Coronary Plaque in People With HIV vs Non-HIV Asymptomatic Community and Symptomatic Higher-Risk Populations

Background People with HIV (PWH) have a high burden of coronary plaques; however, the comparison to people without known HIV (PwoH) needs clarification. Objectives The purpose of this study was to determine coronary plaque burden/phenotype in PWH vs PwoH. Methods Nonstatin using participants from 3 contemporary populations without known coronary plaques with coronary CT were compared: the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) studying PWH without cardiovascular symptoms at low-to-moderate risk (n = 755); the SCAPIS (Swedish Cardiopulmonary Bioimage Study) of asymptomatic community PwoH at low-to-intermediate cardiovascular risk (n = 23,558); and the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) of stable chest pain PwoH (n = 2,291). The coronary plaque prevalence on coronary CT was compared, and comparisons were stratified by 10-year atherosclerotic cardiovascular disease (ASCVD) risk, age, and coronary artery calcium (CAC) presence. Results Compared to SCAPIS and PROMISE PwoH, REPRIEVE PWH were younger (50.8 ± 5.8 vs 57.3 ± 4.3 and 60.0 ± 8.0 years; P < 0.001) and had lower ASCVD risk (5.0% ± 3.2% vs 6.0% ± 5.3% and 13.5% ± 11.0%; P < 0.001). More PWH had plaque compared to the asymptomatic cohort (48.5% vs 40.3%; P < 0.001). When stratified by ASCVD risk, PWH had more plaque compared to SCAPIS and a similar prevalence of plaque compared to PROMISE. CAC = 0 was more prevalent in PWH (REPRIEVE 65.2%; SCAPIS 61.6%; PROMISE 49.6%); among CAC = 0, plaque was more prevalent in PWH compared to the PwoH cohorts (REPRIEVE 20.8%; SCAPIS 5.4%; PROMISE 12.3%, P < 0.001). Conclusions Asymptomatic PWH in REPRIEVE had more plaque than asymptomatic PwoH in SCAPIS but had similar prevalence to a higher-risk stable chest pain cohort in PROMISE. In PWH, CAC = 0 does not reliably exclude plaque.

H IV affects around 38 million peo- ple worldwide. 1People with HIV (PWH) live longer due to the development of successful antiretroviral therapy.However, PWH often demonstrates an accelerated development of chronic diseases, including increased rates of cardiovascular disease. 2 The pathomechanism of accelerated cardiovascular disease development among PWH is not fully understood but is explained in part by increased systemic inflammation and residual immune activation.
Among PWH, cardiovascular disease may occur at a relatively young age, despite the lower traditional cardiovascular risk profile.After controlling for traditional cardiovascular risk factors, the rate of cardiovascular events, such as myocardial infarction or stroke, is nearly doubled in PWH compared to people without known HIV (PwoH). 3,46][7] Moreover, among a large primary prevention cohort of individuals with well-controlled HIV, noncalcified, nonobstructive, and vulnerable plaques were common. 8 other non-HIV populations, it is well understood that underlying cardiovascular disease burden is strongly associated with concurrent traditional cardiovascular risk factors.Coronary CT angiography (CTA) images were acquired using either retrospective ECGgated or prospectively ECG-triggered protocols according to local protocols and guidelines for the assessment of coronary plaque.Coronary CTA images were interpreted by using the 18-segment coronary segment model. 13A coronary plaque resulting in $50% stenosis severity was defined as an obstructive disease. 14For REPRIEVE and PROMISE, coronary CT datasets were analyzed at the same U.S. central core laboratory. 8,15For SCAPIS, CTs were interpreted at the participating sites. 9C score, the prevalence of any coronary plaque on coronary CTA, and obstructive plaque ($50% stenosis) were compared as assessed on the study entry coronary CT.P ¼ 0.001).PWH had the lowest low-density lipoprotein cholesterol levels (2.8 AE 0.8 vs 3.5 AE 0.9 and 3.2 AE 0.8 mmol/L; P < 0.001), the lowest rate of diabetes (0.4% vs 5.0% and 14.6%; P < 0.001), and 10year ASCVD risk (5.0 AE 3.2 vs 6.0 AE 5.3 and 13.5 AE 11.0, P < 0.001) compared to asymptomatic and symptomatic PwoH.Similar results were obtained comparing the 3 cohorts irrespective of statin use (Supplemental Table 2).

PRESENCE OF CAD. Any form of coronary plaque was more prevalent in PWH than in the asymptomatic
PwoH cohort (48.5% vs 40.3%;P < 0.001).When stratified by age groups, coronary plaque was more prevalent in REPRIEVE as compared to PwoH in SCAPIS (P < 0.001, across all age groups) (Figure 1A).
Further, across age groups, plaque prevalence was similar to the symptomatic population (Figure 1A).
Among male participants, compared to PWH stable chest pain, PwoH in PROMISE had more and asymptomatic PwoH in SCAPIS had less prevalent coronary plaque.Among women, PWH in REPRIEVE had similar amounts of prevalent plaque as stable chest pain PwoH in PROMISE but more than asymptomatic PwoH in SCAPIS (Figures 1B and 1C).The prevalence of plaque in REPRIEVE PWH was similar to SCAPIS PwoH participants who were 10 years older; for example, the prevalence of plaque was similar between the 40 and 44-year group in REPRIEVE and the 50 and 54-year group in SCAPIS and between the 50 and 54-year group in REPRIEVE and the 60 and 64year group in SCAPIS (Figure 1A).These results were consistent when considering all participants in the PwoH cohorts, including those on statin therapy (Supplemental Figures 1A to 1C).
When considering the full PwoH cohorts independent of statin use, the prevalence of CAD in REPRIEVE was higher than among SCAPIS participants but similar compared to PwoH PROMISE (Supplemental Figure 3).4A and 4B).In our sensitivity analysis, we observed the same results among all SCAPIS and PROMISE participants in contrast to REPRIEVE participants (Supplemental Figure 4).

DISCUSSION
A large primary prevention cohort of PWH with well-controlled HIV (REPRIEVE) had a greater burden of coronary plaque than a community cohort at similar cardiovascular risk (SCAPIS) and a similar burden of coronary plaque to a stable chest pain population at increased cardiovascular risk (PROM-ISE).As assessed among patients with CAC ¼ 0, exclusively noncalcified plaque was more common in REPRIEVE than in SCAPIS, and a substantial proportion (21%) of low-risk PWH with CAC ¼ 0 had atherosclerotic plaque, more than in the PwoH cohorts.
These results corroborate and extend prior findings describing premature and prevalent coronary plaque among PWH.In the large case-control study by Guaraldi et al, 17   Prior studies have suggested prevalent coronary plaque among PWH, including the predominance of noncalcified plaques. 5,6In the Multicenter AIDS Cohort Study cohort, HIV-infected men had more prevalent and extensive noncalcified plaque compared to non-HIV males, independent of CAD risk factors. 19In this analysis, the presence of any type of noncalcified plaque (including exclusively noncalcified and mixed types of plaques) was similar between PWH and symptomatic PwoH.However, when assessing participants with a CAC ¼ 0, we found a greater prevalence of coronary plaque among PWH when compared to asymptomatic and symptomatic PwoH.This finding may be explained by a greater However, little is known about the prevalence and phenotype of atherosclerotic coronary plaques in PWH when compared to non-HIV populations.This study aims to compare the burden and phenotype of atherosclerotic coronary plaque in a primary prevention cohort of PWH-without cardiovascular disease symptoms at low-to-intermediate cardiovascular risk-to asymptomatic and symptomatic PwoH to better understand differences in coronary plaque characteristics between PWH and PwoH.METHODS STUDY POPULATION.Three contemporary multicenter clinical trial populations with and without a known HIV and without known history of coronary plaque who underwent coronary CT imaging were included.We studied participants recruited in the following clinical trials: first, a primary prevention PWH cohort at low-to-moderate cardiovascular risk enrolled in the mechanistic CT substudy of the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) (n ¼ 755); 11 second, an asymptomatic community cohort at low-intermediate cardiovascular risk from the SCAPIS (Swedish Cardiopulmonary Bioimage Study) (n ¼ 23,558); 9 and finally, a symptomatic stable chest pain cohort at intermediate risk from the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) (n ¼ 2,291). 10We A B B R E V I A T I O N S A N D A C R O N Y M S ASCVD = atherosclerotic cardiovascular disease CAC = coronary artery calcification CT = computed tomography PWH = people with HIV PwoH = people without known HIV Department of Radiology, Medical Center-University of Freiburg, University of Freiburg, Freiburg im Breisgau, Germany; g Metabolism Unit, Massachusetts General Hospital & Harvard Medical School, Boston, Massachusetts, USA; h Department of Medicine, provide the detailed study-specific inclusion and exclusion criteria in Supplemental

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J A C C : A D V A N C E S , V O L . 3 , N O .6 , 2 0 2 4Karady et alJ U N E 2 0 2 4 : 1 0 0 9 6Plaque in HIV vs Non-HIV Populations

CAC [ 0
SUBGROUP.Most of REPRIEVE (65.2%),SCAPIS (61.6%), and nearly half of PROMISE (49.6%) participants had CAC ¼ 0. In this subgroup, plaques were significantly more prevalent in PWH (REPRIEVE 20.8% vs SCAPIS 5.4% [P < 0.001] and vs PROMISE 12.3% [P < 0.001]).Further, when stratified by age and 10-year ASCVD risk, the prevalence of coronary plaque was significantly greater in PWH compared to low, borderline, and intermediate-risk asymptomatic (P < 0.001) and symptomatic (P < 0.05) PwoH (Figures an approximately 10-year shift in coronary atherosclerotic risk factor occurrence was observed among PWH compared to age, sex, and gender-matched PwoH.In our analysis-the first comparison assessing anatomically phenotyped coronary plaque occurrence by coronary CT imaging of large PWH vs PwoH cohorts-premature coronary atherosclerotic disease occurred 10 years earlier among PWH than in an asymptomatic community cohort.Further, this is the first time that plaque prevalence among PWH at low cardiovascular risk has been compared to symptomatic individuals at increased cardiovascular risk, and we observed a similar prevalence of plaque across different age groups.Stratifying by ASCVD risk group, we saw a higher prevalence of coronary plaque among PWH at low ASCVD risk compared to symptomatic chest pain participants.This observation corroborates prior findings describing calculators designed for cardiovascular risk estimation to underestimate cardiovascular risk among PWH. 18A possible explanation for the latter finding is that in the lower ASCVD risk categories, immune activation and other factors related to HIV infection contribute to the

FIGURE 1
FIGURE 1 Presence of Any Coronary Atherosclerotic Plaque in REPRIEVE vs SCAPIS vs PROMISE Participants Without Established Coronary Heart Disease as Stratified by Age

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CENTRAL ILLUSTRATION Coronary Plaque in PWH vs PwoHKarady J, et al.JACC Adv.2024;3(6):100968.Asymptomatic REPRIEVE PWH at low-to-intermediate cardiovascular risk had more prevalent coronary artery plaque compared to an asymptomatic community PwoH SCAPIS cohort at low cardiovascular risk, and similar prevalence of plaque When compared to an older, higher-risk stable chest pain PwoH PROMISE cohort.PROMISE ¼ Prospective Multicenter Imaging Study for Evaluation of Chest Pain; PWH ¼ people with HIV; PwoH ¼ people without known HIV; REPRIEVE ¼ Randomized Trial to Prevent Vascular Events in HIV; SCAPIS ¼ Swedish Cardiopulmonary Bioimage Study.Karady et al J A C C : A D V A N C E S , V O L . 3 , N O .6 , 2 0 2 Plaque in HIV vs Non-HIV Populations J U N E 2 0 2 4 : 1 0 0 9 6 8

Table 1
P < 0.001).The rate of current smokers was the highest in REPRIEVE compared to the other populations (24.0%vs 12.1%, P < 0.001 and 20.3%,P ¼ 0.031),while the rate of former smokers was similar among the 3 trial populations (31.2% vs 34.4% and 31.9%,both P > 0.05).REPRIEVE PWH had lower systolic blood pressure than SCAPIS PwoH and PROMISE PwoH (123 AE 13 vs 125 AE 17 and 131 AE 17; RESULTSPOPULATION.Baseline characteristics of the populations stratified by sex are summarized in Table1.PWH in REPRIEVE, when compared to SCAPIS asymptomatic and PROMISE stable chest pain populations, had fewer women (16.4% vs 48.7% and 53.2%, respectively, P < 0.001) and were younger (50.8 AE 5.8 vs 57.3 AE 4.3 and 60.0 AE 8.0 years,

Table 3 )
. Prevalent obstructive plaque was the lowest

Table 3 )
. Similar trends were observed when considering the total PwoH populations (Supplemental Table4).

TABLE 1
Characteristics of REPRIEVE vs SCAPIS vs PROMISE Participants Without Established Coronary Heart Disease Who Underwent Successful Coronary Values are mean AE SD or n (%). a SCAPIS does not register data on race or ethnic background.However, the majority of the participants were born in Sweden (ca 84%) or other European countries (ca 10%), with ca 2.5% representation from the Middle-East.b Other race includes participants self-identifying as Native or Indigenous to the enrollment region; more than one race (with no single race noted as predominant); or of an unknown race.CT ¼ computed tomography; HDL ¼ high-density lipoprotein; LDL ¼ low-density lipoprotein; PROMISE ¼ Prospective Multicenter Imaging Study for Evaluation of Chest Pain; REPRIEVE ¼ Randomized Trial to Prevent Vascular Events in HIV; SCAPIS ¼ Swedish Cardiopulmonary Bioimage Study.
FIGURE 2 Presence of Any Noncalcified Coronary Atherosclerotic Plaque of REPRIEVE vs SCAPIS vs PROMISE Participants Without Established Coronary Heart Disease as Stratified by Age ASCVD ¼ atherosclerotic cardiovascular disease; CAD ¼ coronary artery disease; PROMISE ¼ Prospective Multicenter Imaging Study for Evaluation of Chest Pain; REPRIEVE ¼ Randomized Trial to Prevent Vascular Events in HIV; SCAPIS ¼ Swedish Cardiopulmonary Bioimage Study.Presence of Any Coronary Atherosclerotic Plaque of REPRIEVE vs SCAPIS vs PROMISE Participants Without Established Coronary Heart Disease as Stratified by 10-Year Risk for Atherosclerotic Cardiovascular Disease PROMISE ¼ Prospective Multicenter Imaging Study for Evaluation of Chest Pain; REPRIEVE ¼ Randomized Trial to Prevent Vascular Events in HIV; SCAPIS ¼ Swedish Cardiopulmonary Bioimage Study.Prevalence of Any Atherosclerotic Plaque in the Subgroup with CAC ¼ 0 FIGURE 3STRENGTHS AND LIMITATIONS.Importantly, all 3 cohorts were free of known cardiovascular disease, and participants were not using statins in the primary analysis.The 2 PwoH cohorts were selected as they represent the range of ASCVD risk among a primary prevention, middle-aged population.However, this approach also has limitations.First, we compared cohort-level data between one PWH and 2 PwoH FIGURE 4 B A (A) Stratified by Age.(B) Stratified by 10-year risk for atherosclerotic cardiovascular disease.ASCVD ¼ atherosclerotic cardiovascular disease; CAC ¼ coronary artery calcium score; CAD ¼ coronary artery disease.REPRIEVE (16.4%) was lower compared to PROMISE (50.6%) and SCAPIS (51.6%).Fourth, while reasonably expected to be rare, HIV status was not recorded in the SCAPIS and PROMISE trials.Finally, the studies also differed in racial/ethnic composition.White individuals represented 54% of REPRIEVE and 76% of PROMISE, while race was not collected in SCAPIS; SCAPIS participants were "mainly northern European ancestry".This paper received NIH grants U01HL123336 to the REPRIEVE Clinical Coordinating Center and U01HL123339 to the REPRIEVE Data Coordinating Center, as well as funding from Kowa Pharmaceuticals, Gilead Sciences, and ViiV Healthcare.The National Institute of