Kitrinos K M, Corsa A C, Worth A, Hedskog C, Brainard D M, Miller M D, Mo H
Gilead Sciences, Inc., Foster City, CA, USA.
J Viral Hepat. 2018 Feb;25(2):126-133. doi: 10.1111/jvh.12783. Epub 2017 Oct 4.
The study aimed to evaluate the effects of baseline hepatitis C virus (HCV) nonstructural protein 5A (NS5A) resistance-associated substitutions (RASs) on sustained virologic response to ledipasvir (LDV)-containing regimens in the absence of sofosbuvir (SOF) in patients with HCV genotype (GT) 1 infection across 6 phase 2 clinical studies. We analysed data from 1103 patients who received either LDV + vedroprevir (NS3 protease inhibitor) + tegobuvir (NS5B inhibitor) ± ribavirin or LDV + ribavirin + pegylated interferon. Population sequencing of HCV NS5A was performed at baseline and at virologic failure from patient plasma samples. Of 1045 patients with available baseline sequences, 747 (67.7%) had GT1a, and 298 (26.9%) had GT1b infection. The overall prevalence of NS5A RASs at baseline was 9.4%; 7.6% (57/747) and 13.8% (41/298) of patients with GT1a and GT1b infection, respectively. The majority of GT1a-infected patients with NS5A RASs at baseline had a single NS5A RAS (78.9%) at NS5A positions K24R, M28T, Q30H/L, L31M and Y93H/N/C/S. The spectrum of NS5A RASs detected in GT1b patients was much less diverse compared to GT1a patients, with all patients harbouring a single NS5A RAS either L31M or Y93H/C. For patients treated with LDV-containing regimens in the absence of SOF, the presence of baseline NS5A RASs was associated with low SVR rates. In patients with virologic failure, nearly all had either pre-existing and/or emergent NS5A RASs: 287/287 (100%) and 40/42 (95.2%) patients with GT1a and GT1b infection, respectively. Three novel NS5A substitutions were identified as emergent NS5A RASs: K26E and S38F in GT1a; and L31I in GT1b. In conclusion, the presence of NS5A RASs at baseline reduced the SVR rate in patients treated with LDV in combination vedroprevir + tegobuvir ± ribavirin or ribavirin + pegylated interferon. Virologic failure was associated with the detection of NS5A RASs in nearly all patients. These results suggest that the resistance barrier may differ depending on HCV drug combination and may be more important than that of the individual DAAs.
该研究旨在通过6项2期临床研究，评估丙型肝炎病毒（HCV）基因型（GT）1感染患者在无索磷布韦（SOF）情况下，基线丙型肝炎病毒非结构蛋白5A（NS5A）耐药相关置换（RASs）对含来迪派韦（LDV）方案持续病毒学应答的影响。我们分析了1103例接受LDV + 维帕他韦（NS3蛋白酶抑制剂）+ 替比夫定（NS5B抑制剂）± 利巴韦林或LDV + 利巴韦林 + 聚乙二醇干扰素治疗患者的数据。在基线和病毒学失败时，对患者血浆样本进行HCV NS5A群体测序。在1045例有可用基线序列的患者中，747例（67.7%）为GT1a感染，298例（26.9%）为GT1b感染。基线时NS5A RASs的总体患病率为9.4%；GT1a和GT1b感染患者中分别为7.6%（57/747）和13.8%（41/298）。基线时存在NS5A RASs的大多数GT1a感染患者在NS5A的K24R、M28T、Q30H/L、L31M和Y93H/N/C/S位点有单个NS5A RAS（78.9%）。与GT1a患者相比，GT1b患者中检测到的NS5A RASs谱更单一，所有患者均有单个NS5A RAS，即L31M或Y93H/C。对于在无SOF情况下接受含LDV方案治疗的患者，基线NS5A RASs的存在与低SVR率相关。在病毒学失败的患者中，几乎所有患者都有既往存在和/或新出现的NS5A RASs：GT1a和GT1b感染患者分别为287/287（100%）和40/42（95.2%）。三个新的NS5A置换被鉴定为新出现的NS5A RASs：GT1a中的K26E和S38F；GT1b中的L31I。总之，基线时NS5A RASs的存在降低了接受LDV联合维帕他韦 + 替比夫定 ± 利巴韦林或利巴韦林 + 聚乙二醇干扰素治疗患者的SVR率。病毒学失败与几乎所有患者中检测到NS5A RASs相关。这些结果表明，耐药屏障可能因HCV药物组合而异，可能比单个直接抗病毒药物更重要。
