Coronary Heart Disease, HIV Infection, and HAART

Coronary artery disease is the most serious health threat in the U.S. and is projected to remain the number one cause of death for the next 50 years. Heart disease causes more than 700,000 deaths annually, and women are 10 times more likely to die of heart disease than breast cancer. For a significant proportion of affected individuals, the first symptom of heart disease is death.

As HIV positive people live longer due to effective antiretroviral therapy, cardiovascular disease has become an increasingly pressing concern for this group as well. In a study described in the August 20, 2008 issue of AIDS, Lawrence Kingsley and colleagues examined associations between coronary artery calcification -- an early sign of cardiovascular disease -- and antiretroviral therapy among participants in the Multicenter AIDS Cohort Study (MACS).

A heart attack or acute myocardial infarction (MI) occurs when one of the arteries that supplies the heart muscle becomes blocked.

HAART and Coronary Heart Disease

Use of combination antiretroviral therapy has been associated with metabolic abnormalities including hyperlipidemia (elevated blood lipids), hyperglycemia, insulin resistance, hypertension (high blood pressure), and changes in body fat distribution (lipodystrophy). As a result, there is growing concern about the potential of HAART to significantly increase the risk of atherosclerotic coronary heart disease (CHD).

Several studies have evaluated the association between HAART and ischemic cardiovascular disease risk, according to a brief review by the authors. Four of these [1-4] did not show an adverse association. One study [5] found increased CHD risk at younger ages, with a risk reduction at older ages, Five studies [6-10] concluded that HAART increased cardiovascular risk. Yet another study [11] showed a 2-fold increased risk of acute myocardial infarction (MI; heart attack) among HIV positive men and women compared with HIV negative control subjects, but this study included no data on HAART usage.

Further clouding the controversy are data from the SMART study [12], which showed an increased risk of cardiovascular events among patients who interrupted HAART when their CD4 count rose above 350 cells/mm3, suggesting that HIV itself or immunological factors play a role in CHD risk. Several other studies assessing the relationship between sub-clinical coronary atherosclerosis, HIV infection, and HAART have produced equivocal results. Three studies [13-15] showed no association with HIV or HAART.

These contradictory findings are probably due in part to different study designs and populations, but also to the limitations of observational methods in controlling confounding, limited follow-up periods, lack of antiretroviral therapy data, and the absence of HIV negative control subjects, the authors suggested.

Because of its prospective nature and the detailed information it contains about antiretroviral use among a multiethnic study population of HIV positive and HIV negative men, they wrote, MACS is an optimal cohort in which to evaluate these issues, avoiding many of the limitations of other studies.

This present report focuses on sub-clinical coronary atherosclerosis ("hardening" of the arteries due to build-up of plaque, inflammation, and loss of elasticity). The primary aim of the study was to estimate the effects of chronic HIV infection and cumulative HAART exposure on the presence and extent of coronary artery calcification (CAC) -- calcium deposits in the coronary arteries that supply blood to the heart -- assessed using computed tomography.

The researchers selected CAC as a measure of sub-clinical atherosclerosis since calcification is not normally present in arterial walls. In addition, CAC measurements correlate strongly with the total area of atherosclerotic plaque, have high reproducibility, and have established value in coronary event risk prediction, the authors noted.

This cross-sectional analysis included 947 male MACS participants: 332 HIV negative, 84 HIV positive HAART-naive, and 531 HIV positive HAART-experienced.

The primary outcome was CAC score. The presence of CAC was defined as a calcification score above 10. Among those with CAC present, scores were used to determine the extent of CAC.

Results

• Overall, about one-third of study participants were diagnosed as having CAC.

• Increasing age was most strongly associated with both prevalence and extent of CAC for all study groups.

• CAC was present in 48% of HIV positive patients compared with 40% of HIV negative individuals.

• HIV infection (OR 1.35) and long-term HAART use (OR 1.33) slightly increased the odds of having CAC after adjusting for age, race/ethnicity, family history, smoking, high-density lipoprotein (HDL or "good") cholesterol, low-density lipoprotein (LDL or "bad") cholesterol, and hypertension.

• In contrast, after adjusting for these same covariates, the extent of CAC was lower among HAART users.

• Among those not taking lipid-lowering therapy, HAART duration of at least 8 years was associated with significantly reduced CAC scores.

In conclusion, the study authors wrote, "HAART use may have different effects on the presence and extent of coronary calcification. Although prevalence of calcification was marginally increased among long-term HAART users, the extent of calcification was significantly reduced among HAART users compared with HIV seronegative controls."

Discussion

Questions left unanswered by this study include the extent to which management of cholesterol and triglycerides may influence subsequent coronary atherosclerosis.

"Our data also raise a question as to whether the high proportion of HIV-infected men without evidence of CAC currently receiving lipid-lowering drug therapy should continue to do so, given the potential drug side effects and cost," the study authors observed.

The authors noted that the MACS researchers will perform a 3-year follow-up assessment of CAC. "This will enable the study to address remaining primary questions," they wrote, "including whether there is slowed progression of coronary calcification among those on HAART and those receiving lipid-lowering therapy, identification of factors associated with incident coronary calcification, and associations between lipoprotein particle distribution, particle size, and coronary atherosclerosis."

8/22/08

Reference
LA Kingsley, J Cuervo-Rojas, A Munoz, and others. Subclinical coronary atherosclerosis, HIV infection and antiretroviral therapy: Multicenter AIDS Cohort Study. AIDS 22(13): 1589-1599. August 20, 2008.

Citations

1. SA Bozzette and others. Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus infection. New England Journal of Medicine 348: 702-710. 2003.

2. L Escaut and others. Coronary artery disease in HIV-infected patients. Intensive Care Medicine 29: 969-973. 2003.

3. D Klein and others. Do protease inhibitors increase the risk for coronary heart disease in patients with HIV-1 infection? Journal of Acquired Immune Deficiency Syndromes 30:471-477. 2002.

4. PM Coplan and others. Incidence of myocardial infarction in randomized clinical trials of protease inhibitor-based antiretroviral therapy: an analysis of four different protease inhibitors. AIDS Research and Human Retroviruses 19: 449-455. 2003.

5. JS Currier and others. Coronary heart disease in HIV-infected individuals. Journal of Acquired Immune Deficiency Syndromes 33: 506-512. 2003.

6. The D:A:D Study Group. Class of antiretroviral drugs and the risk of myocardial infarction. New England Journal of Medicine 356: 1723-1735. 2007.

7. A d'Arminio and others. Cardio- and cerebrovascular events in HIV-infected persons. AIDS 18: 1811-1817. 2004.

8. M Krause and others (for the Clinical Epidemiology Group from the French Hospital Database). Increased risk of myocardial infarction with duration of protease inhibitor therapy in HIV-infected men. AIDS 17: 2479-2486. 2003.

9. V Rickerts and others. Incidence of myocardial infarctions in HIV-infected patients between 1983 and 1998: the Frankfurt HIV-cohort study. European Journal of Medical Research 5: 329-333. 2000.

10. SD Holmberg and others. Protease inhibitors and cardiovascular outcomes in patients with HIV-1. Lancet 360: 1747-1748. 2002.

11. VA Triant and others. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. Journal of Clinical Endocrinology & Metabolism 92: 2506-2512. 2007.

12. The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. New England Journal of Medicine 355: 2283-2296. 2006.

13. Acevedo M, Sprecher DL, Calabrese L, Pearce GL, Coyner DL, Halliburton SS, et al. Pilot study of coronary atherosclerotic risk and plaque burden in HIV patients: 'a call for cardiovascular prevention'. Atherosclerosis 163:349-354. 2002.

14. A Mangili. Risk of cardiovascular disease in a cohort of HIV-infected adults: a study using carotid intima-media thickness and coronary artery calcium score. Clinical Infectious Diseases 43: 1482-1489. 2006.

15. R Talwani and others. Electron beam computed tomography for assessment of coronary artery disease in HIV-infected men receiving antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes 30: 191-195. 2002.