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

摘要 海地是加勒比地区感染艾滋病毒(PWH)人数最多的国家。有较高的发病风险。 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，在一定程度上是由高高血压率推动的， 空腹血糖和高体重指数。开始抗逆转录病毒治疗后早期体重增加是很常见的 治疗(ART)，特别是在以整合酶链转移抑制物(INSTI)为基础的方案的PWH中。这个 富马酸替诺福韦、拉米夫定和多洛替格韦(TLD)的Insti联合方案是 在LMICs中最常开出的ART方案，但目前几乎没有关于 在这些环境下ART的体重增加。因此，迫切需要创新的方法来实现1) 确定TLD中伴随体重增加的心脏代谢性疾病风险的特征和严重程度 LMICs的受者，包括胰岛素敏感性、血压、血脂和全身炎症；以及2) 确定体重增加的代谢机制，以指导开发和实施 有效的防治策略。 盖斯基奥(Groupe Haitien d‘Etude Du Sarcome et des Inhibition Opportunities)是全球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 他在国立卫生研究院关于艾滋病毒和相关合并症的研究方面有37年的跟踪记录。建房 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 数据分析阐明TLD体重增加和心脏代谢的生物能量途径 LMIC中PWH的后果，那里的饮食和生活方式因素与较高收入国家不同。 目标1将评估TLD的体重增加是否与胰岛素抵抗、血压、 血脂异常，还有炎症。我们将招募200名在GHESKIO发起TLD的先前天真的ART患者 12至24个月前，体重增加3%与10%相比，以定义与以下因素相关的因素 体重增加，包括社会人口统计变量、食欲、食品安全和体力活动，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，以及 与心血管疾病有关的炎症标志物。AIM 2将确定与以下相关的代谢和脂质途径 TLD暴露的前12个月体重增加的代谢组和脂组分析。我们将招收60人 ART-幼稚患者启动TLD并在基线和12岁时进行空腹代谢和脂组分析 花了几个月的时间来确定容易导致体重增加的抗逆转录病毒治疗前途径。该项目将开发新的能力， 在GHESKIO和更广泛的CCASAnet内进行的复杂的心脏代谢研究和分析，以及 这项研究的结果将提供初步数据，表明TLD的体重增加是否代表着一种 在世界各地的低收入中等收入国家广泛实施这一方案的背景下，对健康结果的威胁。

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.