这项研究分析了NS3和NS5A的突变频率,在现实生活中的患者队列的持久性和药物敏感性,在直接作用抗病毒(DAA)治疗后,丙型肝炎病毒(HCV)治疗失败。
来自105名感染HCV基因型(G)1a(6,5.7%)的患者的NS3/NS5ASanger序列,G1b(94,89.5%),G3a(4,3.8%),分析了DAA治疗失败后的G4(1.1.0%)。使用geno2pheno算法鉴定NS3和NS5A抗性相关取代(RAS),并与临床变量相关。使用逻辑回归检查时间趋势。
在87.9%的暴露于此类药物的患者中发现了NS5ARAS,而在59.1%的HCV蛋白酶暴露受试者中发现了NS3RAS。NS3RAS的频率随着纤维化分期而增加,从F0/F1个体的40.0%到肝硬化患者的81.8%(F4,p=0.094)。28A/V/M的NS5A突变频率为7.6%,30K/Q/R为10.6%,31I/F/M/V的42.4%,93H为75.8%。对于NS3,最常见的RAS为56F-23.7%,168A/E/I/Y/T/V-14.0%,117H-5.4%。对glecaprevir/pibrentasvir的易感性,velpatasvir/voxlaprevir,elbasvir/grazoprevir保留了92.9%,43.4%,and,25.3%的患者,分别。NS3RAS的频率随着从失败到采样的时间而降低(趋势p=0.034)。NS5ARAS频率在24个月内保持稳定。
DAA治疗失败后,NS5A和NS3RAS在晚期肝病患者中常见,频率增加。在大多数情况下,尽管存在RAS,保留了遗传障碍较高的DAA组合的易感性。
This study analysed the NS3 and NS5A mutation frequencies, persistence and drug susceptibility in a cohort of real-life patients, with failed hepatitis C virus (HCV) therapy following directly acting antiviral (DAA) treatment.
NS3/NS5A Sanger sequences from 105 patients infected with HCV genotype (G) 1a (6,5.7%), G1b (94,89.5%), G3a (4,3.8%), and G4 (1,1.0%) post DAA treatment failure were analysed. NS3 and NS5A resistance-associated substitutions (RASs) were identified using the geno2pheno algorithm and associated with clinical variables. Time trends were examined using logistic regression.
NS5A RAS were found in 87.9% of sequences derived from patients exposed to this class of agents, whereas NS3 RAS was found in 59.1% of HCV protease-exposed subjects. The frequency of the NS3 RAS increased with fibrosis stage, from 40.0% among F0/F1 individuals to 81.8% among patients with liver cirrhosis (F4, p = 0.094). NS5A mutation frequencies were 7.6% for 28A/V/M, 10.6% for 30 K/Q/R, 42.4% for 31I/F/M/V, and 75.8% for 93H. For NS3, the most common RASs were 56F-23.7%, 168A/E/I/Y/T/V-14.0%, and 117H-5.4%. Susceptibility to glecaprevir/pibrentasvir, velpatasvir/voxlaprevir, and elbasvir/grazoprevir was retained in 92.9%, 43.4%, and, 25.3% of patients, respectively. The frequency of NS3 RAS decreased with time elapsed from failure to sampling (p = 0.034 for trend). NS5A RAS frequency remained stable over the 24-months.
Following DAA treatment failure, NS5A and NS3 RASs were common with increasing frequency among patients with advanced liver disease. In most cases, despite the presence of RASs, susceptibility to DAA combinations with higher genetic barrier was retained.