Mo Hongmei, Hedskog Charlotte, Lawitz Eric, Brainard Diana M, Yang Jenny, Delaney William, Worth Angela, Miller Michael D
Gilead Sciences Inc, Foster City, CA, USA.
Gilead Sciences Inc, Foster City, CA, USA.
Antiviral Res. 2017 Apr;140:151-157. doi: 10.1016/j.antiviral.2017.01.015. Epub 2017 Jan 26.
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 log 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.
NS3蛋白酶抑制剂（PI）GS-9256在一项单药治疗研究以及与其他直接抗病毒药物（DAA）联合用于治疗慢性丙型肝炎病毒（HCV）感染的研究中均显示出抗病毒活性。在一项针对HCV基因1型（GT1）感染患者的1期单药治疗研究中，对GS-9256的耐药谱进行了调查。通过群体测序（截断值为15%），在纳入该研究的54例患者中，基线时未观察到36、155、156、168和170位的PI耐药相关替代（RAS），然而，在41%的患者基线时检测到PI RAS Q80K。在接受75mg研究性蛋白酶抑制剂（PI）GS-9256每日两次（BID）、300mg GS-9256每日一次（QD）和200mg GS-9256每日两次治疗三天的患者中，治疗后分别在9/21、3/7和8/8的患者中观察到NS3 RAS（A156V、R155K、D168G/E/N/V）。治疗后在任何患者中均未选择Q80K。在200mg每日两次的队列中，平均最大病毒载量反应为-3.0±0.42 log IU/mL HCV RNA。在第4天检测到RAS的患者中，超过50%的患者在第14天通过群体测序不再能检测到突变。1例患者的R155K突变持续至第24周。表型分析表明，R155、A156和D168位的替代显著降低了对GS-9256的敏感性。总之，尽管基线时未检测到NS3 PI RAS，但在大多数接受GS-9256单药治疗的患者中迅速选择了NS3 PI RAS。在患者中鉴定出的R155、A156和D168替代在体外使对GS-9256和其他PI的敏感性降低。
