Our study shows that HIV-infected children have higher levels of the biomarkers of vascular dysfunction than do an urban cohort of otherwise healthy children. These biomarkers have been associated with obesity, insulin resistance and atherosclerotic cardiovascular risk in adults.6
In particular, biomarkers associated with inflammation, endothelial dysfunction, and procoagulation were higher in infected children than in controls. Clinical factors associated with these biomarkers of vascular dysfunction were more related to HIV disease severity (low CD4 counts and higher viral load) than to antiretroviral drug exposure. Furthermore, abdominal adiposity, as reflected by higher waist:hip ratio, was the best anthropometric correlate of these biomarkers.
Since the introduction of highly active antiretroviral therapy (HAART), HIV disease in developed nations has transitioned from an almost uniformly fatal illness to a disease in which therapies are now targeted toward indefinite viral suppression.11
Although certain cardiovascular risk factors, such as hyperlipidemia, diabetes and endothelial dysfunction, were present before the advent of HAART,12, 13
they have increased both in prevalence and severity.14
These cardiovascular risks and metabolic complications have been better described in adults,2, 3, 14
more limited data are available on children.15–19
Potential contributors to increased cardiovascular risk in adults include HIV alone, specific types of HAART therapy, sex, life style habits (exercise, smoking), and successful viral suppression.3, 20, 21
In children, PI therapy is associated with several cardiovascular risk factors.4
For HIV-infected children, the true impact of these CVD risk factors can only be appreciated after years of follow-up: most have not aged sufficiently to reach the associated endpoints. However, the multinational Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group in adults with HIV infection found an incidence of coronary heart disease (CHD) of 3.5/1000 person-years and 11% of all recorded patient deaths caused by myocardial infarction, stroke, or other cardiovascular events.3
Relative risks up to 25% higher than those in the general population have been cited3, 22
and substantiated.23, 24
Several studies of subjects without HIV infection found that biomarkers of vascular dysfunction predict adverse cardiovascular events.25, 26
Increasing evidence indicates the importance of vascular inflammation or dysfunction in the pathogenesis of cardiovascular disease in HIV-infected individuals.27
Vascular dysfunction may be a result of the direct cytopathic effects of the virus on the endothelial cell or of the inflammation and oxidative stress28, 29
associated with chronic immune activation induced by the virus.30
Further, dysfunction may be induced by the metabolic consequences of the disease and its therapies, or by a combination of both.
Several studies in adults report associations between biomarkers of endothelial dysfunction such as ICAM, VCAM, E-selectin, P-selectin, and VWF, and the platelet factor, P-selectin, among others, with HIV disease severity.31, 32
These findings suggest that HIV itself may cause immune activation and be an important mechanism for cardiovascular risk31
and effective antiretroviral therapy decreases these vascular inflammatory biomarkers. 32
Finally, the HIV tat
proteins induce VCAM-1, ICAM-1, MCP-1 and other inflammatory chemokines that disrupt the vascular endothelium in coronary vessels.13, 33, 34
In addition MCP-1 has been proposed to activate viral infection.35
Alternatively, HIV-infected patients have metabolic conditions often related to antiretroviral therapy, including dyslipidemia, insulin resistance, and abnormal fat distribution, that can contribute to the activation or injury of the endothelium.27
Certain antiretroviral agents also appear to damage endothelial mitochondrial DNA and are toxic to the endothelial cell itself, including the ability to induce apoptosis.36–38
Protease inhibitors can increase mitochondrial production of reactive oxygen species,38
increase endothelial cell permeability39
and leukocyte adhesion40
in cell culture. Johnson41
reported higher levels of proinflammatory cytokines in the subcutaneous adipose tissue of HIV-infected individuals with lipodystrophy, when compared to those without. Others have found associations between these biomarkers, HAART, and metabolic dysfunction.42
Thus, antiretroviral therapy could directly or indirectly (through changes in the metabolic profile) increase levels of these biomarkers.
Studies on vascular inflammatory pathways and vascular dysfunction (ie, vessel compliance, distensibility and structure) in HIV-infected children have been limited.43–46
McComsey showed greater carotid intima media thickness and higher levels of certain biomarkers among 31 HIV-infected children.46
A study of 49 children found that vascular dysfunction (stiffness) was greater in HIV-infected children than in controls, independent of known CV risk factors and antiretroviral therapy.43
However, other studies show carotid intima thicknesses are similar to controls.46
Charakida found among 83 HIV-infected children,45
carotid intima thickness was greater than it was in controls, as were the abnormalities in flow-mediated vasodilation. These differences were more pronounced in children receiving PIs and lipid abnormalities did not account for these differences. Interestingly, some pre-HAART studies in children showed increased coronary artery calcifications,47
suggesting the contribution of baseline immune activation to cardiovascular risk.
Limitations of the Study
As with many studies of cardiovascular risk in children, finding risk may not always equate to adverse outcomes. Only continued longitudinal follow-up of children will definitively confirm that our findings translate to cardiovascular disease events. Although we tried to limit the number of outcomes to those that differed between cases and controls and the number of predictors that were linked to progressive HIV disease, we cannot rule out false positive findings secondary to multiple statistical testing. Confirmatory studies are needed. We have not evaluated the association of other metabolic parameters (lipids, insulin resistance) or other known risk factors such as family history, smoking exposure and alcohol intake on our outcomes because of incomplete data on the entire sample. These metabolic factors and health behaviors need to be critically evaluated as potential causative factors in the future. However, early data in another study48
suggest there are minimal relationships. Finally, our control group was slightly unbalanced in age and race. However, all of our analyses were adjusted for these demographic factors.
We evaluated early mechanistic factors for cardiovascular disease in children with HIV infection. Elevations of the biomarkers of vascular dysfunction in HIV-infected children provide strong evidence of ongoing cardiovascular risk in this population. Disease severity and truncal adiposity were both independently associated with higher levels of these biomarkers of vascular dysfunction, suggesting that these biomarkers and other cardiovascular risk factors should be closely monitored in children with those characteristics. There were no associations with antiretroviral therapy. Long-term evaluation of cardiovascular risk, incorporating complete metabolic screens, as well as interventions to modify this risk, should be considered.