AWARE Project 3: Utilization, effectiveness, safety, and persistence of GLP-IRA and LAAR therapies among people living with and without HIV

Yale University, New Haven CT

Investigators

Abstract

People with HIV (PWH) experience more “inflammaging” characterized by chronic inflammation, immune dysfunction, and debilitating geriatric syndromes than people without HIV (PWoH). Inflammaging is most pronounced while HIV-1 RNA is unsuppressed but continues even after suppression and is exacerbated by unhealthy alcohol use and obesity. Further, psychological stress modifies the risk of unhealthy alcohol use and excess weight gain and influences the ability to adhere to daily antiretrovirals all of which can influence inflammaging. The Alcohol Harm Paradox (see Overall Grant) suggests members of socio-economic disadvantaged groups – may experience more psychological stress. Before we can effectively intervene on this health risk, we need to identify appropriate treatments. Two recent advances in pharmacotherapy may be uniquely effective against inflammaging among PWH and especially beneficial to SMGs with unhealthy alcohol use. Long-acting antiretrovirals (LAARs), administered by injection once a month, improve HIV-1 RNA suppression among those with difficulty adhering to a daily oral ART regimen. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) promote weight loss, and clinical evidence suggests GLP1-RAs reduce alcohol craving. We hypothesize that those with unhealthy alcohol use and those socioeconomically disadvantaged are less likely to receive LAARs than those without these factors, but are more likely to achieve viral suppression on LAARs than oral ART. Further, GLP-1RAs (e.g. semaglutide) are effective at weight loss and may decrease alcohol craving–addressing two causes of inflammaging. We hypothesize that SMGs, those with unhealthy alcohol, and those socioeconomically disadvantaged are less likely to receive GLP-1RAs than those without these factors, but more likely to lose weight and decrease alcohol use than those not receiving them. This Project will utilize state-of-the-art causal modeling methods to address critical knowledge gaps by systematically evaluating real-world utilization, effectiveness, safety, and discontinuation of GLP-1RAs (in PWH and PWoH) and LAARs (in PWH) with and without AUD. For Aim 1, we will characterize utilization of these medications over time and compare utilization by AUD history and community disadvantage measured by Area Deprivation Index (ADI). For Aim 2, we will quantify the effectiveness of GLP-1RAs and LAARs in reducing alcohol consumption, promoting weight loss, and determine impact on HIV-1 RNA suppression and CD4 response. For Aim 3, we will assess the safety and potential rebounds after discontinuation across these diverse groups. By employing state-of-the-art causal modeling techniques, we expect these analyses will provide real-world evidence to guide use of these therapies in a highly understudied population that is typically excluded from clinical trials. Achieving these aims will generate real-word evidence on the potential of GLP1RAs and LAARs to improve health outcomes in PWH and PWoH by informing targeted clinical trials and clinical management within these vulnerable and clinically complex patient populations.