Gozlan Yael, Bucris Efrat, Shirazi Rachel, Rakovsky Avia, Ben-Ari Ziv, Davidov Yana, Veizman Ella, Saadi Tarek, Braun Marius, Cohen-Naftaly Michal, Shlomai Amir, Shibolet Oren, Zigmond Ehud, Katchman Helena, Menachem Yoram, Safadi Rifaat, Galun Eitan, Zuckerman Eli, Nimer Assy, Hazzan Rawi, Maor Yaakov, Saif Abu Moch, Etzion Ohad, Lurie Yoav, Mendelson Ella, Mor Orna
Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat Gan, Israel.
Liver Disease Center, Sheba Medical Center, Ramat Gan, Israel.
Antivir Ther. 2019;24(3):221-228. doi: 10.3851/IMP3301.
Direct-acting antiviral (DAA) therapy has dramatically increased sustained virological response rates in HCV-infected patients. However, resistance-associated substitutions (RAS) interfering with NS3- and NS5A-targeted therapy, still emerge. This real-life study analysed the type and frequency of RAS in rare cases of patients failing DAA regimens in 12 clinical centres in Israel.
Blood samples and clinical data from 49 patients who failed various DAAs were collected. RAS identified in the NS3 and NS5A regions by population (Sanger) and next-generation sequencing (NGS) were compared by treatment regimen and HCV subtypes.
The majority (71.4%, 35/49) of patients were infected with the genotype (GT)1b strain, while 12.2% (6/49) carried GT1a and 14.3% GT3a/b (7), GT4a (1) and GT1b/GT3a. RAS were identified in 85.7% (42/49) of failures, of which 90.5% (38/42) were clinically relevant RAS (known to be associated with a specific GT and DAA in patients failing therapy or those with more than twofold change in in vitro replicon assays). The most abundant RAS were 168A/E/Q/G/N/V (32.6%, 16/49) identified in NS3, and 93H/N (61.2%, 30/49), 31I/M/V (34.7%, 17/49) and 30R/H/K (12.2%, 6/49), identified in NS5A. Significantly more clinically relevant RAS were identified in NS5A (82.2%, 37/45) than in NS3 (35.7%, 10/28; P<0.01). While RAS were identified in all GT1a, GT3b and GT4a failures (100%, 10/10), only 71.8% (28/39) of GT1b or GT3a failures had RAS (P=0.09). In four cases, NGS identified additional clinically relevant RAS and in one patient, NGS deciphered coexistence of GT3a and GT1b infections.
Our findings, together with additional real-life data, will contribute to the optimization of retreatment in DAA failure, when cost-related and suboptimal regimens must be employed.
直接抗病毒（DAA）疗法显著提高了丙型肝炎病毒（HCV）感染患者的持续病毒学应答率。然而，仍会出现干扰针对NS3和NS5A的治疗的耐药相关替代（RAS）。这项真实世界研究分析了以色列12个临床中心接受DAA方案治疗失败的罕见患者中RAS的类型和频率。
收集了49例接受各种DAA治疗失败患者的血样和临床数据。通过群体（桑格）测序和二代测序（NGS）在NS3和NS5A区域鉴定的RAS，按治疗方案和HCV亚型进行比较。
大多数患者（71.4%，35/49）感染了基因1b型（GT1b）毒株，12.2%（6/49）携带GT1a，14.3%携带GT3a/b（7例）、GT4a（1例）和GT1b/GT3a。在85.7%（42/49）的治疗失败患者中鉴定出RAS，其中90.5%（38/42）为临床相关RAS（已知与治疗失败患者或体外复制子试验中变化超过两倍的患者的特定GT和DAA相关）。最常见的RAS是在NS3中鉴定出的168A/E/Q/G/N/V（32.6%，16/49），以及在NS5A中鉴定出的93H/N（61.2%，30/49）、31I/M/V（34.7%，17/49）和30R/H/K（12.2%，6/49）。在NS5A中鉴定出的临床相关RAS（82.2%，37/45）显著多于NS3（35.7%，10/28；P<0.01）。虽然在所有GT1a、GT3b和GT4a治疗失败患者中均鉴定出RAS（100%，10/10），但只有71.8%（28/39）的GT1b或GT3a治疗失败患者有RAS（P=0.09）。在4例患者中，NGS鉴定出额外的临床相关RAS，在1例患者中，NGS解读出GT3a和GT1b感染共存。
我们的研究结果以及其他真实世界数据，将有助于在必须采用与成本相关且并非最佳的方案时，优化DAA治疗失败后的再治疗。
