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

海地基于多替拉韦的抗逆转录病毒治疗相关的心脏代谢后果和体重增加途径。

• 批准号: 10750906
• 负责人: John Koethe
• 金额: $ 15.63万
• 依托单位: GHESKIO CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-10 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750906
• 关键词: Address; Americas; Amino Acids; Area; Argentina; Automobile Driving; Bioenergetics; Blood Pressure; Body Weight; Body fat; Brazil; Carbohydrates; Cardiometabolic Disease; Cardiovascular Diseases; Caribbean region; Central America; Chile; Clinic; Clinical; Clinical Research; Country; Data; Data Analyses; Desire for food; Development; Diastolic blood pressure; Diet; Disease; Dyslipidemias; Enrollment; Epidemic; Epidemiology; Fasting; Fumarates; General Population; HIV; Haiti; Haitian; Health; Honduras; Hospitals; Human; Hypertension; Immunology; Incidence; Income; Infection; Inflammation; Infrastructure; Insulin Resistance; Integrase; Laboratories; Lamivudine; Life Style; Link; Lipids; Liver diseases; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Mexico; Multiomic Data; Outcome; Pathway interactions; Patients; Persons; Peru; Physical activity; Prevalence; Prevention strategy; Prospective, cohort study; Regimen; Research; Research Activity; Research Personnel; Resources; Severities; Site; South America; Tenofovir; United States National Institutes of Health; Universities; Weight Gain; Woman; antiretroviral therapy; blood pressure elevation; cardiometabolism; comorbidity; disorder risk; experience; fasting plasma glucose; food security; high body mass index; high risk; improved; inflammatory marker; inhibitor; innovation; insulin sensitivity; lifestyle factors; lipid metabolism; lipidomics; low and middle-income countries; member; metabolic phenotype; metabolomics; mortality; multidisciplinary; nutrition; phenotypic data; sociodemographic variables; systemic inflammatory response; treatment strategy

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.

抽象的 海地在加勒比海人数最多的艾滋病毒（PWH）人数最多。 PWH具有更高的发展风险 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）的居民部分由高血压率升高，升高 空腹血糖和高体重指数。开始抗逆转录病毒后，体重增加很普遍 治疗（ART），尤其是在集成酶链转移抑制剂（INSTI）方案中的PWH中。这 替诺福韦毒素，lamivudine和dolutegravir（TLD）的含有辅助的组合方案是 LMIC中最常见的处方艺术方案，但目前几乎没有有关后果的数据 在这些情况下，艺术体重增加。因此，对1）的创新方法迫切需要 确定心脏代谢疾病风险的特征和严重性参与TLD的体重增加 LMIC的接受者，包括胰岛素敏感性，血压，脂质谱和全身注射；和2） 确定体重增加的代谢机制，以指导开发和实施 有效的预防和治疗策略。 Gheskio（海地D'Etude du Sarcome et des感染机会）是最大的艾滋病毒诊所 美洲，CCASANET的创始成员（加勒比海，中美洲和南美艾滋病毒网络 流行病学），并具有37年的NIH研究记录艾滋病毒和相关合并症。建筑 在此基础设施上，我们的多学科研究将利用先进的代谢表型和多瘤 数据分析以阐明TLD和心脏代谢的体重增加的生物能途径 LMIC中PWH的后果，饮食和生活方式因素与高收入国家不同。 AIM 1将评估TLD的体重增加是否与胰岛素抵抗，血压升高有关 血脂异常和炎症。我们将招募200名先前没有艺术的患者，他们在Gheskio发起了TLD 12至24个月以前，体重<3％与10％的体重相比，定义了与 体重增加，包括社会人口统计学变量，食欲，粮食安全和体育锻炼，以及是否是否 体重增加与较高的HOMA-IR，禁食脂质，收缩压和舒张压以及 与CVD相关的炎症标记。 AIM 2将确定与之相关的代谢和脂质途径 我们将注册60 Art-Neïve患者在基线和12个 几个月来确定易于体重增加的前途径。该项目将为 在Gheskio和CCASANET内进行了精致的心脏代谢研究和分析，更广泛地 这项研究的结果将提供有关tld体重增加是否代表新兴的初步数据 在世界各地的LMIC中，该方案广泛实施的背景下，对健康结果的威胁。