HIV-1 subtype, specific drug resistance in patients failing Dolutegravir-based 1st, 2nd or 3rd line regimens: the International epidemiological Databases to Evaluate AIDS (IeDEA)

摘要 艾滋病毒感染的抗逆转录病毒疗法(ART)一直是全球最成功的公共卫生干预措施之一。 但艾滋病毒耐药性的出现是对结束艾滋病毒流行的一种威胁。下一阶段的 全球艾滋病毒的反应将依赖于整合酶链转移抑制剂(InSTI)，特别是多洛替格列韦(DTG)， 强大的抗逆转录病毒，具有很高的抗药性遗传屏障。DTG被推荐用于所有治疗路线(1， 二线和三线)，来自同一类别的药物是为前 暴露预防。对DTG选择的突变和它们的光谱的了解有限 对表型易感性的影响，特别是在非B亚型病毒中，以及突变的重要性 整合酶基因之外。建立可靠的系统以早期检测INSTI耐药性是至关重要的 艾滋病毒治疗计划，并发展对DTG耐药性在哪里以及如何发生的真实理解 世界各地的人。我们建议在美国国立卫生研究院资助的国际流行病学数据库中这样做，以评估艾滋病 (IeDEA)和抗逆转录病毒治疗队列合作(ART-CC)。具体地说，我们的目标是：i)确定 病毒学失败的成人和青少年中Insti耐药突变的模式和谱 基于DTG的ART方案和HIV-1亚型；ii)确定病毒学失败和耐药性的风险因素 青少年和成人对基于DTG的抗逆转录病毒治疗；以及iii)调查新的抵抗力之间的相关性 HIV-1亚型间的基因型别和表型INSTI耐药性。总共有46个IeDEA站点和7个ART-CC 来自32个国家的队列将参与这项研究。十个站点和队列将贡献现有数据(Sanger 序列和临床数据)，而不是前瞻性地招募患者；19个站点和队列将做出贡献 切换和失败时的样本或序列对，32个将贡献关于青少年的数据。我们将包括 成人(≥18岁)和青少年(10-17岁)病毒学失败(病毒载量≥1000拷贝/毫升) 以艺术为基础。分析将基于大约4600名未能通过基于DTG的ART的患者和大约490名患有 DTG耐药突变。我们将使用Illumina MiSeq Next进行全基因组测序- 用于检测整合酶突变和整合酶外突变(例如，在3‘端)的生成测序平台 Nef基因的多尿路区域)。我们将把这些数据与来自北方的现有序列数据结合起来 美国和欧洲的同龄人。我们将比较不同频率下Insti DRM的患病率 ART方案和HIV-1亚型的阈值(20%、5%和2%)。我们将确定病毒学失败的预测因素 和耐药性，并通过进行 对HIV-1亚型范围内的选定样本进行表型测试。我们的建议有三个关键 优势：i)在一个庞大的全球网络中汇集临床和序列数据，以探索决定因素 第一、第二和第三线抗逆转录病毒疗法患者对DTG的耐药性；ii)纳入多种HIV-1亚型 地理领域和iii)结合临床、流行病学、生物学和计算领域的专业知识。

ABSTRACT Antiretroviral therapy (ART) of HIV infection has been one of the most successful public health interventions in history, but the emergence of HIV drug resistance is a threat to ending the HIV epidemic. The next phase of the global HIV response will rely on integrase strand transfer inhibitors (InSTIs), particularly dolutegravir (DTG), a potent antiretroviral with a high genetic barrier to resistance. DTG is recommended for all lines of treatment (1st, 2nd- and 3rd-line) by the World Health Organization, and drugs from the same class are developed for pre- exposure prophylaxis. There is limited understanding of the spectrum of DTG-selected mutations and their effects on phenotypic susceptibility, particularly in non-B subtype viruses, and of the importance of mutations outside of the integrase gene. It is critical to establish robust systems for early detection of InSTI resistance in HIV treatment programs, and develop an understanding of where and how resistance to DTG occurs in real world cohorts. We propose to do this in the NIH-funded International epidemiology Databases to Evaluate AIDS (IeDEA) and the Antiretroviral Therapy Cohort Collaboration (ART-CC). Specifically, we aim i) to determine the patterns and spectrum of InSTI drug resistance mutations in adults and adolescents with virologic failure on DTG-based ART by regimen and HIV-1 subtype; ii) to identify risk factors for virologic failure and resistance in adolescents and adults on DTG-based ART; and iii) to investigate correlations between novel resistance genotypes and phenotypic InSTI resistance across HIV-1 subtypes. In total, 46 IeDEA sites and 7 ART-CC cohorts from 32 countries will participate in this study. Ten sites and cohorts will contribute existing data (Sanger sequences and clinical data), rather than prospectively recruiting patients; 19 sites and cohorts will contribute pairs of samples or sequences at switch and failure, and 32 will contribute data on adolescents. We will include adults (≥18 years) and adolescents (10-17 years) with virologic failure (viral load ≥1000 copies/mL) on any DTG- based ART. Analyses will be based on about 4600 patients failing DTG-based ART and about 490 patients with DTG drug resistance mutations. We will perform whole genome sequencing using the Illumina MiSeq next- generation sequencing platform to detect integrase mutations and mutations outside integrase (e.g. in the 3' polypurine tract region of the nef gene). We will combine the data with existing sequence data from North American and European cohorts. We will compare the prevalence of InSTI DRMs at different frequency thresholds (20%, 5%, and 2%) by ART regimen and HIV-1 subtype. We will identify predictors of virologic failure and drug resistance, and characterize the phenotypic effect of novel resistance genotypes by performing phenotypic testing on selected specimens across the range of HIV-1 subtypes. Our proposal has three key strengths: i) the pooling of clinical and sequence data across a vast global network to explore the determinants of DTG resistance in people on 1st, 2nd-, and 3rd-line ART; ii) inclusion of multiple HIV-1 subtypes across geographic areas and iii) combining expertise from clinical, epidemiological, biological, and computational fields.