Effects of HIV Pre-Exposure Prophylaxis (PrEP) on Cardiovascular-Kidney-Metabolic Health and Risk for Cardiovascular Disease - PROJECT ABSTRACT Tenofovir-containing antiretroviral therapy has been associated with increased risk for metabolic conditions and cardiovascular disease (CVD) among persons with HIV; yet it is less clear if chronic use of tenofovir-based HIV pre-exposure prophylaxis (PrEP) may affect risk for these conditions in individuals without HIV. Evidence from PrEP clinical trials and limited observational studies suggests that the use of emtricitabine/tenofovir disoproxil fumarate (TDF) and emtricitabine/tenofovir alafenamide (TAF) for HIV PrEP may affect CVD risk through changes in metabolic profile and kidney dysfunction. Through the efforts of the U.S. Ending the HIV Epidemic Initiative (EHE), oral PrEP use, especially generic TDF, is likely to increase significantly and expand to include individuals at substantial risk for HIV who are older and with more comorbidities. Existing PrEP trials and open-label studies of younger populations with short follow-up were not designed to evaluate long-term CVD risk, and findings have limited generalizability due to relatively lower number of persons of color among trial participants. Considering the interplay among metabolic risk factors, chronic kidney disease, and the cardiovascular system, it is critical to evaluate effects of PrEP on cardiovascular-kidney-metabolic (CKM) health among diverse populations. However, no cohort exists to comprehensively evaluate both metabolic and renal outcomes and clinical management and control of metabolic risk factors over time in clinical care settings. We propose to use electronic health record data from 3 integrated health care systems in California and Mid-Atlantic States (Maryland, District of Columbia, Virginia) to conduct a longitudinal cohort study of diverse PrEP candidates with or without initiation of oral PrEP during 2012-2024. We will estimate observational analogues of both intention-to-treat effect and per-protocol effect of PrEP use on CKM health, risk of clinical CVD events, and all-cause mortality. We will also evaluate the differences in treatment initiation and control of metabolic risk factors. We will use a novel sex-specific and race-free risk calculator that combines measures of cardiovascular, kidney and metabolic health to predict 10- and 30-year risk for total CVD, atherosclerotic CVD, and heart failure. Specific Aims are: 1) to examine associations between PrEP use and incident CKM conditions; 2) to assess differences in treatment initiation and control of metabolic risk factors among PrEP users compared with non-users without HIV; 3) to examine associations between PrEP use and risk of cardiovascular events (primary outcome) and all-cause mortality (secondary outcome) in individuals aged 30-79 years with no prior history of CVD. This study aligns with, and advances, the national priorities to elucidate the impact of PrEP on heart, lung, blood, and sleep conditions (NOT-HL-21-025), and will generate much-needed empirical evidence to inform guidelines for prescribing PrEP and help develop tailored prevention strategies to reduce cardiovascular morbidity and mortality among individuals taking PrEP.
