Title: Predictive Approaches for Cardiovascular Disease and Stroke Risk Among People Living with HIV: A Narrative Review
Abstract:
Background: Cardiovascular disease (CVD) and stroke have emerged as the leading causes of non-AIDS-related mortality among people living with HIV (PLWH) in the antiretroviral therapy (ART) era. Approximately 1.2 million Americans and 38 million individuals globally are living with HIV, with life expectancy now approaching that of the general population. PLWH face a 1.3 to 2-fold elevated cardiovascular risk driven by chronic immune activation, persistent systemic inflammation, endothelial dysfunction, and ART-related metabolic effects. However, established risk stratification tools, including the Framingham Risk Score (FRS) and ACC/AHA Pooled Cohort Equations (PCE), were developed in HIV-negative populations and underestimate absolute cerebrovascular risk in PLWH. No validated stroke-specific risk prediction model for this population currently exists.
Objectives: To synthesize evidence on: (1) the biological mechanisms underlying excess CVD and stroke risk in PLWH; (2) the epidemiological burden of CVD and stroke in this population; (3) the performance and limitations of existing risk prediction tools; (4) stroke-specific risk factor characterization by subtype; and (5) primary prevention evidence: providing a clinically integrated framework for improved HIV-specific risk stratification.
Method: A narrative review was conducted following SANRA quality criteria. A purposive literature search was performed across PubMed/MEDLINE, Embase, and Google Scholar through April 2025 using terms including HIV, PLWH, cardiovascular disease, stroke, risk prediction, risk stratification, and antiretroviral therapy. Evidence was synthesized thematically across biological mechanisms, epidemiological burden, tool performance, stroke-specific findings, and prevention data.
Key Findings: PLWH face significantly elevated risks of dyslipidemia (HR 1.53), coronary artery disease (HR 1.37), myocardial infarction (HR 1.47), and stroke (OR 1.31) compared to HIV-negative individuals. All available CVD risk tools demonstrate only moderate discrimination in PLWH (C-statistics 0.65-0.77) with consistent underestimation, most severely in women, younger patients, and racial and ethnic minorities. Stroke emerged as the most critically under-addressed outcome. The D:A:D international prospective multicohort study, the largest primary study of stroke in PLWH, demonstrated that ischemic and hemorrhagic strokes carry fundamentally distinct risk factor profiles. Ischemic stroke was most strongly predicted by prior cardiovascular events (HR 4.03; 95%CI 2.91-5.57), smoking (HR 1.90; 1.41-2.56), and male sex (HR 1.62; 1.14-2.31). Hemorrhagic stroke was dominated by impaired renal function (HR 4.80; 2.47-9.36) and hepatitis C coinfection, variables absent from all current risk tools. CD4 below 200 cells/μl predicted hemorrhagic stroke specifically; viral load was not independently associated with either subtype. The REPRIEVE randomized trial (n=7,769; 5.6-year follow-up) demonstrated a 35% reduction in major adverse cardiovascular events, including stroke, with Pitavastatin (HR 0.65; 95%CI 0.48-0.90), confirming CVD preventability in PLWH while exposing the inadequacy of current risk classification for equitable trial enrollment.
Conclusion: Current CVD risk stratification tools fail PLWH through systematic underestimation and the absence of HIV-specific and stroke-subtype-specific predictive variables. Future instruments must integrate renal function, immunological biomarkers, and subtype-aware stroke prediction, validated in diverse populations. Given proven CVD preventability from REPRIEVE, accurate risk identification is an essential and currently unmet prerequisite for equitable preventive care in this population.
