Genes, substance use, and HIV outcomes in people living with HIV across the US

抗逆转录病毒疗法（ART）对许多艾滋病毒感染者的治疗是有效的 （PLWH）。ART使大多数PLWH的寿命接近正常。我们已经证明，在2010年， 在2016年的临床护理中，病毒载量（VL）检测不到。然而，有许多因素影响着10%的人， 目前尚未发现，其中许多人面临使用药物的挑战。即使是那些压抑的人， 毒性的威胁仍然存在，并且存在可变的CD4恢复率和毒性率。拟议的研究将 确定导致结果的遗传变异，包括反应较差和毒性较大， 在所有艾滋病毒携带者和艾滋病患者中进行抗逆转录病毒疗法，特别是针对目前和以前的注射吸毒者。我们将： 目标1.确定ART方案总体VL抑制和CD4恢复的模式和预测因素， 在关键亚组中，包括目前和以前的注射吸毒者和特定物质的使用者。我们将确定 遗传变异、基因和途径是否影响ART方案的VL抑制和CD4恢复。 目标二。确定当前治疗时代HIV治疗毒性的模式和预测因素，如肝脏 和肾损伤、认知下降和虚弱的总体和亚组，包括当前和既往IDU，和 特定物质的使用者。我们将确定影响结果的遗传变异，基因和途径。 目标3.识别PLWH中的冲动性预测因子和延迟贴现（DD）测量结果 总体、当前和既往IDU以及特定物质的使用者。我们将研究 冲动和关键艾滋病毒护理级联结果，包括参与护理，ART启动，VL抑制， 以及ART依从性和其他风险行为。我们将识别遗传变异、基因和途径 与冲动以及与特定药物使用模式和这些结果的关联。 目标4。应用系统药理学方法来确定ART模式与 作用和肝毒性。我们还将确定生物学途径，受相互作用， 临床相关ART方案和注射药物使用。 我们将利用艾滋病中心的全面临床数据和标本生物储存库， 综合临床系统研究网络（CNICS）队列。CNICS数据包括> 70，000个评估 迄今为止的物质使用情况，详细说明先前和当前的物质使用情况、使用途径和模式， 使用频率。我们将使用8977 PLWH已有的广泛遗传数据， 对另外5000名PLWH进行基因分型。我们将重点关注抗逆转录病毒疗法的反应、抗逆转录病毒疗法的毒性和艾滋病毒护理 采用最新流行病学和遗传分析的级联步骤，解决至关重要的差距 科学知识。

Antiretroviral therapy (ART) has been effective in treating HIV infection for many people living with HIV (PLWH). ART enables most PLWH to live near-normal lifespans. We have shown that ~90% of PLWH in clinical care in 2016 had an undetectable viral load (VL). However, a number of factors influence the 10% who are not yet undetectable, many of whom face challenges from substance use. Even for those who suppress, threats of toxicities remain, and there are variable CD4 recovery and toxicity rates. The proposed research will identify genetic variants that contribute to outcomes including poorer responses and greater toxicities from ART among all PLWH and particularly for current and prior injection drug users (IDU). We will: Aim 1. Determine patterns and predictors of VL suppression and CD4 recovery by ART regimen overall and among key subgroups including current and prior IDU and users of specific substances. We will determine whether genetic variants, genes, and pathways impact VL suppression and CD4 recovery by ART regimen. Aim 2. Determine patterns and predictors of HIV treatment toxicities in the current treatment era such as liver and renal injury, cognitive decline, and frailty overall and by subgroups including current and prior IDU, and users of specific substances. We will identify genetic variants, genes, and pathways that impact outcomes. Aim 3. Identify impulsivity predictors and outcomes as measured by delayed discounting (DD) among PLWH overall, current and prior IDU, and users of specific substances. We will examine associations between impulsivity and key HIV care cascade outcomes including engagement in care, ART initiation, VL suppression, and ART adherence and other risk behaviors. We will identify genetic variants, genes, and pathways associated with impulsivity and the associations with specific drug use patterns and these outcomes. Aim 4. Apply a systems pharmacology approach to identify biological pathways between ART mode of action and liver toxicity. We will also identify biological pathways that are affected by interactions between clinically relevant ART regimens and injection drug use. We will leverage the comprehensive clinical data and specimen biorepository of the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort. CNICS data include >70,000 assessments of substance use to date, detailing prior and current substance use, routes of use, and patterns and frequency of use. We will use extensive genetic data already available on 8977 PLWH and add new genotyping for 5000 additional PLWH. We will focus on response to ART, ART toxicities, and HIV care cascade steps using state of the art epidemiology and genetic analyses to address critically important gaps in scientific knowledge.