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

抗逆转录病毒疗法(Art)对许多艾滋病毒携带者有效地治疗艾滋病毒感染。 (公共卫生署)。抗逆转录病毒治疗使大多数PLWH能够过上接近正常的寿命。我们已经表明，大约90%的PLWH在 2016年的临床护理有无法检测到的病毒载量(VL)。然而，有许多因素会影响10%的人 并不是无法检测到，其中许多人面临着物质使用的挑战。即使对那些镇压的人来说， 毒性的威胁仍然存在，而且有不同的CD4回收率和毒性比率。拟议的研究将 找出导致结果的基因变异，包括较差的反应和更大的毒性 在所有PLWH，特别是目前和以前的注射吸毒者(IDU)中使用抗逆转录病毒药物。我们会： 目的1.确定ART方案对VL抑制和CD4恢复的模式和预测因素 在关键亚群中，包括目前和以前的吸毒者和特定物质的使用者。我们将决定 基因变异、基因和途径是否影响ART方案抑制VL和恢复CD4。 目的2.确定当前治疗时代艾滋病毒治疗毒性的模式和预测因素，如肝脏 和肾损伤、认知能力下降和虚弱，总体上和包括现在和以前的注射吸毒者在内的亚组，以及 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。 目的3.确定PLWH中的冲动性预测因素和通过延迟折扣(DD)衡量的结果 总体而言，目前和以前的注射吸毒者以及特定物质的使用者。我们将研究它们之间的关联 冲动和关键的HIV护理级联结果，包括参与护理，ART启动，VL抑制， 以及坚持艺术和其他危险行为。我们将确定遗传变异、基因和途径 与冲动有关，与特定的药物使用模式和这些结果有关。 目的4.应用系统药理学方法确定ART模式和ART模式之间的生物学途径 作用和肝脏毒性。我们还将确定受相互作用影响的生物途径 临床相关的抗逆转录病毒治疗方案和注射用药。 我们将利用艾滋病中心的全面临床数据和标本生物库 综合临床系统研究网络(CNICs)队列。CNICS数据包括&gt；70,000项评估 到目前为止的物质使用情况，详细说明以前和现在的物质使用情况、使用路线和模式 使用频率。我们将使用8977 PLWH上已有的大量遗传数据，并添加新的 对5000例额外的PLWH进行基因分型。我们将重点关注抗逆转录病毒药物、抗逆转录病毒药物中毒和艾滋病毒治疗的反应。 使用最先进的流行病学和基因分析来解决至关重要的差距的级联步骤 在科学知识方面。

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.