Emergence of telaprevir-resistant variants detected by ultra-deep sequencing after triple therapy in patients infected with HCV genotype 1
Emergence of telaprevir-resistant variants detected by ultra-deep sequencing after triple therapy in patients infected with HCV genotype 1
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DOI：
10.1002/jmv.23579
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发表时间：
2013-06-01
影响因子：
12.7
通讯作者：
Kumada, Hiromitsu
中科院分区：
文献类型：
--
作者：
Akuta, Norio;Suzuki, Fumitaka;Kumada, Hiromitsu
使用超深度测序技术，本研究旨在研究在既往双联治疗无应答者中，在开始特拉匹韦/聚乙二醇干扰素（PEG-IFN）/利巴韦林三联治疗后，是否可以在基线预测特拉匹韦耐药变异体（HCV NS 3区aa 36、aa 54、aa 155、aa 156和aa 170位置的氨基酸取代）的出现。14例感染HCV基因型1的患者，他们对以前的PEG-IFN/利巴韦林没有反应，接受了24周的三联疗法，并通过超深度测序评估了特拉普韦耐药变异体的出现（总覆盖率中超过0.2%的氨基酸取代）。持续病毒学应答率为28.6%（14例患者中的4例），Arg 70（核心aa 70替换）和部分应答（既往对PEG-IFN/利巴韦林应答的类型）患者的持续病毒学应答率显著高于其他患者。通过直接测序在7.1%（14例患者中的1例）中检测到基线时的特拉帕韦耐药变异，通过超深度测序在21.4%（14例患者中的3例）中检测到。在10名没有表现出持续病毒学应答者的患者中，通过超深度测序检查了特拉普韦耐药变异体的出现。无论基线时的变异频率如何，病毒载量重新升高时均出现新发变异（1例患者出现极高频变异[T54 S：99.9%]，2例患者出现极低频变异[V36 A：0.2%;和V170 A：0.4%]，7例患者出现无法检测到的变异）。它的结论是，这是很难预测在基线出现特拉匹韦耐药变异开始后，在以前的无应答者的HCV基因型1的三联治疗，即使使用超深度测序。医学病毒学杂志85：10281036，2013。(c)2013 Wiley Periodicals，Inc.
Using ultra-deep sequencing technology, the present was designed to investigate whether the emergence of telaprevir-resistant variants (amino acid substitutions of aa36, aa54, aa155, aa156, and aa170 positions in HCV NS3 region) after commencement of triple therapy of telaprevir/peginterferon (PEG-IFN)/ribavirin could be predicted at baseline in previous non-responders to dual therapy. Fourteen patients infected with HCV genotype 1 who did not respond to previous PEG-IFN/ribavirin, received a 24-week regimen of triple therapy, and were evaluated for appearance of telaprevir-resistant variants (amino acid substitutions of more than 0.2% among the total coverage) by ultra-deep sequencing. The sustained virological response rate was 28.6% (4 of 14 patients), which was significantly higher in patients with Arg70 (substitution at core aa70) and partial response (type of previous response to PEG-IFN/ribavirin) than in other patients. Telaprevir-resistant variants at baseline were detected in 7.1% (1 of 14 patients) by direct sequencing and in 21.4% (3 of 14 patients) by ultra-deep sequencing. The appearance of telaprevir-resistant variants was examined by ultra-deep sequencing in 10 who did not show sustained virological responders. De novo variants emerged at re-elevation of viral load, regardless of variant frequencies at baseline (one patient with very high frequency variants [T54S: 99.9%], two patients with very low frequency variants [V36A: 0.2%; and V170A: 0.4%], and seven patients of undetectable variants). It is concluded that it is difficult to predict at baseline the emergence of telaprevir-resistant variants after commencement of triple therapy in prior non-responders of HCV genotype 1, even with the use of ultra-deep sequencing. J. Med. Virol. 85: 10281036, 2013. (c) 2013 Wiley Periodicals, Inc.