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ACTG Reports REPRIEVE Study HIV+
Heart Disease Risk with CT Angiography
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AIDS Clinical Trials Group
Los Angeles, Calif. - The AIDS Clinical Trials Group (ACTG), the largest global HIV research network, today announced that findings from a sub-study of REPRIEVE (A5332/A5332s, an international clinical trial studying heart disease prevention in people living with HIV) have been published in the Journal of the American Medical Association Network Open (JAMA Network Open). The study found that approximately half of study participants, who were considered by traditional measures to be at low-to-moderate risk of future heart disease, had atherosclerotic plaque in their coronary arteries.
"baseline data..... using CT scanners..... from the mechanistic substudy of REPRIEVE provide useful information on the degree and type of CAD among this primary prevention group. Plaque was seen in nearly 50% and CAC in 35% of our population, despite a mean age of 51 years and a median ASCVD risk of 4.5%."
CVD is a major source of morbidity and mortality among PWH receiving ART, but little is known regarding the extent of CAD and key associated factors in those with low to moderate traditional cardiovascular risk. This study, performed in a large primary prevention cohort of relatively young patients, expands our understanding of CAD in HIV, demonstrating a substantial prevalence of coronary atherosclerosis, including vulnerable plaque. Markers of innate immune activation and arterial inflammation are associated with CAD in this group with well-controlled HIV disease.
Coronary CTA was performed on at least 64 slice CT scanners according to a standardized protocol consistent with the Society of Cardiovascular CT guidelines for clinical coronary CTA17 (eMethods in Supplement 1).
Conclusions and Relevance In this study of a large primary prevention cohort of individuals with well-controlled HIV and low to moderate ASCVD risk, CAD, including noncalcified, nonobstructive, and vulnerable plaque, was highly prevalent. Participants with plaque demonstrated higher levels of immune activation and arterial inflammation, independent of traditional ASCVD risk and HIV parameters.
This study found a substantial prevalence of CAD even in young PWH with low traditional ASCVD risk. Key markers of innate immune activation and arterial inflammation were associated with CAD in this group with well-controlled HIV disease, independent of traditional risk factors. Further study of this cohort will help to determine the effects of statin therapy to modulate these pathways and reduce plaque in this population.
......Studies to date have shown excess CAD occurring at a younger age among PWH.25 Two key studies using CTA suggested an increased prevalence of plaque in this population. However, such studies have often been limited to men13 and/or have been relatively small.11,14 To our knowledge, prior studies have not assessed plaque using CTA in a prospectively recruited asymptomatic primary prevention cohort with low to moderate ASCVD risk, assessed in the current era of modern ART, using the gold standard ACC/AHA pooled cohort equation (PCE) for risk calibration. This question is of critical importance to the large group of relatively young PWH at risk for but without known CVD. In this regard, these baseline data from the mechanistic substudy of REPRIEVE provide useful information on the degree and type of CAD among this primary prevention group. Plaque was seen in nearly 50% and CAC in 35% of our population, despite a mean age of 51 years and a median ASCVD risk of 4.5%. Plaque characteristics in this group suggest a low prevalence of significant stenosis, but vulnerable plaque characteristics were seen in nearly one-quarter. It will be critical in future studies to determine how this unique plaque phenotype relates to major adverse cardiovascular events over time.
Assessment of Coronary Artery Disease With Computed Tomography Angiography and Inflammatory and Immune Activation Biomarkers Among Adults With HIV Eligible for Primary Cardiovascular Prevention
JAMA Netw Open. 2021
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 in approximately one-fifth of participants; plaque indices were associated with ASCVD risk scores and, independently, indices of inflammation and immune activation.
Meaning These findings suggest that people with HIV at low to moderate risk of cardiovascular disease have a significant prevalence of coronary plaque associated with inflammation and immune activation markers.
Abstract
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 Measures The 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).
Results The 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 with plaque in adjusted modeling, independent of traditional risk indices and HIV parameters (eg, IL-6: adjusted odds ratio, 1.07; 95% CI, 1.02-1.12; P = .01).
Conclusions and Relevance In this study of a large primary prevention cohort of individuals with well-controlled HIV and low to moderate ASCVD risk, CAD, including noncalcified, nonobstructive, and vulnerable plaque, was highly prevalent. Participants with plaque demonstrated higher levels of immune activation and arterial inflammation, independent of traditional ASCVD risk and HIV parameters.
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News Release 29-Jun-2021
ACTG announces publication of REPRIEVE sub-study in JAMA Network Open, providing insights into cardiovascular disease risk among people living with HIV
AIDS Clinical Trials Group
Los Angeles, Calif. - The AIDS Clinical Trials Group (ACTG), the largest global HIV research network, today announced that findings from a sub-study of REPRIEVE (A5332/A5332s, an international clinical trial studying heart disease prevention in people living with HIV) have been published in the Journal of the American Medical Association Network Open (JAMA Network Open). The study found that approximately half of study participants, who were considered by traditional measures to be at low-to-moderate risk of future heart disease, had atherosclerotic plaque in their coronary arteries.
While it is well-known that people living with HIV are at increased risk of cardiovascular events, including heart attacks and strokes, little is understood about the prevalence and extent of atherosclerosis in heart blood vessels and associated biological factors. The Mechanistic sub-study of REPRIEVE was designed to specifically identify factors that contribute to cardiovascular disease among people living with HIV.
"This sub-study of REPRIEVE is seeking to better understand why people living with HIV develop heart disease, even when their HIV is well controlled and they don't have many traditional risk factors," said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles. "REPRIEVE is the largest study of cardiovascular disease among people living with HIV and this is an important early report that sets the stage for future important findings."
Today's publication describes baseline data on 755 participants between the ages of 40 and 75 years old, who were enrolled at 31 sites across the United States. The sub-study used coronary CT angiography to assess the amount of plaque in participants' coronary arteries and then correlated those findings with blood samples that measured inflammation and immune activation.
Nearly half the participants (49 percent) had plaque in their coronary arteries, though the plaques were mostly seen in just a few areas of the coronary arteries. The presence of plaque was associated with a higher burden of risk factors, but also with higher levels of inflammation independent of traditional risk scores. In almost all individuals (97 percent), the plaque was mild and did not cause a narrowing of more than 50 percent of the coronary artery. While significant narrowing was rare, about one-quarter of participants (23 percent) had plaque with features that could potentially cause problems in the future (also known as vulnerable plaque).
In the general population, epidemiologic studies have shown that future cardiovascular disease increases with higher ASCVD PCE (atherosclerotic cardiovascular disease pooled cohort equation) risk scores, an index of traditional risk. REPRIEVE recruited participants with low to moderate ASCVD risk and a low average 10-year risk score of 4.5 percent. The clinical significance of mild or even significant plaque in asymptomatic people with low cardiovascular risk is unknown, as is the effectiveness of statin therapy to prevent cardiovascular disease in this population. REPRIEVE will address these important questions by following these participants to determine if the plaque reported in the Mechanistic sub-study of REPRIEVE is clinically significant (whether it is related to future cardiovascular events), whether statin therapy can reduce plaque and markers of inflammation, and if statin therapy can reduce the incidence of heart attacks and strokes.
"Heart disease is a major cause of illness and death among people living with HIV, including those with well-controlled HIV disease receiving antiretroviral treatment," said Steven Grinspoon, M.D., Massachusetts General Hospital. "Until now, our understanding of coronary artery disease among people living with HIV has been very limited. These findings significantly expand our knowledge and provide important insights that will lay the foundation to ultimately help us better support the health and well-being of people living with HIV."
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