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

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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.