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

美国艾滋病毒感染者的基因、物质使用和艾滋病毒结果

基本信息

批准号：
9752506
负责人：
Heidi M. Crane
金额：
$ 79.09万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9752506
关键词：
Abbreviations Acquired Immunodeficiency Syndrome Address Adherence Affect Aging Alcohol or Other Drugs use Behavior Biological Biometry Cardiac Caring Clinical Clinical Data Clinical assessments Collection Communities Comorbidity Consequences of HIV Data Drug Targeting Drug usage Drug user Environment Epidemiology Face Frequencies Genes Genetic Genetic Predisposition to Disease Genotype HIV HIV Infections Hepatotoxicity Impaired cognition Impulsivity Information Systems Infrastructure Injecting drug user Injury Kidney Knowledge Liver Liver diseases Longevity Measurement Measures Methodology Narcotics Outcome Pathway interactions Patient Outcomes Assessments Pattern Penetration Pharmaceutical Preparations Pharmacology Phenotype Population Positioning Attribute Recovery Regimen Research Resources Risk Risk Behaviors Risk Factors Route Sampling Site Specimen Subgroup System Talents Time Toxic effect Treatment-related toxicity Validation Viral Load result adjudication antiretroviral therapy biobank clinical care clinically relevant cohort discount discounting drug disposition drug metabolism drug of abuse frailty genetic analysis genetic variant genome-wide improved outcome injection drug use innovation interest multidisciplinary outcome prediction response side effect spelling therapy adherence transmission process

项目摘要

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.

抗逆转录病毒疗法（ART）已对许多艾滋病毒感染者有效治疗艾滋病毒感染（艾滋病病毒感染者）。 ART 使大多数 PLWH 能够过上接近正常的寿命。我们已经表明，约 90% 的 PLWH 2016 年临床护理的病毒载量 (VL) 无法检测到。然而，有很多因素影响这 10% 的人尚未被发现，其中许多人面临药物滥用的挑战。即使对于那些压制的人来说，毒性威胁依然存在，并且 CD4 回收率和毒性率存在差异。拟议的研究将识别导致结果的遗传变异，包括较差的反应和更大的毒性对所有 PLWH，特别是当前和既往注射吸毒者 (IDU) 进行抗逆转录病毒治疗。我们将：目标 1. 确定 ART 方案总体和 VL 抑制和 CD4 恢复的模式和预测因素关键分组包括当前和以前的注射吸毒者以及特定物质的使用者。我们将确定遗传变异、基因和通路是否影响 ART 方案的 VL 抑制和 CD4 恢复。目标 2. 确定当前治疗时代 HIV 治疗毒性的模式和预测因素，例如肝脏毒性总体和亚组（包括当前和既往注射吸毒者）的肾损伤、认知能力下降和虚弱，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。目标 3. 确定 PLWH 中通过延迟贴现 (DD) 衡量的冲动预测因素和结果总体、当前和以前的注射吸毒者以及特定物质的使用者。我们将检查之间的关联冲动和关键的 HIV 护理级联结果，包括护理参与、ART 启动、VL 抑制、 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有关。目标 4. 应用系统药理学方法来识别 ART 模式之间的生物途径作用和肝毒性。我们还将确定受之间相互作用影响的生物途径临床相关的 ART 方案和注射药物的使用。我们将利用艾滋病中心的综合临床数据和样本生物存储库综合临床系统研究网络 (CNICS) 队列。 CNICS 数据包括超过 70,000 项评估迄今为止的物质使用情况，详细说明之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 名 PLWH 现有的广泛遗传数据，并添加新的对另外 5000 名感染者进行基因分型。我们将重点关注抗逆转录病毒疗法、抗逆转录病毒疗法的毒性和艾滋病毒护理使用最先进的流行病学和遗传分析的级联步骤来解决至关重要的差距在科学知识中。