In This Article
- Researchers in Massachusetts General Hospital's multidisciplinary Metabolism Unit were among the first to demonstrate excess coronary plaque in people with HIV
- These findings led to the initial demonstration that atherosclerotic plaque in this population was also more inflamed and had features suggesting increased likelihood of rupture
- The global REPRIEVE trial, with its diverse population, is the first large-scale study aimed at preventing HIV-related heart disease
- Chief of the Metabolism Unit, Steven Grinspoon, MD, is co-principal investigator in the REPRIEVE trial's Clinical Coordinating Center at Mass General
- Mass General investigators believe research focused on acquired inflammation and HIV may have implications for other inflammatory diseases, including COVID-19
Researchers in Massachusetts General Hospital's multidisciplinary Metabolism Unit have published several landmark studies involving the connections between acquired inflammation, heart disease, and HIV infection. Results from these studies were critical in establishing the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) trial, the first large-scale primary HIV prevention trial.
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"Our work using a Mass General database first suggested a major increase in the prevalence of heart disease in people with HIV, established excess inflamed plaque, and demonstrated effects of statin therapy to reduce this plaque in preliminary studies, suggesting a strategy to prevent heart disease in HIV-infected patients," says Steven Grinspoon, MD, chief of the Metabolism Unit.
Connection Between HIV and Increased Heart Disease Incidence
While pursuing investigations involving metabolic disorders and HIV, Dr. Grinspoon and his team noticed that the incidence of heart disease in patients with HIV was almost twofold higher than in individuals who did not have HIV. To make this seminal observation, they utilized Mass General Brigham's Research Patient Data Registry (RPDR). The RPDR is a longitudinal database of every ICD-9-coded patient visit at Mass General and Brigham and Women's Hospital.
"The RPDR allows you to determine the prevalence of a disease in a hospital cohort, the kinds of medicines clinicians are using, risk factors, and whether people with HIV have higher rates of cardiovascular events than the general population," says Dr. Grinspoon. "It's an effort to learn from our patients and harnesses the collective experience of the many doctors treating thousands of HIV patients over time in a highly experienced hospital like Mass General."
After publishing these findings in the Journal of Clinical Endocrinology & Metabolism in 2007, their subsequent research led to additional discoveries:
- First demonstration of excess coronary plaque in people with HIV (published in AIDS)
- First demonstration that the excess plaque was non-calcified plaque, which is more susceptible to rupture (published in AIDS)
Mass General investigators went on to show that this plaque was also more inflamed in an important 2012 Journal of the American Medical Association paper. In it, they matched HIV and non-HIV subjects by sex, age (patients were in their early 50s) and Framingham risk score. They assessed arterial wall inflammation using 18fluorine-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET).
"FDG-PET scanning looks for metabolically active tissue and inflammatory processes. It's based on the uptake and utilization of glucose," says Dr. Grinspoon. "We applied this technique to look at the aorta, and on the FDG-PET, people with HIV had more inflammation."
His team corroborated their findings in a paper in the Journal of Infectious Diseases with the novel breast cancer molecular imaging agent tilmanocept, which physicians normally use to image the sentinel node in breast cancer.
"We had the novel idea to apply this more specific imaging agent to people with HIV, to extend the results from our PET study. We saw increased macrophage specific inflammation in association with specific markers of inflammation," says Dr. Grinspoon. "That allowed us to directly image earlier disease involving inflammatory cells in the vessel wall."
Preventing HIV-related Heart Disease in the REPRIEVE Trial
This early research in cardiovascular disease and HIV has culminated in the global REPRIEVE trial. REPRIEVE has enrolled more than 7,500 patients with HIV across 12 countries and is investigating the use of the statin medication pitavastatin calcium to reduce their heart disease risk.
"Statins not only lower LDL, they have some interesting anti-inflammatory properties on the innate -immune pathways activated in HIV," says Dr. Grinspoon, who is also co-principal investigator in the trial's Clinical Coordinating Center at Mass General. "The idea is to get a two-for-one hit: reducing LDL and inflammation, leading to heart disease prevention."
REPRIEVE is also one of the most diverse large global trials, adds Dr. Grinspoon. "We've enrolled almost 50% people of color and over 30% women. We're getting close to the end of the trial, and that's exciting."
REPRIEVE Leads to Additional Key Observations
In a mechanistic sub-study of REPRIEVE analyzing 800 people, Dr. Grinspoon and his colleague Michael Lu, MD, MPH, co-principal investigator of the Data Coordinating Center at Mass General, demonstrated significant excess coronary plaque in younger patients with low traditional cardiovascular risk. This plaque was related to the same inflammatory pathways they had identified in earlier, smaller studies.
"This JAMA Network Open paper really confirmed our hypothesis of excess vulnerable plaque associated independently with inflammatory indices, as we now await the results of the main trial to determine if a statin strategy prevents associated cardiovascular events," says Dr. Grinspoon, who was senior author for the study.
Other research has shown significant inflammatory differences in HIV-infected women and men.
"Women have less coronary disease than men, but if you compare HIV-positive women to HIV-non-infected women and make the same comparison among HIV-positive men and non-infected men, the relative increase is greater in women."
Exploring Chronic Inflammatory Conditions in the COVID-19 Era
Dr. Grinspoon's research may have implications for other inflammatory diseases, including COVID-19. COVID-19 does not continue to live in the body after recovery like HIV does, but chronic inflammation exists with both.
"HIV is a valuable model of acquired inflammation and adipose changes that will hopefully be more generalizable to other populations. For example, people with psoriasis and other autoimmune disorders have more heart disease. Lipodystrophic patients can have excess fat in their liver. These strategies may be good for those patients, too," says Dr. Grinspoon.
"These studies of chronic inflammatory conditions in HIV may inform the field for the study of COVID-related, long-term inflammatory consequences and may provide a framework for studying ongoing inflammation in another viral infection. Some of our studies looking at inflammation, imaging and anti-inflammatory strategies will be leveraged in the COVID era."
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