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

项目摘要/摘要 整合酶链转移抑制物(INSTI)相关的艾滋病毒携带者(PWH)体重增加现在是一种 患者和临床医生高度关注的既定现象。肥胖对健康不利 结果，包括心血管疾病、糖尿病和高血压，其中PWH已经 与普通人群，特别是女性相比，处于更高的风险。我们公布的初步数据 研究表明，在相对较短的随访期内，转而使用INSTI的病毒抑制女性表现出更大的 体重、其他肥胖指标、血压和血红蛋白A1c%与 继续接受非INSTI抗逆转录病毒疗法(ART)的妇女，导致心血管疾病风险类别恶化。我们的 新的初步数据显示，在有临床显著体重增加的女性中，那些改用 INSTI患者血清生物标志物(脂联素、肿瘤坏死因子𝛼)和血浆代谢组的变化与 与接受非INSTI抗逆转录病毒治疗的女性相比，更大的胰岛素抵抗和炎症反应，支持我们的 假设INSTI可能扰乱胰岛素信号转导，导致胰岛素抵抗和增加胰岛素储存 脂肪--导致体重增加。这项建议解决了关键的知识差距，包括按性别划分的 观察到的体重增加的持续时间、心脏代谢的长期后果和潜在机制 关于INSTI的使用-我们将通过利用MACS/WIHS联合队列研究(CCS)来解决差距， 艾滋病毒携带者和高危艾滋病毒(-)控制人群中最大和最长的纵向间隔队列 我们建议将CCS强大的临床数据和生物谱库整合在一起，以更好地 了解INSTI相关的体重增加，以便在ART选择和未来风险/收益评估期间提供信息 确定先发制人干预和/或新药物靶点的机会。我们提出的目标是：1) 评估特定性别的模式和体重随时间变化的预测因子 增加INSTI；2)评估改用或增加INSTI后按性别划分的心脏代谢风险的变化； 以及3)确定与体重增加和随后的 INSTI开始后的心脏代谢风险。为了实现这一点，收集的体重变化数据和 在CCS中登记的接受病毒抑制的男性和女性的心脏代谢风险指标 或将INSTI添加到ART将与那些留在非INSTI ART的患者和共同登记的风险患者进行比较 在5年内控制艾滋病毒(-)。此外，代谢和炎症特征与INSTI体重有关 Gain将与心脏代谢风险指标相结合，使用综合社区检测和 差异网络分析生物信息学工具用于确定与 心脏代谢性疾病的风险增加。这项研究将为INSTI提供新的病理生理学见解。 诱导体重增加，并可能通过告知个性化的方式改变ART治疗指南的范式 高危患者使用这些药物的治疗策略。

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.