Sex Differences in the Risk of Stroke Associated With Traditional and Non-Traditional Factors in a US Cohort of People With HIV Infection

Abstract

Background and objectives: Although stroke risk associated with HIV may be greater for women than men, little is known about whether the impact of different factors on cerebrovascular risk varies by sex in people with HIV (PWH) and contributes to stroke risk disparities in this population. The primary objective of this study was to examine whether sex modifies the effect of demographics, cardiometabolic factors, health-related behaviors, and HIV-specific variables on stroke risk in PWH from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort.

Methods: In this observational cohort study, we analyzed data from clinical encounters for PWH followed at 5 CNICS sites from approximately 2005 to 2020. All potential stroke events were adjudicated by neurologists. Patient-reported outcomes collected at clinic visits, including substance use and depression, were also available. We used Cox proportional hazards models to determine whether sex modified the association of predictors of interest with incident stroke.

Results: Among 13,573 PWH (19% female sex at birth, mean age 44 years, mean follow-up 5.6 years), female sex was associated with a higher risk of stroke only among individuals aged 50 years or younger (hazard ratio [HR] 2.01 at age 40 [1.25-3.21] vs HR 0.60 at age 60 [0.34-1.06]; p = 0.001 for the interaction). Younger female participants who developed a stroke were more likely to have treated hypertension, a higher cardiovascular risk score, and detectable HIV than younger male participants whereas these factors were comparable by sex among older participants who developed a stroke. Sex modified the effect of detectable HIV (HR 4.66 for female participants [2.48-8.74] vs HR 1.30 for male participants [0.83-2.03]; p = 0.001 for the interaction), methamphetamine use (HR 4.78 for female participants [1.47-15.56] vs HR 1.19 for male participants [0.62-2.29]; p = 0.04 for the interaction), and treated hypertension (HR 3.44 for female participants [1.74-6.81] vs HR 1.66 for male participants [1.14-2.41]; p = 0.06 for the interaction) on stroke risk.

Discussion: Younger female participants with HIV were at elevated cerebrovascular risk compared with younger male participants. Several risk factors had a greater adverse effect on stroke risk in female participants than in male participants, including HIV viremia, methamphetamine use, and treated hypertension. These findings underscore the importance of a personalized approach to predict and prevent cerebrovascular risk among PWH.

Figure 1. Factors Associated With Stroke in People With HIV From CNICS

In the overall cohort, cardiovascular risk factors, including treated hypertension and diabetes mellitus, and a detectable viral load were associated with an increased risk of stroke while a higher CD4 count was protective against stroke. In addition to the factors shown in the figure, the multivariable model was also adjusted for CNICS site, systolic blood pressure, diastolic blood pressure, total cholesterol, HDL cholesterol, LDL cholesterol, and physical activity. CNICS = Centers for AIDS Research Network of Integrated Clinical Systems.

Figure 2. Kaplan-Meier Estimate for Survival Free of Stroke by Sex at Birth and Age at Baseline

Female participants younger than 50 years had higher rates of stroke compared with male participants in the same age range. A similar pattern was not observed among female and male participants older than 50 years, who had more comparable rates of stroke.

Figure 3. Differential Impact of Female Sex at Birth on Stroke Risk by Age

At younger ages (40 years), female sex compared with male sex at birth was associated with an increased risk of stroke. At older ages (60 years), female sex at birth was associated with a lower risk of stroke.