Lack of impact of pre-existing T97A HIV-1 integrase mutation on integrase strand transfer inhibitor resistance and treatment outcome.
Lack of impact of pre-existing T97A HIV-1 integrase mutation on integrase strand transfer inhibitor resistance and treatment outcome.
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DOI：
10.1371/journal.pone.0172206
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Miller MD
中科院分区：
文献类型：
--
作者：
Abram ME;Ram RR;Margot NA;Barnes TL;White KL;Callebaut C;Miller MD
T97 A是与整合酶链转移抑制剂（Integrase strand transfer inhibitor，TIMI）抗性相关的HIV-1整合酶多态性。使用来自16项临床研究的汇总数据，我们调查了T97 A（既存和紧急）的患病率及其对INSTI初治患者的ESTI敏感性和治疗反应的影响，这些患者接受了基于埃替拉韦（EVG）或雷特拉韦（RAL）的方案。在基于INSTI的治疗之前，原发性HIV-1耐药相关突变（RAM）不存在，T97 A很少预先存在（1.4%; 3367个整合酶序列中的47个）;最常见于非B（5.3%）而非B（0.9%）HIV-1亚型。在基于INSTI的治疗期间，很少有患者发生病毒学失败，出现了紧急的T97 A RAM（3%; 3881例患者中的122例），其中T97 A在存在（n = 6）或不存在（n = 8）原发性T97 A RAM的情况下很少出现。既存和紧急T97 A患者人群之间的比较（即，在没有原发性RAMs的情况下）在体外显示EVG或RAL易感性没有显著差异。此外，在所有测试的含T97 A的病毒中，仅38-44%表现出对EVG和/或RAL的敏感性降低（均为低幅度; <11倍），而所有病毒均保持对度鲁特韦的敏感性。在既存T97 A的患者中，17例进行了临床随访：16例实现了病毒学抑制，1例保持了T97 A和INSTI敏感性，没有进一步产生耐药性。总的来说，T97 A是一种罕见的整合酶多态性，在非B HIV-1亚型中富集，可使EVG和/或RAL的易感性降低。然而，T97 A的检测不影响对EVG或RAL的基于INSTI的治疗的反应。这些结果表明，在既存T97 A患者中启动基于INSTI的治疗的风险非常低。
T97A is an HIV-1 integrase polymorphism associated with integrase strand transfer inhibitor (INSTI) resistance. Using pooled data from 16 clinical studies, we investigated the prevalence of T97A (pre-existing and emergent) and its impact on INSTI susceptibility and treatment response in INSTI-naive patients who enrolled on elvitegravir (EVG)- or raltegravir (RAL)-based regimens. Prior to INSTI-based therapy, primary INSTI resistance-associated mutations (RAMs) were absent and T97A pre-existed infrequently (1.4%; 47 of 3367 integrase sequences); most often among non-B (5.3%) than B (0.9%) HIV-1 subtypes. During INSTI-based therapy, few patients experienced virologic failure with emergent INSTI RAMs (3%; 122 of 3881 patients), among whom T97A emerged infrequently in the presence (n = 6) or absence (n = 8) of primary INSTI RAMs. A comparison between pre-existing and emergent T97A patient populations (i.e., in the absence of primary INSTI RAMs) showed no significant differences in EVG or RAL susceptibility in vitro. Furthermore, among all T97A-containing viruses tested, only 38–44% exhibited reduced susceptibility to EVG and/or RAL (all of low magnitude; <11-fold), while all maintained susceptibility to dolutegravir. Of the patients with pre-existing T97A, 17 had available clinical follow-up: 16 achieved virologic suppression and 1 maintained T97A and INSTI sensitivity without further resistance development. Overall, T97A is an infrequent integrase polymorphism that is enriched among non-B HIV-1 subtypes and can confer low-level reduced susceptibility to EVG and/or RAL. However, detection of T97A does not affect response to INSTI-based therapy with EVG or RAL. These results suggest a very low risk of initiating INSTI-based therapy in patients with pre-existing T97A.