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首页> 外文期刊>Infection and Drug Resistance >Clinical and virological properties of hepatitis C virus genotype 4 infection in patients treated with different direct-acting antiviral agents
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Clinical and virological properties of hepatitis C virus genotype 4 infection in patients treated with different direct-acting antiviral agents

机译：不同直接作用抗病毒药物治疗的丙型肝炎病毒基因型4感染的临床和病毒学特征

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Background: The efficacy of direct-acting antivirals (DAAs) depends on the hepatitis C virus (HCV) genotype 4 (GT4) subtype which are used in the treatment of HCV. We aimed to -retrospectively investigate the baseline prevalence of HCV NS5A and NS5B polymorphisms and their impact on virological outcome in GT4-infected patients treated with various DAA regimens. Patients and methods: Available plasma samples from HCV GT4-infected patients treated with different DAA regimens were analyzed at baseline and after treatment failure, where applicable. Sanger sequencing of patient-derived NS5A and NS5B regions was performed on all available samples, while ultradeep pyrosequencing (UDPS) of NS5A and NS5B regions was performed only on samples from treatment failures at different time points. Results: Sustained virological response (SVR) was achieved by 96% (48/50) of patients. Of 16 patients with baseline NS5A sequence, polymorphisms at amino acid positions associated with drug resistance were detected only at position 58: P58 (69.2%) and T58 (30.8%). Of 21 patients with baseline NS5B sequence, N142S was detected only in the two treatment failures, both with GT4d were treated with sofosbuvir (SOF)-based regimens, suggesting a potential involvement in SOF efficacy. Two patients (patient 1 [Pt1] and patient 2 [Pt2]) relapsed. In Pt1, NS5A-T56I and NS5A-Y93H/S emerged. In Pt2, NS5A-L28F emerged and a novel NS5B resistance-associated substitution (RAS), L204F, representing 1.5% of the viral population at baseline, enriched to 71% and 91.6% during and after treatment failure, respectively. UDPS of NS5B from Pt2 indicated a mixed infection of approximately 1:5, GT1a:GT4d, at baseline and GT4d during failure. Phylogenetic analysis of NS5A sequences indicated no clustering of HCV strains from patients achieving SVR vs patients who relapsed. The mean genetic distance in NS5A sequences was 5.8%, while a lower genetic distance (3.1%) was observed in NS5B sequences. Conclusion: Results from these analyses confirm the importance of UDPS in the analysis of viral quasispecies variability and the identification of novel RASs potentially associated with DAA treatment failure in HCV GT4-infected patients.
机译：背景：直接作用抗病毒药（DAA）的疗效取决于用于治疗HCV的丙型肝炎病毒（HCV）基因型4（GT4）亚型。我们的目的是回顾性调查在接受各种DAA方案治疗的GT4感染患者中HCV NS5A和NS5B多态性的基线患病率及其对病毒学结局的影响。患者和方法：在基线和治疗失败后（适用时）分析了接受不同DAA方案治疗的HCV GT4感染患者的可用血浆样本。对所有可用样品进行患者来源的NS5A和NS5B区的Sanger测序，而仅对不同时间点因治疗失败而导致的样品进行NS5A和NS5B区的超深焦磷酸测序（UDPS）。结果：96％（48/50）的患者实现了持续的病毒学应答（SVR）。在16位具有基线NS5A序列的患者中，与耐药性相关的氨基酸位置的多态性仅在位置58处检测到：P58（69.2％）和T58（30.8％）。在21位具有基线NS5B序列的患者中，仅在两次治疗失败中均检测到N142S，均使用基于sofosbuvir（SOF）的方案对GT4d进行了治疗，表明可能参与了SOF疗效。两名患者（患者1 [Pt1]和患者2 [Pt2]）复发。在Pt1中，出现了NS5A-T56I和NS5A-Y93H / S。在Pt2中，出现了NS5A-L28F，一个新的NS5B抗药性相关取代（RAS）L204F在基线时占病毒种群的1.5％，在治疗失败期间和治疗后分别增至71％和91.6％。来自Pt2的NS5B的UDPS表明在基线和故障期间GT4d的混合感染约为1：5，即GT1a：GT4d。对NS5A序列的系统进化分析表明，与实现复发的患者相比，实现SVR的患者的HCV株没有聚集。 NS5A序列的平均遗传距离为5.8％，而NS5B序列的平均遗传距离较低（3.1％）。结论：这些分析的结果证实了UDPS在分析病毒准种变异性以及鉴定与HCV GT4感染的患者的DAA治疗失败相关的新型RAS方面的重要性。

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