HIV and the immune system linked to heart disease in women

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1 CATIE-News CATIE s bite-sized HIV and hepatitis C news bulletins. HIV and the immune system linked to heart disease in women 26 September 2013 The widespread availability of potent combination anti-hiv therapy (commonly called ART or HAART) in Canada, Australia, the U.S. and Western Europe has greatly improved the health of HIV-positive people. Deaths from AIDSrelated infections are now much less common, at least among HIV-positive people who get tested, make regular clinic visits and take ART every day exactly as directed. Inflammation HIV infection activates the immune system, causing it to release chemical signals that incite inflammation throughout the body. This is a normal response to an infection, as the body mobilizes to contain an invading germ. However, in many cases, the immune system is not able to squelch HIV. Treatment for HIV significantly reduces levels of HIVrelated inflammation, but ART does not eliminate the inflammation associated with HIV infection, perhaps because the virus continues to persist, albeit at relatively low levels. As a result, inflammation persists and this carries the potential to gradually degrade many organ systems. Gender Several studies have found a link between an increased risk for serious cardiovascular disease (heart attack, stroke) and HIV infection, particularly among men. However, comparatively less is known about the impact of prolonged HIV infection on the cardiovascular health of women. Observational studies in France and North America suggest that HIV-positive women have an increased risk for heart attack, in some cases as high as three-fold greater than among HIV-negative women. Precisely why this increased risk occurs has not been clear, until very recently. Uncovering risks Researchers in Boston have intensely studied women, both HIV positive and negative, to better understand the interactions between their immune and cardiovascular systems. In the Boston study, all women were free from symptoms of cardiovascular disease (CVD) and did not have a history of CVD. Using high-resolution X-ray scans (CT scans) of the women s arteries, researchers found that HIV-positive women were more likely to have more sticky deposits in their arteries called plaque, specifically non-calcified plaque (NCP). These are unstable deposits of fat and other materials that can burst and trigger the formation of blood clots. If the clot formed is sufficiently large, it can block an artery and lead to a heart attack. Researchers linked the presence of NCP to certain inflammatory signals produced by cells of the immune system called monocytes. These and other findings are discussed later in this report. Study details Researchers at New England s leading medical centre, Massachusetts General Hospital, recruited 90 women. None of them had a history of or symptoms of CVD and they were distributed as follows: 60 HIV-positive women 30 HIV-negative women

2 All women were recruited from the same communities to ensure that they had similar CVD risk and socio-economic factors. As our focus will be on the HIV-positive women, here is their average profile: age 47 years ethno-racical composition 75% women of colour, 25% white women time since HIV diagnosis 15 years 98% were taking ART 84% had a viral load less than 50 copies/ml CD4+ count 600 cells 17% had higher-than-normal blood pressure 8% were currently taking a class of cholesterol medicines commonly called statins 15% had type 2 diabetes 50% smoked tobacco 47% were undergoing menopause 5% currently injected street drugs 10% currently used cocaine in general, most women were at least overweight Results Plaque Overall, HIV-positive and -negative women seemed to have similar amounts of plaque in their arteries. However, when researchers focused on the presence of non-calcified plaque, HIV-positive women had significantly more of these unstable deposits in their arteries. Even when researchers took into account well-known risk factors for CVD such as older age, smoking tobacco, abnormal cholesterol levels and so on HIV-positive women were still found to have elevated deposits of NCP. The research team also compared findings from HIV-positive women to information in their database of men (with and without HIV) and found that the average levels of blood sugar and so-called good cholesterol (HDL-C) in HIVpositive women were significantly greater than in men. In contrast, men had significantly elevated levels of triglycerides in their blood. Focus on the immune system Compared to men with or without HIV infection, HIV-positive women were more likely to have elevated levels of the following proteins and cells in their blood: soluble CD163 (scd163) soluble CD14 (scd14) activated CD4+ cells Other proteins that have previously been associated with HIV-related inflammation in some studies with HIV-positive people interleukin-6 and high-sensitivity C-reactive protein were not statistically elevated among HIV-positive women in the Boston study. Taking many factors into account, researchers found that HIV infection was significantly linked to the presence of NCP in the arteries of women. A key finding In the present study of relatively young women without symptoms of or a history of CVD and who had generally good control of HIV, researchers found increased activation of the immune system and greater amounts of unstable deposits in the arteries of HIV-positive women compared to HIV-positive men and HIV-negative women. These deposits, called NCP, are unstable and prone to rupture; in previous studies with HIV-negative people, they are associated with an increased risk for heart attacks. Different cells and proteins

3 There are many cells of the immune system. Historically, the main focus of HIV research has been on T-cells (such as CD4+ and CD8+ cells) as well as B-cells. A relatively understudied group of immune cells is called monocytes; in their mature form, they are called macrophages. These cells play many roles, including alerting the immune system to the presence of invading germs, amplifying the immune response and attacking infected cells. Aging and immune activation In the present study, researchers found high levels of scd14 and scd163 in the blood of HIV-positive women. These proteins are shed into the blood when monocytes are activated. In general, in people who are aging, excess scd163 is found in the blood and monocytes and macrophages appear to be somewhat dysfunctional as they are less able to control infections. In the present study, the high levels of scd163 and other proteins and activated cells in the blood of HIV-positive women suggests that their immune systems have prematurely aged, by between 10 and 15 years compared to HIVnegative women of the same age. In theory, the chronic immune activation found in HIV-positive women combined with dysfunctional monocytes/macrophages could play a role in accelerating the process of CVD. However, this theory remains to be proven. What is being done? Researchers in different countries are testing interventions (such as low-dose Aspirin, fish oil, exercise and antiinflammatory drugs) to try to dampen excess inflammation associated with chronic HIV infection. However, longterm studies will be required to assess if such interventions can prevent heart attacks, strokes and other problems. Well-designed studies to explore these issues are time consuming and very expensive. In the meantime, cardiovascular researchers note that there are factors that can be addressed to improve the health of HIV-positive women. For instance, in the present study there were factors identified among HIV-positive women that are associated with an increased risk for CVD, including the following: smoking tobacco being overweight type 2 diabetes injecting street drugs use of cocaine All of these factors can begin to be addressed with discussion between doctor and patient, increased levels of exercise (when possible), changes to diet, use of medicines to control blood sugar, referrals for psycho-social support, treatment for smoking cessation and addiction counselling. The findings from the present study underscore the unique issues of HIV-positive women and the need for researchers to begin to develop CVD risk calculators that take into account substance use and chronic immune activation. A warning In reviewing the findings from Boston, Dr. Franck Bocarra and Dr. Ariel Cohen, cardiovascular experts based in France, note that if doctors and their HIV-positive patients cannot bring these risk factors under control it is possible that over the coming decade these risk factors could intensify one another and generate an explosive cocktail for CVD. Resources HIV and cardiovascular disease CATIE fact sheet How to Say I Quit and Mean It The Positive Side

4 Sean R. Hosein REFERENCES: 1. Fitch KV, Srinivasa S, Abbara S, et al. Noncalcified coronary atherosclerotic plaque and immune activation in HIV-infected women. Journal of Infectious Diseases. 2013; in press. 2. Boccara F, Cohen A. Immune activation and coronary atherosclerosis in HIV-infected women: Where are we now, and where will we go next? Journal of Infectious Diseases. 2013; in press. 3. Lohse N, Hansen AB, Gerstoft J, et al. Improved survival in HIV-infected persons: consequences and perspectives. Journal of Antimicrobial Chemotherapy Sep;60(3): Freiberg MS, Chang CC, Kuller LH, et al. HIV infection and the risk of acute myocardial infarction. JAMA Internal Medicine Apr 22;173(8): Boccara F, Lang S, Meuleman C, et al. HIV and coronary heart disease: Time for a better understanding. Journal of the American College of Cardiology Feb 5;61(5): Pandrea I, Cornell E, Wilson C, et al. Coagulation biomarkers predict disease progression in SIV-infected nonhuman primates. Blood Aug 16;120(7): Helleberg M, Afzal S, Kronborg G, et al. Mortality attributable to smoking among HIV-1-Infected individuals: A nationwide, population-based cohort study. Clinical Infectious Diseases Mar;56(5): Zanni M, Lo B, Wai B, et al. Increased coronary atherosclerotic plaque vulnerability features on computed tomography angiography among HIV-positive subjects vs. matched HIV-negative controls. In: Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections, 3-6 March 2013, Atlanta, U.S. Abstract Baker J, Huppler-Hullsiek K, Singh A, et al. Monocyte activation but not T cell activation predicts progression of coronary artery calcium in a contemporary HIV cohort. In: Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections, 3-6 March 2013, Atlanta, U.S. Abstract 66LB. 10. Walker J, Burdo T, Miller A, et al. Elevated numbers of CD163+ macrophages in the hearts of SIV-positive rhesus macaques with cardiac diseases are decreased using PA300. In: Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections, 3-6 March 2013, Atlanta, U.S. Abstract Martin GE, Gouillou M, Hearps AC, et al. Age-associated changes in monocyte and innate immune activation markers occur more rapidly in HIV infected women. PLoS On e. 2013;8(1):e Hearps AC, Martin GE, Angelovich TA, et al. Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell Oct;11(5):867-75

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