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治疗（ART）是2000年最成功的公共卫生干预措施之一。 艾滋病是人类历史上最严重的疾病之一，但艾滋病毒耐药性的出现对结束艾滋病流行构成威胁。下一阶段 全球艾滋病毒的应对将依赖于整合酶链转移抑制剂（InSTI），特别是度鲁特韦（DTG）， 具有高遗传抗性屏障的强效抗逆转录病毒药物。DTG推荐用于所有治疗线（第一， 二线和三线），而同一类别的药物是为预防癌症而开发的。 暴露预防。对DTG选择性突变的谱及其与基因突变的关系的理解有限。 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 在整合酶基因之外。关键是要建立强大的系统，以早期检测InSTI耐药性， 艾滋病毒治疗方案，并发展对DTG耐药性在真实的中发生的位置和方式的理解 世界同行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评估艾滋病 抗逆转录病毒治疗队列协作（ART-CC）。具体而言，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 按方案和HIV-1亚型分类的基于DTG的ART; ii）确定HIV-1患者中病毒学失败和耐药的风险因素， 青少年和成年人对DTG为基础的ART;和iii）调查新的耐药性之间的相关性 HIV-1亚型的基因型和表型InSTI抗性。总共有46个IeDEA站点和7个ART-CC 来自32个国家的队列将参加这项研究。10个研究中心和队列将提供现有数据（桑格 序列和临床数据），而不是前瞻性招募患者; 19个研究中心和队列将提供 转换和失败时的样本或序列对，32个将提供青少年数据。我们将包括 接受任何DTG治疗的病毒学失败（病毒载量≥1000拷贝/mL）的成人（≥18岁）和青少年（10-17岁）- 分析将基于约4600名基于DTG的ART失败的患者和约490名基于DTG的ART失败的患者 DTG耐药突变。接下来我们将使用Illumina MiSeq进行全基因组测序- 第二代测序平台，以检测整合酶突变和整合酶外的突变（例如，在3'端的突变）。 nef基因的多嘌呤区）。我们将联合收割机的数据与现有的序列数据从北 美国和欧洲的同伙。我们将比较不同频率的InSTI DRMs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子 和耐药性，并通过进行表征新的耐药基因型的表型效应 对HIV-1亚型范围内的选定标本进行表型检测。我们的建议有三个关键 优势：i）在庞大的全球网络中汇集临床和序列数据，以探索决定因素 1、2、3线抗逆转录病毒疗法人群中的DTG耐药性; ii）包括多种HIV-1亚型， 地理区域和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.