Gilead Sciences, Inc., Foster City, California, USA.
Gilead Sciences, Inc., Foster City, California, USA
J Clin Microbiol. 2019 Mar 28;57(4). doi: 10.1128/JCM.01844-18. Print 2019 Apr.
Voxilaprevir is a direct-acting antiviral agent (DAA) that targets the NS3/4A protease of hepatitis C virus (HCV). High sequence diversity of HCV and inadequate drug exposure during unsuccessful treatment may lead to the accumulation of variants with reduced susceptibility to DAAs, including NS3/4A protease inhibitors such as voxilaprevir. The voxilaprevir susceptibility of clinical and laboratory strains of HCV was assessed. The NS3 protease regions of viruses belonging to 6 genotypes and 29 subtypes from 345 DAA-naive or -experienced (including protease inhibitor) patients and 344 genotype 1 to 6 replicons bearing engineered NS3 resistance-associated substitutions (RASs) were tested in transient-transfection assays. The median voxilaprevir 50% effective concentration against NS3 from protease inhibitor-naive patient samples ranged from 0.38 nM for genotype 1 to 5.8 nM for genotype 3. Voxilaprevir susceptibilities of HCV replicons with NS3 RASs were dependent on subtype background and the type and number of substitutions introduced. The majority of RASs known to confer resistance to other protease inhibitors had little to no impact on voxilaprevir susceptibility, except A156L, T, or V in genotype 1 to 4 which conferred >100-fold reductions but exhibited low replication capacity in most genotypes. These data support the use of voxilaprevir in combination with other DAAs in DAA-naive and DAA-experienced patients infected with any subtype of HCV.
伏西拉普韦是一种直接作用抗病毒药物（DAA），针对丙型肝炎病毒（HCV）的 NS3/4A 蛋白酶。HCV 的序列高度多样化，以及在不成功的治疗中药物暴露不足，可能导致对 DAA 的敏感性降低的变异体积累，包括 NS3/4A 蛋白酶抑制剂，如伏西拉普韦。评估了临床和实验室 HCV 株对伏西拉普韦的敏感性。在瞬时转染试验中，检测了来自 345 名 DAA 初治或经治（包括蛋白酶抑制剂）患者和 344 名携带工程化 NS3 耐药相关取代（RAS）的 1 至 6 型 HCV 复制子的病毒 6 个基因型和 29 个亚型的 NS3 蛋白酶区域。来自蛋白酶抑制剂初治患者样本的 NS3 的伏西拉普韦 50%有效浓度（EC50）中位数范围为基因型 1 的 0.38 nM 至基因型 3 的 5.8 nM。具有 NS3 RAS 的 HCV 复制子对伏西拉普韦的敏感性取决于亚型背景以及引入的取代类型和数量。除了在基因型 1 至 4 中导致 >100 倍降低但在大多数基因型中表现出低复制能力的 A156L、T 或 V 外，大多数已知对其他蛋白酶抑制剂产生耐药性的 RAS 对伏西拉普韦的敏感性几乎没有影响。这些数据支持在感染任何 HCV 亚型的 DAA 初治和经治患者中使用伏西拉普韦与其他 DAA 联合使用。
