直接作用抗病毒治疗失败后 HCV 耐药相关替代 - 来自波兰的真实数据。

HCV resistance-associated substitutions following direct-acting antiviral therapy failure - Real-life data from Poland.

机构信息

Department of Infectious, Tropical Diseases and Immune Deficiency, Pomeranian Medical University in Szczecin, Szczecin, Poland.

Department of Basic Medical Sciences, The School of Health Sciences in Bytom, Medical University of Silesia, Bytom, Poland.

出版信息

Infect Genet Evol. 2021 Sep;93:104949. doi: 10.1016/j.meegid.2021.104949. Epub 2021 Jun 1.

DOI:10.1016/j.meegid.2021.104949

PMID:34087494

Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

摘要

背景

本研究分析了直接作用抗病毒（DAA）治疗后丙型肝炎病毒（HCV）治疗失败的真实患者队列中 NS3 和 NS5A 突变频率、持续性和药物敏感性。

方法

对 105 例经 DAA 治疗失败后感染 HCV 基因型（G）1a（6，5.7%）、G1b（94，89.5%）、G3a（4，3.8%）和 G4（1，1.0%）的患者的 NS3/NS5A Sanger 序列进行了分析。使用 geno2pheno 算法鉴定 NS3 和 NS5A 耐药相关替代（RAS），并与临床变量相关联。使用逻辑回归检查时间趋势。

结果

在暴露于该类药物的患者中，87.9%的 NS5A RAS 序列中发现了 RAS，而在暴露于 HCV 蛋白酶的患者中，59.1%的 NS3 RAS 序列中发现了 RAS。随着纤维化阶段的增加，NS3 RAS 的频率也增加，从 F0/F1 个体中的 40.0%增加到肝硬化患者中的 81.8%（F4，p=0.094）。NS5A 突变频率为 28A/V/M 为 7.6%，30K/Q/R 为 10.6%，31I/F/M/V 为 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%和 117H-5.4%。对 glecaprevir/pibrentasvir、velpatasvir/voxlaprevir 和 elbasvir/grazoprevir 的敏感性分别保留在 92.9%、43.4%和 25.3%的患者中。随着从失败到采样的时间推移（趋势 p=0.034），NS3 RAS 的频率降低。NS5A RAS 频率在 24 个月内保持稳定。