Gozlan Yael, Ben-Ari Ziv, Moscona Roy, Shirazi Rachel, Rakovsky Aviya, Kabat Arij, Veizman Ella, Berdichevski Tania, Weiss Peretz, Cohen-Ezra Oranit, Lurie Yoav, Gafanovich Inna, Braun Marius, Cohen-Naftaly Michal, Shlomai Amir, Shibolet Oren, Zigmond Ehud, Zuckerman Eli, Carmiel-Haggai Michal, Nimer Assy, Hazzan Rawi, Maor Yaakov, Kitay-Cohen Yona, Shemer-Avni Yonat, Kra-Oz Zipi, Schreiber Licita, Peleg Ofer, Sierra Saleta, Harrigan P Richard, 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. 2017;22(5):431-441. doi: 10.3851/IMP3123. Epub 2017 Jan 9.
Direct-acting antiviral (DAA) treatment regimens and response rates of patients with HCV genotype-1 (GT1) are currently considered subtype-dependent. Identification of clinically relevant resistance-associated substitutions (RASs) in the NS3 and NS5A proteins at baseline and in DAA failures, may also impact clinical decisions.
In a multicentre cohort study (n=308), NS3 or NS5B sequencing (n=248) was used to discriminate between GT1 subtypes. The correlation between baseline NS3 and NS5A RASs on the 12-week sustained virological response (SVR12) rates of 160 of the patients treated with second-generation DAAs was also assessed. Post-treatment resistance analysis was performed on samples from 58 patients exhibiting DAA virological failure.
GT1a, GT1b and GT1d subtypes were identified in 23.0%, 75.4% and 1.2% of tested samples. GT1b was most prevalent (97.7%, 128/131) among patients born in the former Soviet Union. The Q80K NS3 RAS was identified in 17.5% (10/57) of the GT1a carriers, most of whom were Israeli-born. NS3 and NS5A baseline RASs showed a negligible correlation with SVR12 rates. Treatment-emergent RASs were observed among 8.9% (4/45) and 76.9% (10/13) of first- and second-generation DAA failures, respectively, with D168V/E (NS3), Y93H and L31M (NS5A) being the most prevalent mutations.
NS3 sequencing analysis can successfully discriminate between GT1 subtypes and identify NS3 amino acid substitutions. While pre-treatment NS3 and NS5A RASs marginally affect second-generation DAA SVR12 rates, post-treatment resistance analysis should be considered prior to re-therapy.
目前认为，丙型肝炎病毒1型（GT1）患者的直接抗病毒（DAA）治疗方案和缓解率具有亚型依赖性。在基线时以及DAA治疗失败时，鉴定NS3和NS5A蛋白中临床相关的耐药相关替代位点（RAS），可能也会影响临床决策。
在一项多中心队列研究（n = 308）中，采用NS3或NS5B测序（n = 248）来区分GT1亚型。还评估了160例接受第二代DAA治疗的患者基线NS3和NS5A RAS与12周持续病毒学应答（SVR12）率之间的相关性。对58例出现DAA病毒学失败的患者的样本进行治疗后耐药性分析。
在23.0%、75.4%和1.2%的检测样本中分别鉴定出GT1a、GT1b和GT1d亚型。在前苏联出生的患者中，GT1b最为常见（97.7%，128/131）。在17.5%（10/57）的GT1a携带者中鉴定出Q80K NS3 RAS位点，其中大多数是在以色列出生。NS3和NS5A基线RAS与SVR12率之间的相关性可忽略不计。在第一代和第二代DAA治疗失败的患者中，分别有8.9%（4/45）和76.9%（10/13）观察到治疗中出现的RAS，其中D168V/E（NS3）、Y93H和L31M（NS5A）是最常见的突变。
NS3测序分析能够成功区分GT1亚型并鉴定NS3氨基酸替代位点。虽然治疗前NS3和NS5A RAS对第二代DAA的SVR12率影响较小，但在再次治疗前应考虑进行治疗后耐药性分析。
