Camus G, Han B, Asselah T, Hsieh D, Dvory-Sobol H, Lu J, Svarovskaia E, Martin R, Parhy B, Miller M D, Brainard D M, Kersey K, Abergel A, Mo H
Gilead Sciences, Inc., Foster City, CA, USA.
Department of Hepatology, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Université Paris-Diderot and INSERM UMR1149, Clichy, France.
J Viral Hepat. 2018 Feb;25(2):134-143. doi: 10.1111/jvh.12795. Epub 2017 Nov 7.
HCV genotype 4 (GT4) has often been overlooked in drug development, even though it infects ~20 million people worldwide. Ledipasvir/sofosbuvir and sofosbuvir/velpatasvir were highly efficacious in GT4 HCV-infected patients from GS-US-337-1119 and GS-US-342-1138. Here, we characterize the resistance profile of ledipasvir (LDV) and velpatasvir (VEL) in patients with GT4 HCV infection. NS5A deep-sequencing was performed for 454 patients infected with HCV GT4 at baseline, including 44 patients enrolled in GS-US-337-1119 and 116 patients enrolled in GS-US-342-1138, and at relapse for patients with virologic failure. LDV and VEL susceptibilities of 56 patient isolates were determined. In GS-US-337-1119, SVR12 rates were 100% for all subtypes except 4b and 4r. Phenotypic assessment of 56 HCV NS5A patient isolates from various GT4 subtypes indicated that LDV had high potency for the common subtypes 4a/d, and subtypes 4c/f/k/l/m/n/o/p/r/t despite the presence of resistance-associated substitutions (RASs). For the rare GT4b, LDV median EC was higher, but with a broad range of individual values. Importantly, all GT4b isolates tested had 2-4 NS5A RASs, some including Y93H. Similarly, the 2 GT4r infected patients who had virologic relapse had rare triple RASs. Reversion of these substitutions to the consensus residue significantly increased LDV susceptibility. In GS-US-342-1138, all patients achieved SVR12, regardless of their subtype or presence of RASs. In vitro data confirmed that VEL is potent against all GT4 isolates tested. LDV and VEL are potent antiviral drugs, estimated to be effective against >95% and >99%, respectively, of GT4 HCV isolates.
丙型肝炎病毒基因4型（GT4）在药物研发中常常被忽视，尽管全球约有2000万人感染该病毒。来迪派韦/索磷布韦以及索磷布韦/维帕他韦在GS-US-337-1119和GS-US-342-1138研究中感染GT4型丙型肝炎病毒的患者中显示出高效性。在此，我们对感染GT4型丙型肝炎病毒患者中来迪派韦（LDV）和维帕他韦（VEL）的耐药谱进行了特征分析。对454例基线感染GT4型丙型肝炎病毒的患者进行了NS5A深度测序，其中包括GS-US-337-1119研究中的44例患者以及GS-US-342-1138研究中的116例患者，对病毒学失败患者在复发时也进行了测序。测定了56株患者分离株对LDV和VEL的敏感性。在GS-US-337-1119研究中，除4b和4r亚型外，所有亚型的12周持续病毒学应答（SVR12）率均为100%。对来自不同GT4亚型的56株丙型肝炎病毒NS5A患者分离株进行的表型评估表明，尽管存在耐药相关置换（RASs），LDV对常见亚型4a/d以及亚型4c/f/k/l/m/n/o/p/r/t仍具有高效力。对于罕见的GT4b亚型，LDV的半数有效浓度（EC）中位数较高，但个体值范围较宽。重要的是，所有检测的GT4b分离株均有2 - 4个NS5A RASs，有些包括Y93H。同样，2例发生病毒学复发的GT4r感染患者有罕见的三重RASs。将这些置换回复为共有残基可显著增加LDV的敏感性。在GS-US-342-1138研究中，所有患者均实现了SVR12，无论其亚型或是否存在RASs。体外数据证实VEL对所有检测的GT4分离株均有强效作用。LDV和VEL都是强效抗病毒药物，估计分别对>95%和>99%的GT4型丙型肝炎病毒分离株有效。
