整合酶抑制剂耐药突变的监测用于传播的 HIV-1 药物耐药性。
Integrase strand transfer inhibitor (INSTI)-resistance mutations for the surveillance of transmitted HIV-1 drug resistance.
机构信息
Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA, USA.
Université de Paris, IAME, INSERM, F-75018, Paris, France; AP-HP, Hôpital Bichat, Laboratoire de Virologie, F-75018, Paris, France.
出版信息
J Antimicrob Chemother. 2020 Jan 1;75(1):170-182. doi: 10.1093/jac/dkz417.
BACKGROUND
Integrase strand transfer inhibitors (INSTIs) are expected to be widely adopted globally, requiring surveillance of resistance emergence and transmission.
OBJECTIVES
We therefore sought to develop a standardized list of INSTI-resistance mutations suitable for the surveillance of transmitted INSTI resistance.
METHODS
To characterize the suitability of the INSTI-resistance mutations for transmitted HIV-1 drug resistance (TDR) surveillance, we classified them according to their presence on published expert lists, conservation in INSTI-naive persons, frequency in INSTI-treated persons and contribution to reduced in vitro susceptibility. Mutation prevalences were determined using integrase sequences from 17302 INSTI-naive and 2450 INSTI-treated persons; 53.3% of the INSTI-naive sequences and 20.0% of INSTI-treated sequences were from non-B subtypes. Approximately 10% of sequences were from persons who received dolutegravir alone or a first-generation INSTI followed by dolutegravir.
RESULTS
Fifty-nine previously recognized (or established) INSTI-resistance mutations were present on one or more of four published expert lists. They were classified into three main non-overlapping groups: 29 relatively common non-polymorphic mutations, occurring in five or more individuals and significantly selected by INSTI treatment; 8 polymorphic mutations; and 22 rare mutations. Among the 29 relatively common INSTI-selected mutations, 24 emerged as candidates for inclusion on a list of INSTI surveillance drug-resistance mutations: T66A/I/K, E92G/Q, G118R, F121Y, E138A/K/T, G140A/C/S, Y143C/H/R/S, S147G, Q148H/R/K, N155H, S230R and R263K.
CONCLUSIONS
A set of 24 non-polymorphic INSTI-selected mutations is likely to be useful for quantifying INSTI-associated TDR. This list may require updating as more sequences become available from INSTI-experienced persons infected with HIV-1 non-subtype B viruses and/or receiving dolutegravir.
背景
整合酶链转移抑制剂（INSTIs）有望在全球范围内广泛使用，因此需要监测耐药性的出现和传播。
目的
我们旨在开发一套适用于监测传播性 INSTI 耐药性的标准化 INSTI 耐药突变列表。
方法
为了确定 INSTI 耐药突变是否适合用于监测传播性 HIV-1 药物耐药性（TDR），我们根据其在已发表的专家列表中的存在情况、INSTI 初治个体中的保守性、INSTI 治疗个体中的频率以及对体外敏感性降低的贡献程度进行分类。通过对 17302 例 INSTI 初治和 2450 例 INSTI 治疗个体的整合酶序列进行分析，确定突变的流行率；53.3%的 INSTI 初治序列和 20.0%的 INSTI 治疗序列来自非 B 亚型。大约 10%的序列来自接受单独多替拉韦或第一代 INSTI 后换用多替拉韦的个体。
结果
4 份已发表的专家列表中有 59 种先前已识别（或已确定）的 INSTI 耐药突变。这些突变分为 3 个主要的非重叠组：29 种相对常见的非多态性突变，在 5 个或更多个体中出现，并且受到 INSTI 治疗的显著选择；8 种多态性突变；以及 22 种罕见突变。在 29 种相对常见的 INSTI 选择突变中，24 种突变被确定为纳入 INSTI 监测药物耐药突变列表的候选者：T66A/I/K、E92G/Q、G118R、F121Y、E138A/K/T、G140A/C/S、Y143C/H/R/S、S147G、Q148H/R/K、N155H、S230R 和 R263K。
结论
一组 24 种非多态性 INSTI 选择突变可能有助于定量评估 INSTI 相关 TDR。随着来自 INSTI 经验丰富的感染 HIV-1 非 B 亚型病毒和/或接受多替拉韦个体的更多序列出现，该列表可能需要更新。
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