IMPORTANCE Cardiovascular disease (CVD) is increased among people with HIV (PWH), but little is known regarding the prevalence and extent of coronary artery disease (CAD) and associated biological factors in PWH with low to moderate traditional CVD risk. OBJECTIVES To determine unique factors associated with CVD in PWH and to assess CAD by coronary computed tomography angiography (CTA) and critical pathways of arterial inflammation and immune activation. DESIGN, SETTING, AND PARTICIPANTS This cohort study among male and female PWH, aged 40 to 75 years, without known CVD, receiving stable antiretroviral therapy, and with low to moderate atherosclerotic cardiovascular disease (ASCVD) risk according to the 2013 American College of Cardiology/American Heart Association pooled cohort equation, was part of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), a large, ongoing primary prevention trial of statin therapy among PWH conducted at 31 US sites. Participants were enrolled from May 2015 to February 2018. Data analysis was conducted from May to December 2020. EXPOSURE HIV disease. MAIN OUTCOMES AND MEASURESThe primary outcome was the prevalence and composition of CAD assessed by coronary CTA and, secondarily, the association of CAD with traditional risk indices and circulating biomarkers, including insulin, monocyte chemoattractant protein 1 (MCP-1), interleukin (IL) 6, soluble CD14 (sCD14), sCD163, lipoprotein-associated phospholipase A2 (LpPLA2), oxidized low-density lipoprotein (oxLDL), and high-sensitivity C-reactive protein (hsCRP). RESULTSThe sample included 755 participants, with a mean (SD) age of 51 (6) years, 124 (16%) female participants, 267 (35%) Black or African American participants, 182 (24%) Latinx participants, a low median (interquartile range) ASCVD risk (4.5% [2.6%-6.8%]), and well-controlled viremia.Overall, plaque was seen in 368 participants (49%), including among 52 of 175 participants (30%) with atherosclerotic CVD (ASCVD) risk of less than 2.5%. Luminal obstruction of at least 50% was rare (25 [3%]), but vulnerable plaque and high Leaman score (ie, >5) were more frequently observed (172 of 755 [23%] and 118 of 743 [16%], respectively). Overall, 251 of 718 participants (35%) demonstrated coronary artery calcium score scores greater than 0. IL-6, LpPLA2, oxLDL, and MCP-1 levels were higher in those with plaque compared with those without (eg, median [IQR] IL-6 level, 1.71 [1.05-3.04] pg/mL vs 1.45 [0.96-2.60] pg/mL; P = .008). LpPLA2 and IL-6 levels were associated (continued) Key Points Question What is the extent of coronary artery disease among people with well-controlled HIV and low to moderate risk of atherosclerotic cardiovascular disease (ASCVD), and how is coronary artery disease associated with traditional risk, inflammatory, and immune activation indices? Findings In this cohort study of 755 people with HIV, coronary plaque was highly prevalent. Critical stenosis was rare, but higher-risk plaque features, including vulnerable plaque and high Leaman scores, were seen...

Background In addition to traditional cardiovascular (CV) risk factors, antiretroviral therapy, lifestyle, and HIV-related factors may contribute to future CV events in persons with HIV (PWH). Methods Among participants in the global REPRIEVE randomized trial, we characterized demographics and HIV characteristics relative to ACC/AHA Pooled Cohort Equations (PCE) for atherosclerotic CV disease predicted risk and CV health evaluated by Life’s Simple 7 (LS7; includes smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and glucose). Results Among 7382 REPRIEVE participants (31% women, 45% Black or African American), the median PCE risk score was 4.5% (Q1, Q3: 2.2, 7.2); 29% had a PCE score <2.5% and 9% scored above 10%. PCE score was related closely to known CV risk factors and modestly (<1% difference in risk score) to immune function and HIV parameters. The median LS7 score was 9 (Q1, Q3: 7, 10) of a possible 14. Only 24 participants (0.3%) had 7/7 ideal components, and 36% had ≤2 ideal components; 90% had <5 ideal components. The distribution of LS7 did not vary by age or natal sex, while ideal health was more common in low sociodemographic index countries and among Asians. Poor dietary and physical activity patterns on LS7 were seen across all PCE scores, including the lowest risk categories. Conclusions Poor CV health by LS7 was common among REPRIEVE participants, regardless of PCE. This suggests a critical and independent role for lifestyle interventions in conjunction with conventional treatment to improve CV outcomes in PWH.

Background Emerging data demonstrate that the use of integrase inhibitor (INSTI)-based antiretroviral treatment (ART) is associated with increased weight, but the cardiometabolic health consequences of increased weight remains poorly understood. Methods This analysis examined INSTI use (>6 months) at entry among REPRIEVE participants enrolled in High Income and Latin America/Caribbean Global Burden of Disease regions. Primary analyses used linear and logistic regression; secondary analyses used quantile regression to examine differences across the full data distribution. Characteristics of those with and without INSTI use were balanced using inverse probability of treatment weighting. Results Among 4500 REPRIEVE participants, 1848 were on an INSTI-based regimen at entry for an average of 2.1 ± 1.8 years. Integrase inhibitor use (vs no INSTI use) was associated with higher odds of obesity (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.4–1.9) and higher mean body mass index ([BMI] +1.5kg/m2; 95% CI, 1.0–1.9) and waist circumference (+3.6cm; 95% CI, 2.6–4.6). Differences in weight related to INSTI use were greater in the upper tails of the distribution (+3.1kg/m2 [95% CI, 1.9–4.4] at the 90th centile vs +0.7kg/m2 [95% CI, 0.2–1.2] at the 50th centile) and among women and nonwhite participants, with sex and race having an additive effect on BMI. Conversely, INSTI use was not associated with differences in glucose, low-density lipoprotein cholesterol, or higher odds of metabolic syndrome or hypertension. Conclusions Differences in weight and waist circumference associated with INSTI use are (1) not uniform across people with human immunodeficiency virus, (2) greatest among women and nonwhites, and (3) concentrated at the upper tails of weight distribution. These data identify at-risk subgroups for whom long-term cardiovascular disease outcomes should be carefully assessed.

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Background/Objectives Individuals with HIV are susceptible to visceral fat accumulation, which confers an increased risk of cardiometabolic disease. Advanced software to ascertain visceral fat content from dual-energy X-ray absorptiometry (DXA) has not been validated among this population. We sought to compare DXA with computed tomography (CT) in the measurement of visceral fat cross-sectional area (VAT) in HIV and non-HIV using Bland–Altman analyses. Subjects/Methods Data were combined from five previously conducted studies of individuals with HIV ( n = 313) and controls without HIV ( n = 144) in which paired DXA and CT scans were available. In cross-sectional analyses, DXA-VAT was compared with CT-VAT among participants with and without HIV. In longitudinal analyses, changes in VAT over time were compared between DXA and CT among participants with and without HIV receiving no intervention over 12 months and among individuals with HIV receiving tesamorelin—a medication known to reduce VAT—over 6 months. Results In HIV, DXA underestimated VAT compared with CT among individuals with increased visceral adiposity. The measurement bias was −9 ± 47 cm 2 overall, but became progressively larger with greater VAT ( P < 0.0001), e.g., −61 ± 58 cm 2 among those with VAT ≥ 200 cm 2 . Sex-stratified analyses revealed that the relationship between VAT and measurement bias was especially pronounced in men ( P < 0.0001). Longitudinally, DXA underestimated changes in VAT, particularly among those at the extremes of VAT gain or loss ( P < 0.0001). In contrast to the cross-sectional findings, the tendency for DXA to underestimate longitudinal changes in VAT was evident in both men and women. Analogous findings were seen among controls in cross-sectional and longitudinal analyses. Conclusions DXA underestimated VAT relative to CT in men with and without HIV, who had increased visceral adiposity. DXA also underestimated changes in VAT over time in men and women, irrespective of HIV status. DXA-VAT should be used with caution among both HIV and non-HIV-infected populations.

BACKGROUND Among ART-treated people with HIV (PWH), persistent systemic immune activation contributes to atherogenesis, cardiovascular disease (CVD) events, and mortality. Factors associated with key immune activation indices have not previously been characterized among a global primary CVD prevention cohort of PWH. METHODS Leveraging baseline REPRIEVE data, we interrogated factors associated with soluble CD14 (sCD14) and oxidized LDL (oxLDL). RESULTS The primary analysis cohort included 4,907 from 5 Global-Burden-of-Disease regions (38% female; 48% Black; median age 50y). When levels of sCD14 and oxLDL were characterized by sex, age, and region, female sex and residence in South Asia or Sub-Saharan Africa were associated with higher sCD14 levels while residence in high-income regions was associated with higher oxLDL levels. In fully adjusted models for sCD14, female sex and white race (among those in high-income regions) were associated with higher sCD14 levels while higher BMI and current use of NRTI+INSTI ART were associated with lower sCD14 levels. In fully adjusted models for oxLDL, male sex, residence in high-income regions, white race (among those in high-income regions), and higher BMI were associated with higher oxLDL levels. In a sub-analysis cohort of 1396 women with HIV, increased reproductive age was associated with higher sCD14 levels but not with higher oxLDL levels. CONCLUSIONS Factors associated with oxLDL and sCD14, two key indices of immune-mediated CVD risk, differ. Future studies will elucidate ways in which medications (e.g. statins) and behavioral modifications influence sCD14/oxLDL and the extent to which dampening of these markers mediates CVD-protective effects.

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Abstract Background Patterns of antiretroviral therapy (ART) use and immunologic correlates vary globally, and contemporary trends are not well described. Methods The REPRIEVE trial (Randomized Trial to Prevent Vascular Events in HIV) enrolled persons with human immunodeficiency virus (HIV) who were aged 40–75 years, receiving ART, and had low-to-moderate cardiovascular disease risk. ART use was summarized within Global Burden of Disease (GBD) super-regions, with adjusted linear and logistic regression analyses examining associations with immune parameters and key demographics. Results A total of 7770 participants were enrolled, with a median age of 50 years (interquartile range, 45–55 years); 31% were female, 43% were black or African American, 15% were Asian, 56% had a body mass index &gt;25 (calculated as weight in kilograms divided by height in meters squared), and 49% were current or former smokers. The median CD4 T-cell count was 620/µL (interquartile range, 447–826/ µ L), and the median duration of prior ART use, 9.5 years (5.3–14.8) years. The most common ART regimens were nucleoside/nucleotide reverse-transcriptase inhibitor (NRTI) plus nonnucleoside reverse-transcriptase inhibitor (43%), NRTI plus integrase strand transfer inhibitor (25%), and NRTI plus protease inhibitor (19%). Entry ART varied by GBD region, with shifts during the trial enrollment period. In adjusted analyses, entry CD4 cell count and CD4/CD8 ratio were associated with GBD region, sex, entry regimen, duration of ART, and nadir CD4 cell count; CD4 and CD8 cell counts were also associated with body mass index and smoking status. Conclusions There were substantial variations in ART use by geographic region and over time, likely reflecting the local availability of specific medications, changes in treatment guidelines and provider/patient preferences. The analyses of CD4 cell counts and CD4/CD8 ratios may provide valuable insights regarding immune correlates and outcomes in people living with HIV. Clinical Trials Registration NCT02344290.