Department of Medicine, Stanford University, Stanford, California, USA.
AIDS Res Hum Retroviruses. 2021 Oct;37(10):736-743. doi: 10.1089/AID.2020.0261. Epub 2021 Apr 15.
There has been no systematic review of the prevalence of transmitted integrase strand transfer inhibitor (INSTI) resistance. We systematically searched the English-language PubMed database and GenBank to identify studies published since 2010 reporting 50 or more INSTI-naive HIV-1-infected adults undergoing integrase genotyping. We extracted data related to country, sample year, specimen type, sequencing method, and subtype. For studies with sequences in GenBank, we determined the prevalence of three categories of INSTI-associated resistance mutations: (1) nonpolymorphic INSTI-selected drug resistance mutations (DRMs) that we refer to as surveillance DRMs; (2) rarely selected nonpolymorphic INSTI-associated DRMs; and (3) common polymorphic accessory INSTI-selected DRMs. A total of 103 studies met inclusion criteria including 75 studies in GenBank containing integrase sequences from 16,481 INSTI-naive persons. The median sample year was 2013 (interquartile range: 2008-2014). The prevalence of INSTI surveillance DRMs, rarely selected DRMs, and common polymorphic accessory INSTI-selected DRMs were 0.5%, 0.8%, and 6.2%, respectively. There was no association between the presence of nonpolymorphic surveillance DRM and region, sample year, or subtype. Two surveillance DRMs, E138K and R263K occurred in 0.15% and 0.10% of naive sequences, respectively. Several lines of evidence suggested that the 0.5% prevalence of surveillance DRMs partly reflects the cumulative natural occurrence of these mutations in the absence of selective drug pressure. There was an unexplained temporal increase in the proportion of sequences with polymorphic accessory mutations. The prevalence of INSTI-associated surveillance DRMs is low even in regions where INSTIs have been a major component of antiretroviral therapy for several years. The presence of INSTI-associated surveillance DRMs in INSTI-naive persons likely results from actual cases of transmitted INSTI resistance and from a low background level reflecting the cumulative rare natural occurrence of several nonpolymorphic mutations.
目前尚未对整合酶抑制剂耐药的传播流行率进行系统评估。我们系统地检索了英文的 PubMed 数据库和 GenBank，以确定自 2010 年以来发表的报告了 50 例或更多整合酶基因未发生突变的 HIV-1 感染成人接受整合酶基因分型的研究。我们提取了与国家、样本年份、标本类型、测序方法和亚型相关的数据。对于 GenBank 中包含序列的研究，我们确定了三种整合酶相关耐药突变的流行率：（1）我们称为监测耐药突变的非多态性整合酶选择药物耐药突变；（2）很少选择的非多态性整合酶相关耐药突变；（3）常见多态性辅助整合酶选择药物耐药突变。共有 103 项研究符合纳入标准，其中包括 75 项 GenBank 中的研究，包含了 16481 例整合酶未发生突变的个体的整合酶序列。中位样本年份为 2013 年（四分位间距：2008-2014 年）。整合酶监测耐药突变、很少选择的耐药突变和常见多态性辅助整合酶选择药物耐药突变的流行率分别为 0.5%、0.8%和 6.2%。非多态性监测耐药突变的存在与区域、样本年份或亚型无关。两种监测耐药突变 E138K 和 R263K 分别出现在 0.15%和 0.10%的未发生突变的序列中。有几条证据表明，0.5%的监测耐药突变的流行率部分反映了这些突变在没有选择性药物压力的情况下的累积自然发生。具有多态性辅助突变的序列比例存在无法解释的时间性增加。即使在整合酶抑制剂已成为抗逆转录病毒治疗的主要药物数年的地区，整合酶抑制剂相关监测耐药突变的流行率也很低。整合酶未发生突变的个体中存在整合酶抑制剂相关监测耐药突变可能是由于实际发生的传播性整合酶耐药以及由于几种非多态性突变的累积罕见自然发生而导致的低背景水平。
