Kjellin Midori, Kileng Hege, Akaberi Dario, Palanisamy Navaneethan, Duberg Ann-Sofi, Danielsson Astrid, Kristiansen Magnhild Gangsøy, Nöjd Johan, Aleman Soo, Gutteberg Tore, Goll Rasmus, Lannergård Anders, Lennerstrand Johan
Department of Medical Sciences, Section of Clinical Microbiology, Uppsala University , Uppsala , Sweden.
Gastroenterology and Nutrition Research Group, Department of Clinical Medicine, UiT the Arctic University of Norway , Tromsø , Norway.
Scand J Gastroenterol. 2019 Aug;54(8):1042-1050. doi: 10.1080/00365521.2019.1652846. Epub 2019 Aug 19.
The NS5A resistance-associated substitution (RAS) Y93H is found quite frequently (5-10%) at baseline in direct-acting antiviral agents (DAA) treatment-naïve genotype (GT) 3a patients when studied by the population-sequencing method (cut-off 20%). This RAS may impair HCV DAA treatment response, since it possesses a high fold resistance to daclatasvir (DCV) and velpatasvir (VEL) in GT 3. We investigated the effect of baseline Y93H in patients with GT 3a infection on treatment outcome, with or without resistance-based DAA-treatment during 2014-2017. Treatment in the intervention group ( = 130) was tailored to baseline resistance-findings by population-sequencing method. Detection of baseline Y93H above 20% prompted a prolonged treatment duration of NS5A-inhibitor and sofosbuvir (SOF) and/or addition of ribavirin (RBV). Patients without baseline Y93H in the intervention group and all patients in the control group ( = 78) received recommended standard DAA-treatment. A higher sustained virologic response rate (SVR) in the intervention group was shown compared to the control group at 95.4% (124/130) and 88.5% (69/78), respectively ( = .06). All five patients with baseline Y93H in the intervention group achieved SVR with personalised treatment based on results from resistance testing; either with the addition of RBV or prolonged treatment duration (24w). In the control group, 2/4 patients with Y93H at baseline treated with ledipasvir/SOF/RBV or DCV/SOF without RBV, failed treatment. The results from this real-life study are in accordance with the findings of the randomised controlled trials in 2015 and the EASL-guidelines of 2016, thus, baseline Y93H impacts on DCV and VEL treatment outcome.
当采用群体测序法（临界值为20%）进行研究时，在未经直接抗病毒药物（DAA）治疗的基因型（GT）3a患者基线中，NS5A耐药相关替代（RAS）Y93H相当常见（5%-10%）。这种RAS可能会损害HCV DAA治疗反应，因为它对GT 3中的达卡他韦（DCV）和维帕他韦（VEL）具有高度耐药性。我们调查了2014年至2017年期间GT 3a感染患者基线Y93H对治疗结果的影响，无论是否采用基于耐药性的DAA治疗。干预组（n = 130）的治疗根据群体测序法的基线耐药性检测结果进行调整。基线Y93H检测值高于20%会促使NS5A抑制剂和索磷布韦（SOF）的治疗疗程延长，和/或加用利巴韦林（RBV）。干预组中无基线Y93H的患者以及对照组（n = 78）的所有患者均接受推荐的标准DAA治疗。干预组的持续病毒学应答率（SVR）高于对照组，分别为95.4%（124/130）和88.5%（69/78）（P = 0.06）。干预组中所有五名基线Y93H患者通过基于耐药性检测结果的个性化治疗均实现了SVR；要么加用RBV，要么延长治疗疗程（24周）。在对照组中，4名基线Y93H患者中有2名接受来迪派韦/索磷布韦/利巴韦林或达卡他韦/索磷布韦（未加用RBV）治疗，治疗失败。这项真实研究的结果与2015年随机对照试验以及2016年欧洲肝脏研究学会（EASL）指南的结果一致，因此，基线Y93H会影响DCV和VEL的治疗结果。
