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: 10361513
• 负责人: Jessica Alejandra Alvarez
• 金额: $ 64.39万
• 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 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361513
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Aging; Area; Atherosclerosis; 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; Exhibits; Fasting; Fatty acid glycerol esters; Future; General Population; Glycosylated hemoglobin A; Guidelines; HIV; 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; Risk-Benefit Assessment; Sampling; Selection for Treatments; Serum; Tenofovir; Time; United States Dept. of Health and Human Services; Viral; 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; 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.

项目摘要/摘要 艾滋病毒（PWH）患者的整合酶链转移抑制剂（INSTI）相关的体重增加现在已成为 对患者和临床医生的关注很关注的现象。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 与一般人群相比，风险更高，尤其是妇女。我们已发布的初步数据 证明在相对较短的随访期内，病毒抑制的妇女改用了更大的信息 与体重的增加，其他肥胖度量，血压和血红蛋白A1C％相比 妇女在非INSTI抗逆转录病毒疗法（ART）接受，导致CVD风险类别担心。我们的 新的初步数据表明，在临床上显着体重增加的女性中，那些改用的女性 Instis的血清生物标志物（脂联素，TNF𝛼）和血浆代谢组有变化 与保持非Insti Art的女性相比，更大的胰岛素抵抗和感染，支持我们 假设Instis可能会扰动胰岛素信号传导，从而导致胰岛素抵抗和增加的储存 脂肪 - 领导体重增加。该提案解决了关键知识差距，包括特定于性别的知识差距 观察到的体重增加的持续时间，长期心脏代谢后果和潜在机制 与Insti使用相关 - 我们将通过利用MAC/WIHS组合研究（CCS）来解决gaps 艾滋病毒和高危艾滋病毒（ - ）控制的男女最大，最长的纵向间隔队列 美国我们建议将CCS的强大临床数据和生物传感存储库整合在一起以更好 了解与Insti-Insti-Insti-Clatied Implage Inder在艺术选择期间为未来的风险/福利评估提供信息 确定先发制人干预和/或新型药物靶标的机会。我们提出的目标是：1） 在切换到或 增加学院； 2）评估切换或加入研究所后，通过性别来评估心脏代谢风险的变化； 3）确定与体重增加和随后的性别特异性代谢特征 Insti主动性后的心脏代谢风险。为此，收集了有关体重变化的数据， CCS入学的病毒抑制男人和女人的心脏代谢风险指标 或将其添加到Art的Insti将与剩余的非Insti Art的研究所进行比较，并与之共介绍高危 艾滋病毒（ - ）在5年期间控制。另外，与Insti重量相关的代谢组和炎症特征 增益将与综合社区检测和心脏代谢风险指标相结合， 差异网络分析生物信息学工具，以确定与性别特异性的代谢特征 心脏代谢疾病的风险增加。这项研究将为Instim提供新的病理生理见解 诱导体重增加，并可能通过告知个性化来改变艺术治疗指南的范例 在高危患者中使用这些药物的治疗策略。