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

项目概要/摘要 整合酶链转移抑制剂（Integrase strand-transfer inhibitor，CDFI）与HIV感染者（PWH）体重增加相关， 这一现象引起了患者和临床医生的极大关注。肥胖对健康不利 结果，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，特别是女性，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，病毒抑制的妇女转向INSTI表现出更大的 与对照组相比，体重、其他肥胖指标、血压和血红蛋白A1 c %增加 继续接受非抗逆转录病毒治疗（ART）的妇女，导致心血管疾病风险类别恶化。我们 新的初步数据显示，在临床上体重显著增加的女性中，那些转向 INSTI的血清生物标志物（脂联素、TNFα）和血浆代谢组发生变化， 与接受非抗逆转录病毒治疗的女性相比，胰岛素抵抗和炎症更严重，支持我们的研究。 假设INSTIs可能干扰胰岛素信号传导，导致胰岛素抵抗和胰岛素储存增加。 脂肪导致体重增加。这项建议涉及关键的知识差距，包括性别方面的知识差距。 观察到的体重增加持续时间、长期心脏代谢后果和潜在机制 我们将通过利用MACS/WIHS联合队列研究（CCS）， 艾滋病毒感染者和高危艾滋病毒（-）对照者的最大和最长纵向间隔队列， 我们建议整合CCS的强大临床数据和生物标本库，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/获益评估提供信息， 确定先发制人干预和/或新药物靶点的机会。我们的目标是：1） 评估性别特异性模式和体重变化的预测因素， 2）评估转换或添加INSTI后不同性别的心脏代谢风险变化; 和3）确定与体重增加相关的性别特异性代谢特征和随后的 开始服用抗心律失常药物后的心脏代谢风险。为了实现这一点，收集的体重变化数据和 来自CCS入组的病毒抑制男性和女性的心脏代谢风险指标， 或在ART基础上增加了一种抗逆转录病毒药物的受试者将与仍在接受非抗逆转录病毒药物治疗的受试者和共同入组的风险受试者进行比较 艾滋病毒（-）控制超过5年。此外，代谢组学和炎症特征与体重相关， 增益将与使用综合社区检测的心脏代谢风险指标相结合， 差异网络分析生物信息学工具，以确定性别特异性代谢签名相关的 心脏代谢疾病的风险增加。这项研究将提供新的病理生理学的见解， 诱导体重增加，并可能通过告知个体化的ART治疗指南改变范式 在高危患者中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.