenterology Virus 03 medical and health sciences 0302 clinical medicine Double-Blind Method Virology Internal medicine Drug Resistance Viral medicine Humans Protease Inhibitors Protease inhibitor (pharmacology) 030212 general & internal medicine education Pharmacology education.field_of_study Mutation NS3 Dose-Response Relationship Drug business.industry High-Throughput Nucleotide Sequencing Hepatitis C Chronic Middle Aged Viral Load Hepatitis C Phosphinic Acids Cohort Female business Viral load |
| Zdroj: | Antiviral Research. 140:151-157 |
| ISSN: | 0166-3542 |
| DOI: | 10.1016/j.antiviral.2017.01.015 |
| Popis: | The NS3 protease inhibitor (PI) GS-9256 has demonstrated antiviral activity in a monotherapy study and in combination with other DAAs for treatment of chronic hepatitis C virus (HCV) infection. The resistance profile of GS-9256 was investigated in a phase 1 monotherapy study of patients with HCV genotype (GT) 1 infection. No PI resistance associated substitutions (RASs) at positions 36, 155, 156, 168 and 170 were observed at baseline by population sequencing (15% cutoff) in the 54 patients enrolled in the study, however the PI RAS Q80K were detected in 41% of patients at baseline. In patients who received 75 mg of the investigational protease inhibitor (PI) GS-9256 BID, 300 mg of GS-9256 QD and 200 mg of GS-9256 BID for three days, NS3 RASs (A156V, R155K, D168G/E/N/V) were observed in 9/21, 3/7 and 8/8 post-treatment, respectively. Q80K was not selected in any patients post-treatment. The mean maximal viral load response was −3.0 ± 0.42 log10 IU/mL HCV RNA in the 200 mg BID cohort. In more than 50% of the patients with RASs detected at Day 4, mutations were no longer detectable by population sequencing at Day 14. One patient had the R155K mutation persist to Week 24. Phenotypic analyses showed that substitutions at R155, A156 and D168 significantly reduced susceptibility to GS-9256. In conclusion, NS3 PI RASs were rapidly selected in the majority of patients receiving GS-9256 as monotherapy, despite undetectable levels at baseline. The R155, A156 and D168 substitutions identified in patients confer reduced susceptibility to GS-9256 and other PIs in vitro. |
| Databáze: | OpenAIRE |
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