Assessing the mediating role of kidney function and weight/BMI in the association between INSTI use and blood pressure changes and hypertension in PWH: a secondary analysis of the REPRIEVE study.

Project Summary Our R03 application critically evaluates cardiovascular risks associated with integrase strand transfer inhibitors (INSTIs), focusing on blood pressure and hypertension among people living with HIV. Utilizing data from the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) study, our project aims to address significant gaps in the current understanding of these risks. Aim 1 employs a novel target trial framework to emulate randomized trials using the REPRIEVE dataset, in which INSTI use was not originally randomized. This innovative approach enables the application of advanced causal inference techniques, specifically inverse probability of treatment weighting and inverse probability of censoring weighting, to rigorously assess the effects of INSTIs. These techniques help us adjust for confounding variables, enabling us to draw robust conclusions about the causal impacts of INSTI use on blood pressure. Through this aim, we expect to gain clear insights into the direct effects of INSTIs on cardiovascular health. Aim 2 employs causal mediation methods to dissect the pathways through which INSTIs influence blood pressure. This aim focuses on understanding how changes in kidney function and body mass index mediate these effects. By exploring both direct and indirect effects of INSTIs, mediated through physiological changes, we deepen our understanding of how these drugs impact cardiovascular systems in clinical settings. Our study is distinguished by its global scope, incorporating data from diverse international settings, including South Africa, Brazil, Botswana, Thailand, and the United States. This wide-reaching approach enhances the generalizability of our findings and enables comparative analyses across different geographic and economic contexts. Such comparisons are critical for understanding how systemic health disparities affect the relationship between INSTI use and cardiovascular outcomes. By including data from both high-income and lower-income countries, our study is uniquely positioned to highlight differences in health outcomes and healthcare practices. These insights will allow us to identify specific challenges and opportunities in managing HIV and related comorbid conditions across varied health systems. The methodological innovations and geographic diversity of our research will significantly contribute to the scientific understanding of HIV treatment complications. By generating actionable insights, we aim to inform clinical practices and influence public health policies globally. Ultimately, securing this R03 grant would enable us to make substantial contributions to international health guidelines, significantly improving the management of HIV and comorbid conditions such as hypertension through tailored interventions.