Coronary heart disease in people infected with HIV
ABSTRACTPeople infected with human immunodeficiency virus (HIV) are living longer thanks to effective antiretroviral therapy. As this population ages, cardiovascular disease is becoming an important cause of morbidity and death. The authors of this review discuss the magnitude and likely mechanisms of the risk and strategies for managing it.
KEY POINTS
- Traditional risk factors are the main contributors to cardiovascular disease in this population, although HIV infection is independently associated with increased cardiovascular risk.
- Antiretroviral therapy contributes modestly to the risk of coronary heart disease. Antiretroviral combinations that include protease inhibitors cause the most substantial deleterious changes in lipid levels.
- Most changes in lipids and insulin resistance can be managed by adding lipid-lowering and antiglycemic agents and may not require changes to the antiretroviral regimen.
- Close attention to drug interactions is important when selecting lipid-lowering medications for patients on antiretroviral therapy to avoid dangerous increases in the levels of certain statins.
- Addressing modifiable risk factors such as smoking, obesity, and sedentary lifestyle can have a far greater impact on cardiovascular risk than changes in antiretroviral therapy.
Widespread use of antiretroviral therapy has caused a remarkable decline in rates of morbidity and death related to acquired immunodeficiency syndrome (AIDS) and has effectively made human immunodeficiency virus (HIV) infection a manageable—although not yet curable— chronic condition. And as the HIV-infected population on antiretroviral therapy ages, the prevalence of chronic conditions (eg, cardiovascular disease, hepatic disease, pulmonary disease, non-AIDS cancers) and deaths attributable to these conditions have also increased.1
Many of the traditional risk factors for cardiovascular disease in the general population, including smoking, dyslipidemia, and diabetes, are common in HIV-infected patients, and HIV infection itself independently increases the risk of coronary heart disease. In addition, different antiretroviral combinations can contribute, in varying degrees, to changes in lipid levels and insulin resistance, further increasing coronary risk.
Ultimately, however, the immunologic benefits of antiretroviral therapy for individual patients far exceed the modest increase in cardiovascular risk associated with certain regimens. In most cases, careful selection of the initial antiretroviral regimen and the addition of lipid-lowering or glucose-controlling medications (with close attention to drug interactions) can effectively manage the metabolic changes associated with antiretroviral therapy and obviate any premature modification of virologically suppressive regimens.
TRADITIONAL CARDIAC RISK FACTORS IN HIV PATIENTS
The risk of coronary heart disease in HIV patients is influenced mostly by traditional factors such as age, smoking, diabetes, and dyslipidemia, including high levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C).2
In various large cohorts, HIV-infected men had a higher prevalence of smoking,3 a lower mean HDL-C level,3,4 and a higher mean triglyceride level3,4 than men without HIV infection, placing them at greater risk of coronary heart disease. However, even after adjusting for traditional risk factors, rates of atherosclerosis are still higher in people who are infected with HIV than in those who are not.5
EFFECT OF HIV INFECTION ON CORONARY RISK
HIV infection has been shown to increase coronary risk.
In the Kaiser Permanente database,6 HIV-positive patients had a significantly higher rate of hospitalizations for coronary heart disease than did people who were not infected.
Similarly, in a cohort study of almost 4,000 HIV-infected patients and more than 1 million controls, the risk of acute myocardial infarction was 75% higher for HIV-positive patients than for HIV-negative patients, even after adjusting for sex, race, hypertension, diabetes, and dyslipidemia.5
The Fat Redistribution and Metabolism (FRAM) cross-sectional study7 showed that HIV infection was associated with greater carotid intima media thickness, an established marker of atherosclerosis, independently of traditional risk factors and to virtually the same degree as smoking and male sex.
Other studies of subclinical atherosclerosis in HIV patients have yielded disparate results, likely because of differences in study design, methods of measuring carotid thickness, and characteristics of the study populations (eg, prevalence of cardiovascular risk factors and stage of HIV disease). However, a meta-analysis of six prospective cohort studies, three case-control studies, and four cross-sectional studies confirmed that HIV patients had slightly but statistically significantly greater carotid intima media thickness than HIV-negative people.8
MECHANISMS BY WHICH HIV MAY PROMOTE CORONARY HEART DISEASE
The pathogenesis of coronary heart disease in HIV infection has not been fully elucidated, but the virus appears to contribute directly to the accelerated development of atherosclerosis. It may do so through direct effects on cholesterol processing and transport, attraction of monocytes to the intimal wall, and activation of monocytes to induce an inflammatory response and endothelial proliferation.
Effects on lipids
In early HIV infection, levels of total cholesterol and HDL-C are lower. In more advanced infection, lower CD4+ lymphocyte counts have been associated with lower levels of apolipoprotein B and with smaller LDL-C particles, suggesting that HIV affects lipid processing and delivery to vessel walls.9 HIV infection is also associated with reduced clearance of LDL-C.10 HIV appears to specifically inhibit the compensatory efflux of excess cholesterol from macrophages, thus promoting the formation of foam cells in atherosclerotic plaque.11
Attraction of monocytes to the vessel wall
In vitro studies also suggest that HIV enhances migration of monocytes into the vascular intima during atherosclerotic plaque development by promoting secretion of the chemokine monocyte chemoattractant protein 112 and the expression of endothelial cell adhesion molecules such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), and E-selectin.13
Inflammation
A recent study suggests that chronic inflammation may be a key contributor to the accelerated development of atherosclerosis in HIV patients. Hsue et al14 compared carotid intima media thickness and levels of C-reactive protein (a marker of systemic inflammation) in HIV-positive and HIV-negative patients. The carotid intima media thickness was greater in all groups of HIV patients, irrespective of level of viremia or exposure to antiretroviral therapy, than in healthy controls. In addition, C-reactive protein levels remained elevated in HIV-infected participants regardless of their level of viremia.
These findings suggest not only that HIV-associated atherosclerosis is determined by advanced immunodeficiency, high-level viremia, and exposure to antiretroviral drugs, but also that persistent inflammation due to HIV infection may play an important role in accelerated atherosclerosis.
