Cardiometabolic Consequences And Pathway Of Weight Gain Associated With Dolutegravir-Based Antiretroviral Therapy In Haiti. A Collaborative Study Between GHESKIO And CCASAnet

摘要 海地是加勒比地区艾滋病毒感染者人数最多的国家。威尔斯亲王医院有较高的风险 代谢和心血管疾病（CVD），这是海地人和其他人死亡的主要原因 低收入和中等收入国家（LMIC）的居民，部分原因是高血压发病率高， 空腹血糖和高体重指数。在开始抗逆转录病毒治疗后的早期体重增加是常见的 抗逆转录病毒疗法（ART），特别是PWH中基于整合酶链转移抑制剂（TIMI）的方案。的 含INSTI的富马酸替诺福韦酯、拉米夫定和度鲁特韦（dolutegravir）联合方案是 最常见的处方ART方案在中低收入国家，但目前很少有数据的后果， 在这些情况下，ART的体重增加。因此，迫切需要采取创新办法， 确定肥胖人群中伴随体重增加的心脏代谢疾病风险的特征和严重程度 LMIC中的接受者，包括胰岛素敏感性、血压、血脂和全身性炎症;以及2） 确定体重增加的代谢机制，以指导制定和实施 有效的预防和治疗策略。 GHESKIO（Groupe Haitien d 'Etude du Sarcome et des Infections Opportunities）是海地最大的艾滋病毒诊所， 美洲，CCASAnet（加勒比、中美洲和南美洲艾滋病毒网络）创始成员 流行病学），并拥有37年的美国国立卫生研究院对艾滋病毒和相关合并症的研究记录。建筑 在此基础上，我们的多学科研究将利用先进的代谢表型和多组学 数据分析，以阐明体重增加的生物能量途径， 低收入国家的PWH的饮食和生活方式因素与高收入国家不同。 目标1将评估服用阿司匹林后体重增加是否与胰岛素抵抗、血压、 血脂异常和炎症。我们将入组200例在GHESKIO开始接受ART治疗的既往ART初治患者 12至24个月前，体重增加<3%与> 10%，以定义与 体重增加，包括社会人口学变量、食欲、食物安全和体力活动，以及是否 体重增加与较高的HOMA-IR、空腹血脂、收缩压和舒张压相关， 与CVD相关的炎症标志物。目标2将确定与以下相关的代谢和脂质途径 使用代谢组学和脂质组学分析，在暴露于甲氧苄啶的前12个月内体重增加。我们将招收60名 ART初治患者在基线和第12天开始进行空腹代谢组学和脂质组学分析， 几个月的时间来确定ART前容易导致体重增加的途径。该项目将开发新的能力， GHESKIO和CCASAnet更广泛的复杂心脏代谢研究和分析， 这项研究的结果将提供初步的数据，是否体重增加的基础上可能代表一个新兴的 在世界各地中低收入国家广泛实施这一方案的背景下，这一方案对健康结果构成了威胁。

ABSTRACT Haiti has the largest number of persons with HIV (PWH) in the Caribbean. PWH have a higher risk of developing metabolic and cardiovascular disease (CVD), which are leading causes of mortality among Haitians and other residents of low and middle-income countries (LMICs), driven in part by high rates of hypertension, elevated fasting plasma glucose and high body mass index. Weight gain is common early after starting antiretroviral therapy (ART), particularly among PWH on an integrase strand transfer inhibitor (INSTI)-based regimen. The INSTI-containing combination regimen of tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD) is the most commonly prescribed ART regimen in LMICs, but at present there are few data on the consequences of weight gain on ART in these settings. Consequently, there is a critical need for innovative approaches to 1) Determine the features and severity of cardiometabolic disease risk accompanying weight gain among TLD recipients in LMICs, including insulin sensitivity, blood pressure, lipid profiles and systemic inflammation; and 2) Determine the metabolic mechanisms underlying weight gain to guide the development and implementation of effective prevention and treatment strategies. GHESKIO (Groupe Haitien d’Etude du Sarcome et des Infections Opportunities) is the largest HIV clinic in the Americas, a founding member of CCASAnet (the Caribbean, Central and South America network for HIV epidemiology) and has a 37-year track record of NIH research on HIV and associated comorbidities. Building upon this infrastructure, our multi-disciplinary study will leverage advanced metabolic phenotyping and multiomic data analysis to elucidate the bioenergetic pathways underlying weight gain on TLD and the cardiometabolic consequences among PWH in LMIC, where diet and lifestyle factors differ from higher income countries. Aim 1 will assess whether weight gain on TLD is associated with increased insulin resistance, blood pressure, dyslipidemia, and inflammation. We will enroll 200 previously ART-naïve patients who initiated TLD at GHESKIO 12 to 24 months previously and gained <3% versus 10% body weight to define the factors associated with weight gain including sociodemographic variables, appetite, food security and physical activity, and whether weight gain is associated with higher HOMA-IR, fasting lipids, systolic and diastolic blood pressure, and inflammatory markers linked to CVD. Aim 2 will determine the metabolic and lipid pathways associated with weight gain in the first 12 months of TLD exposure using metabolomic and lipidomic profiling. We will enroll 60 ART-naïve patients initiating TLD and perform fasting metabolomic and lipidomic profiling at baseline and 12 months to identify the pre-ART pathways predisposing to weight gain. This project will develop new capacity for sophisticated cardiometabolic research and analyses at GHESKIO and within CCASAnet more broadly, and the results of this study will provide preliminary data on whether weight gain on TLD may represent an emerging threat to health outcomes in the context of the wide implementation of this regimen in LMICs across the world.