We compared HIV-infected children and NHANES controls on several factors associated with increased risk for premature CVD. Our data show that, compared with NHANES controls, HIV-infected children have lower weights, heights and BMIs, but have similar waist circumferences and subscapular skinfold thicknesses. These findings may suggest a disproportionate higher waist circumference and subscapular skinfold (suggestive of fat redistribution) in our HIV-infected children. However, compared with a smaller, contemporary comparison group, we found heights, weights and BMIs to be similar. Furthermore, our study showed additional risk for premature CVD with higher triglycerides and lower HDL-cholesterol levels in the HIV-infected children (compared with both control groups). PI therapies were associated with adverse lipid profiles, NRTI therapies with greater visceral fat, and NNRTI therapies showed beneficial effects with higher HDL-cholesterol levels and lower visceral adipose tissue. Visceral adipose tissue was significantly associated with waist:hip circumference ratio and BMI correlated poorly with our outcomes. This result may have particular importance in situations where measurement of visceral adipose tissue is impractical, but measurement of waist:hip ratio is simple and may serve as an adequate surrogate.
Before HAART, the majority of HIV-infected children were malnourished and cachextic (13
), severely stunted (24
), and had gastrointestinal (25
) and systemic conditions that would sustain these abnormal nutritional states. With effective antiretroviral therapies, their nutritional condition has improved (14
) and has shifted toward increased metabolic problems (4
). First noted by Carr (3
), the associations of effective ART and metabolic problems documented in adults now are recognized increasingly in children with HIV. Our data confirm existing data and bring new information regarding clinical comparisons between HIV-infected children and national controls, as well as define cardiovascular risk effects of specific classes of ART.
Hyperlipidemia in HIV-infected children was reported before HAART (26
). However, lipid abnormalities have become more pronounced since the advent of HAART (5
). PIs, specifically, have been associated with elevations in cholesterol and triglycerides (27
). In adults with HIV, where the likelihood of myocardial infarction is increased by age alone, studies have shown that the risk of CVD increases substantially for every year on ART (2
). Hyperlipidemia at an early age in childhood is expected to lead to early CVD (28
Studies of HIV-infected children among centers have shown that abnormal fat distribution defined as a shifting of body fat to the abdomen and dorsocervical fat pad and depletion of adipose tissue of the face, limbs and buttock (3)-- can occur in 17% to 33% (6
). In some studies of adults, more than 50% of patients have clinically obvious lipodystrophy, depending on the definition (3
). Fat redistribution can be defined clinically, through skinfold measurements, or rarely through dual x-ray absorptiometry scanning. However, these measures are rough estimates, and investigations of visceral and subcutaneous adiposity in HIV-infected children through more sensitive techniques (such as single-slice CT or MRI) have been limited (16
). Although no standards for visceral and subcutaneous fat are available for children, we found that girls have a greater subcutaneous adipose tissue and non-Hispanic whites have greater amounts of visceral fat in our sample, findings that have been substantiated in other non-HIV studies (30
). Furthermore, NNRTIs were found to be protective against, yet NRTIs associated with, higher visceral adipose tissue levels.
We found that use of different classes of medications (PI, NRTI, NNRTI) influences cardiovascular risk profiles in different ways. PIs appeared to have more adverse effects on lipid profiles. These findings were described early in adults with HIV (2
), and some associations have been found in children (15
). Such therapy may have direct influence on lipid levels by inhibiting an LDL-cholesterol receptor-related protein that blocks the uptake of lipoproteins and their subsequent metabolism (34
) or increases apolipoprotein B metabolism (35
). Other theories include stimulation of VLDL-cholesterol synthesis by PIs, adipogenesis, or lowering the expression of insulin receptors on adipocytes, thus increasing release of free fatty acids with the potential for inducing hepatic production of lipoproteins (34
). NRTIs appear to increase VAT, which has been associated with increased CVD risk. Viral load appeared to uniformly increase cholesterol levels (total [data not shown], HDL, and LDL); effects that have been shown to be beneficial (HDL) and adverse (total, LDL) on CVD risk.
Lastly, we found that NNRTI therapy may have protective effects by decreasing visceral adipose tissue and increasing HDL-cholesterol. The protective effects of NNRTI have been noted in adults (36
). In studies of PI-switching regimens, improvements in lipid levels tend to be more substantial with nevirapine than with efavirenz; this tendency was also observed when nevirapine was used in initial treatment regimens. Further, in the first pediatric SWITCH study, McComsey noted that LDL- and total cholesterol as well as triglycerides decreased in a small number of children whose therapy was changed from a PI to NNRTIs (37
We did not have sufficient sample size to evaluate the independent effects of combined ART. Rather we determined specific effects of each class of drug rather than their combined effects. We collected data to evaluate our study hypothesis that age, race, sex, Tanner stage, BMI, HIV disease status, HIV viral load, and the use of specific antiretroviral therapies would affect risk factors for premature symptomatic CVD. The number of significant associations (P < 0.05) given in is greater than would be expected by chance if there were no associations in the data. Because these associations are exploratory and the sample size is small, and since these associations were determined a priori in our study, we have not adjusted the Type I error to account for multiple comparisons, thus the P-values should be interpreted cautiously.
Children with HIV infection, compared with NHANES and contemporary controls, have adverse cardiac risk factors. We found that PIs and NRTIs contribute to these abnormal profiles, whereas NNRTIs have protective and beneficial effects on these risks in our study. Because readily accessible anthropometric measures such as BMI did not correlate well with metabolic outcomes, HIV-infected children should be proactively monitored for the emergence of these risk factors, regardless of BMI percentiles. Interventions that improve cardiac risk profiles including modifications of lifestyle, such as exercise (37
) and diet, that are known to benefit other populations, should be considered.