Sex Differences in Subclinical Atherosclerosis and Systemic Immune Activation/Inflammation Among People With Human Immunodeficiency Virus in the United States

Abstract

Background: Among people with HIV (PWH), sex differences in presentations of atherosclerotic cardiovascular disease (ASCVD) may be influenced by differences in coronary plaque parameters, immune/inflammatory biomarkers, or relationships therein.

Methods: REPRIEVE, a primary ASCVD prevention trial, enrolled antiretroviral therapy (ART)-treated PWH. At entry, a subset of US participants underwent coronary computed tomography angiography (CTA) and immune phenotyping (n = 755 CTA; n = 725 CTA + immune). We characterized sex differences in coronary plaque and immune/inflammatory biomarkers and compared immune-plaque relationships by sex. Unless noted otherwise, analyses adjust for ASCVD risk score.

Results: The primary analysis cohort included 631 males and 124 females. ASCVD risk was higher among males (median: 4.9% vs 2.1%), while obesity rates were higher among females (48% vs 21%). Prevalence of any plaque and of plaque with either ≥1 visible noncalcified portion or vulnerable features (NC/V-P) was lower among females overall and controlling for relevant risk factors (RR [95% CI] for any plaque: .67 [.50, .92]; RR for NC/V-P: .71 [.51, 1.00] [adjusted for ASCVD risk score and body mass index]). Females showed higher levels of IL-6, hs-CRP, and D-dimer and lower levels of Lp-PLA2 (P < .001 for all). Higher levels of Lp-PLA2, MCP-1, and oxLDL were associated with higher plaque (P < .02) and NC/V-P prevalence, with no differences by sex. Among females but not males, D-dimer was associated with higher prevalence of NC/V-P (interaction P = .055).

Conclusions: Among US PWH, females had a lower prevalence of plaque and NC/V-P, as well as differences in key immune/inflammatory biomarkers. Immune-plaque relationships differed by sex for D-dimer but not other tested parameters. Clinical Trial Registration. ClinicalTrials.gov; identifier: NCT0234429 (date of initial registration: 22 January 2015).

Trial registration: ClinicalTrials.gov NCT00234429.

Keywords: HIV; coronary atherosclerosis; inflammation; reproductive aging; women.

Figure 1.

Prevalence of plaque outcomes by sex and ASCVD risk score. Among all participants, females (compared with males) had a lower prevalence of any plaque, NCP, VP, NC/V-P, and CAC >0. Females also had a lower prevalence of plaque, NCP, VP, NC/V-P, and CAC >0 when grouped by ASCVD risk score (eg, <2.5%, <5%, <7.5%— categories cumulative not mutually exclusive). Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CA, calcified plaque; CAC, coronary artery calcium; NCP, noncalcified plaque; NC/V-P, noncalcified portion or vulnerable features; VP, vulnerable plaque feature.

Figure 2.

Risk of plaque outcomes (females compared with males). Restricted to participants with biomarker and flow data available. For females (compared with males), the prevalence of any plaque was lower in unadjusted analyses and in sequential analyses adjusting for ASCVD risk score, ASCVD risk score and BMI, ASCVD risk score and metabolic syndrome, individual CVD risk factors, individual CVD risk factors and BMI, or ASCVD risk score and HIV-specific risk factors. The prevalence of NC/V-P was lower in females in unadjusted analyses and in analyses adjusting for ASCVD risk score and BMI, individual CVD risk factors, individual CVD risk factors and BMI, or ASCVD risk score and HIV-specific risk factors. The prevalence of CAC >0 was lower among females in unadjusted analyses and in analyses adjusting either for individual CVD risk factors or for individual CVD risk factors and BMI. ¹Metabolic syndrome was defined as presence of any 3 or more of elevated waist circumference, elevated triglycerides, reduced high HDL cholesterol, elevated blood pressure, and elevated fasting glucose. Sex- and population-specific thresholds were applied to classify waist circumference as elevated according to American Heart Association/National Heart Lung Blood Institute cut-points. ^2,3CVD risk factors adjusted for include age, race, cigarette smoking, and HDL cholesterol. Models adjusting for hypertension and total cholesterol would not converge. ⁴HIV-specific risk factors included CD4 count, abacavir exposure, and protease inhibitor exposure. Abbreviations: ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; CAC, coronary artery calcium; CI, confidence interval; CVD, cardiovascular disease; Est., estimated; HIV, human immunodeficiency virus; MS, metabolic syndrome; NCP, noncalcified plaque; NC/V-P, noncalcified portion or vulnerable features; ref., reference; RF, risk factors.

Figure 3.

Immune–plaque relationships, adjusted log binomial regression in single biomarkers, overall and by sex. Adjusted for ASCVD risk score. Effect sizes are estimated per 25% increase in the biomarker. Notably, among females, but not among males, higher levels of D-dimer were associated with higher prevalence of NC/V-P. ¹The validity of the model fit for IL-6 and hs-CRP is questionable for females. Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CI, confidence interval; Est., estimated; hs-CRP, high-sensitivity C-reactive protein; IL-6, interleukin 6; Lp-PLA2, lipoprotein-associated phospholipase A2; MCP-1, monocyte chemoattractant protein-1; NCP, noncalcified plaque; NC/V-P, noncalcified portion or vulnerable features; oxLDL, oxidized LDL; sCD14, soluble CD14; sCD163, soluble CD163.

Figure 4.

Central illustration highlighting sex differences in subclinical atherosclerosis and systemic immune activation/inflammation among with people with HIV in the U.S. Abbreviations: CAC, coronary artery calcium; HIV, human immunodeficiency virus; hs-CRP, high-sensitivity C-reactive protein; IL-6, interleukin 6; Lp-PLA2, lipoprotein-associated phospholipase A2; NC/V-P, noncalcified portion or vulnerable features.