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通过超深度测序研究 HCV 基因型 1b 中simeprevir 耐药变异株的时间演变。

Evolution of simeprevir-resistant variants over time by ultra-deep sequencing in HCV genotype 1b.

机构信息

Department of Hepatology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan.

出版信息

J Med Virol. 2014 Aug;86(8):1314-22. doi: 10.1002/jmv.23966. Epub 2014 May 5.

Abstract

Using ultra-deep sequencing technology, the present study was designed to investigate the evolution of simeprevir-resistant variants (amino acid substitutions of aa80, aa155, aa156, and aa168 positions in HCV NS3 region) over time. In Toranomon Hospital, 18 Japanese patients infected with HCV genotype 1b, received triple therapy of simeprevir/PEG-IFN/ribavirin (DRAGON or CONCERT study). Sustained virological response rate was 67%, and that was significantly higher in patients with IL28B rs8099917 TT than in those with non-TT. Six patients, who did not achieve sustained virological response, were tested for resistant variants by ultra-deep sequencing, at the baseline, at the time of re-elevation of viral loads, and at 96 weeks after the completion of treatment. Twelve of 18 resistant variants, detected at re-elevation of viral load, were de novo resistant variants. Ten of 12 de novo resistant variants become undetectable over time, and that five of seven resistant variants, detected at baseline, persisted over time. In one patient, variants of Q80R at baseline (0.3%) increased at 96-week after the cessation of treatment (10.2%), and de novo resistant variants of D168E (0.3%) also increased at 96-week after the cessation of treatment (9.7%). In conclusion, the present study indicates that the emergence of simeprevir-resistant variants after the start of treatment could not be predicted at baseline, and the majority of de novo resistant variants become undetectable over time. Further large-scale prospective studies should be performed to investigate the clinical utility in detecting simeprevir-resistant variants.

摘要

本研究采用超深度测序技术,旨在随时间推移研究simeprevir 耐药变异体(HCV NS3 区 aa80、aa155、aa156 和 aa168 位置的氨基酸取代)的演变。在 Toranomon 医院,18 例感染 HCV 基因型 1b 的日本患者接受了simeprevir/PEG-IFN/利巴韦林三联治疗(DRAGON 或 CONCERT 研究)。持续病毒学应答率为 67%,IL28B rs8099917 TT 患者显著高于非 TT 患者。6 例未达到持续病毒学应答的患者在基线时、病毒载量再次升高时和治疗结束后 96 周时通过超深度测序检测耐药变异体。在病毒载量再次升高时检测到的 18 种耐药变异体中的 12 种为新出现的耐药变异体。12 种新出现的耐药变异体中有 10 种随时间推移而无法检测到,而 7 种基线检测到的耐药变异体中有 5 种随时间推移而持续存在。在 1 例患者中,基线时(0.3%)的 Q80R 变异体在治疗停止后 96 周时增加(10.2%),而治疗停止后 96 周时(9.7%)新出现的 D168E 耐药变异体也增加。总之,本研究表明,治疗开始后 simeprevir 耐药变异体的出现无法在基线时预测,大多数新出现的耐药变异体随时间推移而无法检测到。应进行进一步的大规模前瞻性研究,以探讨检测 simeprevir 耐药变异体的临床应用价值。

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