Lawitz Eric J, Dvory-Sobol Hadas, Doehle Brian P, Worth Angela S, McNally John, Brainard Diana M, Link John O, Miller Michael D, Mo Hongmei
Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas, USA.
Gilead Sciences, Foster City, California, USA
Antimicrob Agents Chemother. 2016 Aug 22;60(9):5368-78. doi: 10.1128/AAC.00763-16. Print 2016 Sep.
Velpatasvir (VEL, GS-5816) is a novel pan-genotypic hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor with activity against genotype 1 (GT1) to GT6 HCV replicons. In a phase 1b 3-day monotherapy study, patients treated with a 150-mg dose of GS-5816 had a mean maximal HCV RNA decline of ≥3.3 log10 IU/ml in GT1a, -1b, -2, -3, and -4. This report characterizes virologic resistance to VEL in these patients. NS5A resistance-associated substitutions (RASs) were detected by deep sequencing (1% cutoff) pretreatment in 22/70 patients, i.e., 10/35 (29%) patients with GT1a, 1/8 (13%) with GT1b, 4/8 (50.0%) with GT2, 5/17 (29.4%) with GT3, and 2/2 (100.0%) with GT4. In GT1a and GT3 patients, pretreatment RASs were associated with a slightly reduced HCV RNA response compared to that of patients without pretreatment RASs; among patients with GT1b, GT2, and GT4, no significant difference in response was observed in those with or without pretreatment RASs. Following treatment, the pattern of emergent RASs was more complex for GT1a than for the other genotypes. In GT1a, substitutions emerged at positions M28, Q30, L31, P32, H58, E92, and Y93, with the most prevalent substitutions at positions Y93, M28, and L31. RASs were observed at two positions in GT1b and GT2 (Y93 and L31), three positions in GT3 (Y93, L31, and E92), and four positions in GT4 (L28, M31, P32L, and Y93). RASs that were present pretreatment persisted through the 48-week follow-up period; however, RASs emerging during treatment were more likely to decline both in prevalence and in frequency within the viral population during follow-up. (This study has been registered at ClinicalTrials.gov under registration no. NCT01740791.).
维帕他韦（VEL，GS - 5816）是一种新型的泛基因型丙型肝炎病毒（HCV）非结构蛋白5A（NS5A）抑制剂，对1型（GT1）至6型HCV复制子具有活性。在一项1b期3天单药治疗研究中，接受150 mg剂量GS - 5816治疗的GT1a、-1b、-2、-3和-4型患者的HCV RNA平均最大下降幅度≥3.3 log10 IU/ml。本报告描述了这些患者对VEL的病毒学耐药情况。通过深度测序（截断值为1%）在22/70例患者治疗前检测到NS5A耐药相关替代（RASs），即10/35（29%）例GT1a型患者、1/8（13%）例GT1b型患者、4/8（50.0%）例GT2型患者、5/17（29.4%）例GT3型患者和2/2（100.0%）例GT4型患者。在GT1a和GT3型患者中，与无治疗前RASs的患者相比，治疗前RASs与HCV RNA反应略有降低相关；在GT1b、GT2和GT4型患者中，有或无治疗前RASs的患者在反应上未观察到显著差异。治疗后出现的RASs模式在GT1a型中比在其他基因型中更复杂。在GT1a型中，替代出现在M28、Q30、L31、P32、H58、E92和Y93位点，最常见的替代出现在Y93、M28和L31位点。在GT1b和GT2型的两个位点（Y93和L31）、GT3型的三个位点（Y93、L31和E92）以及GT4型的四个位点（L28、M31、P32L和Y93）观察到RASs。治疗前存在的RASs在48周随访期内持续存在；然而，治疗期间出现的RASs在随访期间病毒群体中的流行率和频率更有可能下降。（本研究已在ClinicalTrials.gov注册，注册号为NCT01740791。）
