Khalil Roaa, Al-Mahzoum Kholoud, Barakat Muna, Sallam Malik
Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan.
Department of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy, Applied Science Private University, Amman 11931, Jordan.
Pathogens. 2024 Aug 9;13(8):674. doi: 10.3390/pathogens13080674.
Direct-acting antivirals (DAAs) revolutionized the therapeutics of chronic hepatitis C. The emergence and transmission of HCV variants with resistance-associated substitutions (RASs) can undermine HCV treatment. This study aimed to assess the prevalence and temporal trends of RASs in HCV, with a particular focus on clinically relevant RASs (cr-RASs). Near-complete HCV GenBank sequences archived in the Los Alamos HCV Database were analyzed. The study period was divided into two phases: before 2011 and from 2011 onward. Identification of RASs across three DAA classes (NS3, NS5A, and NS5B inhibitors) was based on the 2020 EASL guidelines. The AASLD-IDSA recommendations were used to identify cr-RASs for three HCV genotypes/subtypes (1a, 1b, and 3) and four DAA regimens: ledipasvir/sofosbuvir; elbasvir/grazoprevir; sofosbuvir/velpatasvir; and glecaprevir/pibrentasvir. The final HCV dataset comprised 3443 sequences, and the prevalence of RASs was 50.4%, 60.2%, and 25.3% in NS3, NS5A, and NS5B, respectively. In subtype 1a, resistance to ledipasvir/sofosbuvir was 32.8%, while resistance to elbasvir/grazoprevir was 33.0%. For genotype 3, resistance to sofosbuvir/velpatasvir and glecaprevir/pibrentasvir was 4.2% and 24.9%, respectively. A significant increase in cr-RASs was observed across the two study phases as follows: for ledipasvir/sofosbuvir in subtype 1a, cr-RASs increased from 30.2% to 35.8% ( = 0.019); for elbasvir/grazoprevir in subtype 1a, cr-RASs increased from 30.4% to 36.1% ( = 0.018); In subtype 1b, neither ledipasvir/sofosbuvir nor elbasvir/grazoprevir showed any cr-RASs in the first phase, but both were present at a prevalence of 6.5% in the second phase ( < 0.001); for sofosbuvir/velpatasvir in genotype 3, cr-RASs increased from 0.9% to 5.2% ( = 0.006); and for glecaprevir/pibrentasvir, cr-RASs increased from 12.0% to 29.1% ( < 0.001). The rising prevalence of HCV RASs and cr-RASs was discernible. This highlights the necessity for ongoing surveillance and adaptation of novel therapeutics to manage HCV resistance effectively. Updating the clinical guidelines and treatment regimens is recommended to counteract the evolving HCV resistance to DAAs.
直接作用抗病毒药物（DAAs）彻底改变了慢性丙型肝炎的治疗方法。具有耐药相关替代（RASs）的HCV变体的出现和传播会破坏HCV治疗。本研究旨在评估HCV中RASs的流行情况和时间趋势，特别关注临床相关RASs（cr-RASs）。对保存在洛斯阿拉莫斯HCV数据库中的近完整HCV基因库序列进行了分析。研究期分为两个阶段：2011年之前和2011年以后。基于2020年欧洲肝脏研究学会（EASL）指南对三类DAA（NS3、NS5A和NS5B抑制剂）中的RASs进行鉴定。美国肝病研究学会（AASLD）-美国感染病学会（IDSA）的建议用于鉴定三种HCV基因型/亚型（1a、1b和3）和四种DAA治疗方案中的cr-RASs：来迪派韦/索磷布韦；艾尔巴韦/格拉瑞韦；索磷布韦/维帕他韦；以及格卡瑞韦/哌仑他韦。最终的HCV数据集包含3443个序列，NS3、NS5A和NS5B中RASs的流行率分别为50.4%、60.2%和25.3%。在1a亚型中，对来迪派韦/索磷布韦的耐药率为32.8%，而对艾尔巴韦/格拉瑞韦的耐药率为33.0%。对于基因型3，对索磷布韦/维帕他韦和格卡瑞韦/哌仑他韦的耐药率分别为4.2%和24.9%。在两个研究阶段观察到cr-RASs有显著增加，如下所示：对于1a亚型中的来迪派韦/索磷布韦，cr-RASs从30.2%增加到35.8%（P = 0.019）；对于1a亚型中的艾尔巴韦/格拉瑞韦，cr-RASs从30.4%增加到36.1%（P = 0.018）；在1b亚型中，来迪派韦/索磷布韦和艾尔巴韦/格拉瑞韦在第一阶段均未显示任何cr-RASs，但在第二阶段两者的流行率均为6.5%（P < 0.001）；对于基因型3中的索磷布韦/维帕他韦，cr-RASs从0.9%增加到5.2%（P = 0.006）；对于格卡瑞韦/哌仑他韦，cr-RASs从1十二点零%增加到29.1%（P < 0.001）。HCV RASs和cr-RASs的流行率呈上升趋势。这凸显了持续监测以及调整新型治疗方法以有效管理HCV耐药性的必要性。建议更新临床指南和治疗方案以应对HCV对DAAs不断演变的耐药性。
