Wyles David, Mangia Alessandra, Cheng Wendy, Shafran Stephen, Schwabe Christian, Ouyang Wen, Hedskog Charlotte, McNally John, Brainard Diana M, Doehle Brian P, Svarovskaia Evguenia, Miller Michael D, Mo Hongmei, Dvory-Sobol Hadas
Division of Infectious Diseases, Denver Health and Hospital Authority, Denver, CO, USA.
Liver Unit, Department of Medical Sciences IRCCS 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy.
Antivir Ther. 2018;23(3):229-238. doi: 10.3851/IMP3181.
Data on persistence of NS5A resistance-associated substitutions (RASs) may have implications for resistance testing approaches and selection of initial and retreatment strategies.
Long-term persistence of NS5A RASs in HCV genotype (GT) 1 infected subjects (n=76) who did not achieve sustained virological response after receiving ledipasvir (LDV) without sofosbuvir (SOF) and were subsequently enrolled in an ongoing 3-year follow-up registry study was investigated by population or deep sequencing.
Of the 76 subjects enrolled, 67 and 9 subjects had GT1a and GT1b infection, respectively. At pretreatment, NS5A RASs were detected in 14% of subjects (11/76) by population sequencing, with three subjects having >1 RAS. All RASs that were detected at pretreatment persisted and were observed at the 96 week visit in the follow-up study (FU96). For the remaining subjects with no detectable RASs at pretreatment, RASs were detected in 98% (63/64) of subjects at virological failure in the parent study and persisted at detectable levels through FU96 in 86% of subjects by deep sequencing (1% cutoff). However, a decline in the quasispecies frequency of most RASs and the number of RASs per subject was observed over time. Phenotypic analysis demonstrated that the majority of NS5A RASs confer similar levels of resistance to LDV and daclatasvir.
The majority of NS5A RASs can persist at detectable levels for >96 weeks post-treatment in subjects who failed treatment with regimens containing an NS5A inhibitor without SOF, suggesting relatively high fitness of NS5A RASs even in the absence of drug pressure.
NS5A 耐药相关替代位点（RASs）的持续性数据可能对耐药性检测方法以及初始治疗和再治疗策略的选择具有重要意义。
通过群体或深度测序，对 76 例 HCV 基因 1 型（GT1）感染患者进行了研究，这些患者在接受不含索磷布韦（SOF）的来迪派韦（LDV）治疗后未实现持续病毒学应答，随后纳入了一项正在进行的为期 3 年的随访登记研究。
在纳入的 76 例患者中，分别有 67 例和 9 例感染 GT1a 和 GT1b。在治疗前，通过群体测序在 14%（11/76）的患者中检测到 NS5A RASs，其中 3 例患者有>1 个 RAS。在治疗前检测到的所有 RASs 在随访研究的 96 周访视时（FU96）仍然存在并被观察到。对于其余在治疗前未检测到 RASs 的患者，在原研究中病毒学失败时，98%（63/64）的患者检测到 RASs，通过深度测序（1%的截断值），86%的患者在 FU96 时 RASs 持续处于可检测水平。然而，随着时间的推移，大多数 RASs 的准种频率和每位患者的 RASs 数量均有所下降。表型分析表明，大多数 NS5A RASs 对 LDV 和达卡他韦具有相似水平的耐药性。
在接受不含 SOF 的含 NS5A 抑制剂方案治疗失败的患者中，大多数 NS5A RASs 在治疗后可在可检测水平持续>96 周，这表明即使在没有药物压力的情况下，NS5A RASs 也具有相对较高的适应性。
