SPPACE INSTI Study: Sex-specific Predictors, Pathways, And Cardiometabolic Effects of Weight Gain Associated with Integrase Strand-Transfer Inhibitors

SPPACE INSTI 研究：与整合酶链转移抑制剂相关的体重增加的性别特异性预测因子、途径和心脏代谢效应

• 批准号: 10789628
• 负责人: Jessica Alejandra Alvarez
• 金额: $ 84.23万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-02 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10789628
• 关键词: Acquired Immunodeficiency Syndrome; Address; Aging; Area; Atherosclerosis; Benefits and Risks; Biological Markers; Biological Specimen Banks; Blood Pressure; Blood Vessels; Body Weight; Body Weight Changes; Body fat; Branched-Chain Amino Acids; Cardiometabolic Disease; Cardiovascular Diseases; Categories; Clinical; Cohort Studies; Communities; Data; Detection; Diabetes Mellitus; Diastolic blood pressure; Energy Metabolism; Enrollment; Epidemic; Exhibits; Fasting; Fatty acid glycerol esters; Future; General Population; Glycosylated hemoglobin A; Guidelines; HIV; HIV/AIDS; Health; Hypertension; Individual; Inflammation; Inflammatory; Insulin Resistance; Integrase; Knowledge; Link; Lipids; Measures; Metabolic; Metabolic Pathway; Mission; Modeling; National Institute of Diabetes and Digestive and Kidney Diseases; Nucleosides; Obesity; Outcome; Pathway Analysis; Pathway interactions; Patients; Pattern; Persons; Pharmaceutical Preparations; Plasma; Population; Publishing; Research; Resolution; Reverse Transcriptase Inhibitors; Risk; Risk Marker; Sampling; Selection for Treatments; Serum; Tenofovir; Time; United States Dept. of Health and Human Services; Viral; Weight; Weight Gain; Woman; Women' s Interagency HIV Study; adiponectin; antiretroviral therapy; bioinformatics tool; cardiometabolic risk; cardiometabolism; cardiovascular disorder risk; clinical data repository; clinically significant; cohort; diabetes risk; disorder risk; experience; follow-up; high risk; individualized medicine; inhibitor; inhibitor therapy; insight; insulin signaling; men; metabolome; metabolomics; new therapeutic target; preemptive intervention; psychosocial; sex; side effect; sociodemographics; treatment guidelines; treatment strategy; waist circumference

Project Summary/Abstract Integrase strand-transfer inhibitor (INSTI)-associated weight gain in people living with HIV (PWH) is now an established phenomenon of great concern to patients and clinicians. Obesity contributes to adverse health outcomes, including cardiovascular disease (CVD), diabetes mellitus, and hypertension, of which PWH already are at a higher risk compared to the general population, particularly women. Our published preliminary data show that over a relatively short follow-up period, virally-suppressed women switching to INSTIs exhibit greater increases in body weight, other adiposity measures, blood pressure, and hemoglobin A1c% compared to women staying on non-INSTI antiretroviral therapy (ART), resulting in a worsening of CVD risk categories. Our new preliminary data show that among women with clinically-significant weight gain, those who switched to INSTIs had changes in serum biomarkers (adiponectin, TNF𝛼) and the plasma metabolome consistent with greater insulin resistance and inflammation compared to women staying on non-INSTI ART, supporting our hypothesis that INSTIs may perturb insulin signaling, resulting in insulin resistance and increased storage of fat—leading to gains in body weight. This proposal addresses key knowledge gaps, including the sex-specific duration of the observed weight gain, long-term cardiometabolic consequences, and underlying mechanisms related to INSTI use—gaps we will address by leveraging the MACS/WIHS Combined Cohort Study (CCS), the largest and longest longitudinal interval cohort of men and women living with HIV and at-risk HIV(-) controls in the U.S. We propose to integrate the robust clinical data and biospecimen repository of the CCS to better understand INSTI-associated weight gain to inform future risk/benefit assessments during ART selection and identify opportunities for preemptive intervention and/or novel drug targets. Our proposed AIMS are: 1) Evaluate sex-specific patterns and predictors of body weight changes over time following the switch to or addition of INSTIs; 2) Assess changes in cardiometabolic risk by sex following switch to or addition of INSTIs; and 3) Determine sex-specific metabolic signatures associated with weight gain and subsequent cardiometabolic risk following INSTI initiation. To accomplish this, data collected on body weight changes and cardiometabolic risk indicators from virally-suppressed men and women enrolled in the CCS who switched to or added an INSTI to ART will be compared to those remaining on non-INSTI ART and to co-enrolled at-risk HIV(-) controls over a 5-year period. In addition, metabolomic and inflammatory profiles linked to INSTI weight gain will be combined with cardiometabolic risk indicators using integrative community detection and differential network analysis bioinformatics tools to determine sex-specific metabolic signatures associated with an increased risk of cardiometabolic disease. This study will provide new pathophysiologic insights into INSTI- induced weight gain and may shift the paradigm for ART treatment guidelines by informing individualized treatment strategies on use of these agents in high-risk patients.

项目概要/摘要 整合酶链转移抑制剂 (INSTI) 与 HIV 感染者 (PWH) 相关的体重增加现已成为一种 已成为患者和临床医生高度关注的现象。肥胖会导致不良健康 结局，包括心血管疾病 (CVD)、糖尿病和高血压，其中 PWH 已经 与一般人群（尤其是女性）相比，她们面临的风险更高。我们公布的初步数据 表明在相对较短的随访期内，转用 INSTI 的病毒抑制女性表现出更大的 与相比，体重、其他肥胖指标、血压和糖化血红蛋白%增加 继续接受非 INSTI 抗逆转录病毒治疗 (ART) 的女性，导致 CVD 风险类别恶化。我们的 新的初步数据显示，在体重明显增加的女性中，那些改用 INSTI 的血清生物标志物（脂联素、TNF𝛼）和血浆代谢组发生变化，与 与接受非 INSTI ART 的女性相比，胰岛素抵抗和炎症更大，支持我们的研究 假设 INSTI 可能扰乱胰岛素信号传导，导致胰岛素抵抗和胰岛素储存增加 脂肪——导致体重增加。该提案解决了关键的知识差距，包括特定性别的知识差距 观察到的体重增加的持续时间、长期心脏代谢后果以及潜在机制 与 INSTI 使用相关的差距，我们将通过利用 MACS/WIHS 联合队列研究 (CCS)、 最大和最长的纵向间隔队列的男性和女性艾滋病毒感染者和高危艾滋病毒（-）控制者 我们建议整合 CCS 强大的临床数据和生物样本库，以更好地 了解 INSTI 相关的体重增加，以便在 ART 选择期间为未来的风险/效益评估提供信息 确定先发制人的干预和/或新药物靶点的机会。我们提出的目标是：1) 评估性别特异性模式和体重随时间变化的预测因素。 添加 INSTI； 2) 评估转用或添加 INSTI 后按性别划分的心脏代谢风险的变化； 3) 确定与体重增加和随后的体重增加相关的性别特异性代谢特征 INSTI 启动后的心脏代谢风险。为了实现这一目标，收集了有关体重变化和 参加 CCS 且转为接受病毒抑制的男性和女性的心脏代谢风险指标 或在 ART 中添加了 INSTI 的患者将与仍在接受非 INSTI ART 的患者以及共同注册的高风险患者进行比较 HIV(-) 控制超过 5 年。此外，代谢组学和炎症特征与 INSTI 体重相关 使用综合社区检测将增益与心脏代谢风险指标相结合 微分网络分析生物信息学工具，用于确定与相关的性别特异性代谢特征 心脏代谢疾病的风险增加。这项研究将为 INSTI 提供新的病理生理学见解 诱导体重增加，并可能通过告知个体化改变 ART 治疗指南的范式 在高危患者中使用这些药物的治疗策略。