BOSTON - Significant amounts of atherosclerotic plaque have been found in the coronary arteries of people with HIV, even in those considered by traditional measures to be at low-to-moderate risk of future heart disease, according to a study published in JAMA Network Open.
This finding emerged from the global REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) study, in which Massachusetts General Hospital (MGH) is playing a key coordinating role. Researchers found that the higher-than-expected levels of plaque could not be attributed simply to traditional cardiovascular disease risk factors like smoking, hypertension, and lipids in the blood, but were independently related to increased arterial inflammation and immune system activation.
"While we know that people living with HIV who are receiving antiretroviral therapy are at increased risk of coronary artery disease, our understanding of the mechanisms behind this phenomenon have been very limited," says Steven Grinspoon, MD, chief of the MGH Metabolism Unit and co-principal investigator of REPRIEVE. "The latest findings from REPRIEVE expand our knowledge and provide important insights that set the stage for further studies to identify effective plaque reduction or prevention strategies, such as the possible use of statin medicines."
REPRIEVE is the largest study of cardiovascular disease among people living with HIV, having enrolled 7,700 participants at more than 100 sites in 12 countries around the world, in collaboration with the AIDS Clinical Trials Group (ACTG). The newly published results are from a subset of the overall trial, consisting of 755 individuals between the ages of 40 and 75 enrolled in 31 sites across the United States. This is the largest study to assess plaque levels in the arteries of people with HIV who have no known heart disease and are eligible for primary cardiovascular prevention. The study used coronary CT angiography to assess plaque and then correlate results with blood samples that measured inflammation and immune activation.
The MGH-led study found that 49 percent of participants had plaque in their coronary arteries. While significant narrowing of the arteries was rare, nearly a quarter had plaque which the researchers considered "vulnerable," that is, at risk for potential future cardiovascular problems. "The prevalence of plaque found in people with HIV was striking, though the number of lesions was limited in most people and only a portion could be explained by traditional risk factors," says co-author Michael Lu, MD, MPH, co-director of the MGH Cardiovascular Imaging Research Center. "We learned that the plaque burden was also associated with higher levels of arterial inflammation and immune system activation independent of traditional risk scores."
Enabling researchers to assess these nontraditional cardiovascular risk factors were two biomarkers which they hypothesized could reflect premature cardiovascular disease among people with HIV. They are interleukin 6 (IL-6), associated with immune system activation, and LpPLA2, associated with arterial inflammation. "It was particularly notable to observe the increased levels of IL-6 in relationship to plaque among relatively healthy people with HIV, inasmuch as immune system activation may have damaging effects on the vessels of the heart over time," notes Grinspoon.
In addition to helping researchers better understand the mechanisms of cardiovascular risk in people with HIV, the two biomarkers will be evaluated in the next phase of REPRIEVE for their ability to predict major events, such as heart attacks and strokes. That ongoing research will also investigate the potential of statin therapy to reduce lipid levels - its primary therapeutic target -- as well as plaque and markers of inflammation.
"We know that cardiovascular disease is occurring among people with HIV at approximately twice the rate of people without the disease," says Grinspoon, "which is why REPRIEVE is so critical in terms of discovering new ways to mitigate those risks so that people with HIV can be assured healthy and full lives."
Grinspoon is a professor of Medicine at Harvard Medical School (HMS). Lu is an assistant professor of Radiology at HMS. REPRIEVE trial leadership team also includes Pamela Douglas, MD, professor of Medicine at Duke University, and Heather Ribaudo, PhD, principal research scientist at the Harvard T.H. Chan School of Public Health. Other MGH investigators include Udo Hoffmann, MD, Borek Foldyna, MD, Markella Zanni, MD, Kathleen Fitch, MSN, Emma Kileel, MPH, Julia Karady, MD, Jana Taron, MD, Thomas Mayrhofer, PhD, Evelynne Fulda, BA, and Kayla Paradis, BS. REPRIEVE is funded through grants from the National Institutes of Health, with additional funding from Gilead Sciences, Inc., Kowa Pharmaceuticals American, Inc., and ViiV Healthcare Ltd.
About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2020, Mass General was named #6 in the U.S. News & World Report list of "America's Best Hospitals."