PROJECT SUMMARY/ABSTRACT Combination antiretroviral therapy (ART) has led to dramatic declines in morbidity and mortality for people with HIV (PWH). However, as PWH age, the risk of cardiovascular disease (CVD) has increased, with a projected lifetime burden among PWH of 65% for men and 44% for women. The higher observed risk of CVD in PWH compared with the general population is a result of the higher prevalence of established CVD risk factors (smoking, alcohol, dyslipidemia), and direct effects of HIV infection, including immunodeficiency and inflammation. Recent studies have also implicated integrase strand inhibitors and other ART with increases in body weight, which may further increase risk of CVD. There are also many understudied social and economic conditions that may contribute to the high CVD risk in PWH, including disparities in healthcare access and treatment, social isolation, history of trauma, and HIV stigma. While most studies have considered the impact of CVD risk factors in isolation, it is well known that many frequently co-occur, such as smoking, alcohol, obesity and depression. Furthermore, the ways in which social factors exacerbate the effect of biomedical CVD risk factors among PWH is not well understood. Using a syndemics framework, which is uniquely suited for the evaluation of the clustering of social and biological conditions in vulnerable populations, we will investigate reasons for the persistently high risk of CVD among PWH. With the team’s interdisciplinary expertise in HIV, CVD and syndemics, our study is designed to understand how social, economic and biological factors combine in PWH, contributing to their high CVD risk. We will leverage comprehensive electronic health record (EHR) data from Kaiser Permanente (KP) and detailed existing survey and biospecimen from the KP Research Bank (KPRB). In Aim 1, we will examine synergistic relationships with major adverse cardiovascular events (MACE) among 29,000 PWH and 1:20 matched people without HIV (PWoH) enrolled in KP from 2000-2021. We will evaluate clusters of social and biological factors available in EHRs such as mental health, substance use disorders (SUD), neighborhood deprivation, and insurance benefits. For Aim 2, we will perform a complementary study within the KPRB to identify synergistic relationships with subclinical CVD among 1,969 PWH (709 with biospecimens) and 1:1 matched PWoH. We will consider additional social factors from surveys that may impact CVD risk, including discrimination and stigma, social isolation, emotional and practical health support, and economic factors. Finally, Aim 3 will involve recruitment of 60 PWH from high-risk clusters identified in Aims 1 and 2 for in-depth qualitative interviews to explore how the syndemic conditions contribute to the high CVD risk. The interviews will inform a follow-up survey of 350 PWH recruited from the same high- risk clusters, to confirm syndemic conditions in a larger sample that could be addressed i...