We conducted a prospective evaluation for evidence of the HIV-associated lipodystrophy syndrome of 26 children infected with HIV-1. Six children had evidence of body fat redistribution. Nine children showed laboratory evidence of insulin resistance. All children with body fat distribution or insulin resistance had been treated with protease inhibitors. Children treated with protease inhibitors had higher total cholesterol, higher low density lipoprotein-cholesterol and higher triglycerides than untreated children.
Human immunodeficiency virus-1-associated lipodystrophy syndrome (HIV-LS) has been associated with the use of protease inhibitors (PIs). 1 Three main components of the syndrome have been described, including body fat redistribution, insulin resistance and abnormal lipids. 2, 3 Although the HIV-LS has been described and studied in adults infected with HIV-1, very little is known about the disorder in HIV-1-positive children. The goal of this study was to examine the relationships between the HIV-LS, PI use, lipid abnormalities and markers of insulin sensitivity children in the pediatric HIV clinic at a medium-sized urban teaching hospital.
The study was approved by the Institutional Review Board, and informed consent was obtained. Participants were children who were undergoing highly active antiretroviral therapy and cared for by our pediatric HIV service. PI use was defined as current or prior use of any PI. The decision to use PI treatment was made independently by the infectious disease consultants (BWS, DJF), who were blinded to laboratory results during the course of the study.
The study consisted of three visits (at entry, 3 months after entry and 6 months after entry). All visits were made between August 1999 and June 2000. At each visit fasting venous blood samples were drawn for serum total, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, triglycerides, free fatty acids, glucose, insulin, HIV-1 RNA and CD4+ lymphocyte count.
Lipodystrophy was defined clinically by physical examination findings of fat accumulation (central obesity or breast hypertrophy) and/or fat wasting in the face, arms or legs. Patients were defined as having hypercholesterolemia if the total cholesterol was >200 mg/dl. Insulin resistance has been defined by a glucose-insulin ratio of <7.0 in prepubertal children. 4
Comparison of laboratory values and clinical data (age, duration of HIV and body mass index) between groups was performed with univariate analysis of variance. Categoric variables such as presence or absence of lipodystrophy and demographic data (sex, race and use of medications) were compared by the chi square method. All P values < 0.05 were considered statistically significant. Statistical calculations were performed using SAS software (SAS Institute Inc., Version 8.0).
Twenty-seven children at the HIV clinic agreed to participate. One patient was subsequently found to be pregnant and was excluded from the study. All patients were infected perinatally. The mean age of the patients was 9.7 years (range, 4.6 to 14.9 years), and duration since diagnosis of HIV-1 infection was 7.4 years (range, 2.2 to 10.7 years). The group consisted of mostly Hispanic (62%) and African American (31%) children who were predominantly male (58%) and prepubertal (69%). When data from the prepubertal and pubertal groups were compared, no statistically significant differences were found for any lipid, glucose or insulin levels (data not shown). For the 19 children treated with PIs, the mean length of treatment with PIs was 2.0 years (range, 0.25 to 3.0 years), and the most common PIs used were ritonavir (68%) and nelfinavir (47%).
Of the 26 patients 6 had abnormalities of body fat distribution. All of these children had been treated with PIs. Five patients had central adiposity; 2 of these also had peripheral thinning, whereas one had both peripheral thinning and temporal wasting. One female child had breast hypertrophy. Body fat abnormalities were not statistically related to use of PIs, age or duration of HIV (data not shown). When compared with those with no evidence of lipodystrophy, those with body fat redistribution showed no significant differences in CD4+ lymphocyte counts, viral loads or lipid, glucose or insulin levels (data not shown). Nine of the 26 children were insulin-resistant (Table 1). All nine of these children had been treated with PIs. Two children showed evidence of both body fat redistribution and insulin resistance.
Lipid abnormalities were noted in the study group. Ten children (38%) were hypercholesterolemic, and 9 of these 10 used PIs. In addition patients treated with PIs had higher entry mean total cholesterol, higher LDL cholesterol and higher triglyceride levels (Table 1). Similar lipid findings were also noted at the 3- and 6-month follow-up visits (data not shown).
We found evidence of HIV-LS in children that included body fat abnormalities, insulin resistance and dyslipidemia. The prevalence of these features in our small study group suggests that the HIV-LS could be a significant problem in HIV-positive pediatric patients. Although caution should be exercised in drawing conclusions regarding causal relationships, we did note that all patients with body fat alterations and insulin resistance had been treated with PIs, and those treated with PIs had abnormal lipid values compared with those not treated. The alterations in lipid metabolism are similar to those reported in the adult HIV literature. 2, 3
Although widely reported in the adult HIV literature, reports of HIV-LS in children are few. Abnormal body fat changes have been reported in children receiving PIs. 5–9 Two recent reports found that compared with children not treated with PIs, those receiving PI therapy had abnormal lipids, including elevated total, LDL cholesterol and HDL cholesterol levels, as well as triglyceride and apolipoprotein B levels. 10, 11 Another report described a group of children receiving antiretroviral therapy and found lipodystrophy in 18% and hypercholesterolemia in 73%. 9
The current study has several limitations. The small sample size limits our ability to detect small changes in lipid levels or markers of insulin resistance. Nonetheless we were able to detect multiple changes, which were consistent during the 6-month study. Certain features of the HIV-LS may become more apparent after longer duration of PI therapy or less apparent after discontinuation of PIs. Longer follow-up of the current cohort is under way to determine the impact of duration of therapy on cholesterol values, insulin resistance and lipodystrophic changes. Because children were already taking PIs at the time of enrollment into the study, we were not able to correlate the body fat changes with initiation of PI therapy. Body fat changes that occurred as a result of other factors may have wrongly been attributed to the HIV-LS. A glucose-insulin ratio may be less sensitive than a glucose clamp in detecting insulin resistance, but the latter was not feasible in the present study. Finally our results may not apply to all pediatric populations; we studied a population of perinatally infected, mostly Hispanic and African-American, children.
There is evidence that abnormal lipids are associated with mortality in patients with HIV. 12 The changes observed in the HIV-LS are associated with increased cardiovascular risk; in fact premature coronary atherosclerosis has been reported in adult patients treated with PIs. 13, 14 Patients infected with HIV-1 have a much better long term prognosis since the advent of highly active antiretroviral therapy. However, adverse side effects such as the HIV-LS may potentially lead to increased morbidity and mortality from cardiovascular disease. Children may be most at risk for these adverse consequences given the young age at which they initiate therapy and therefore the potentially longer duration of therapy. Before the advent of PIs, accelerated atherosclerosis was described in children 15 and young adults 16 infected with HIV-1. Very little is now known about the potential additional risk of the HIV-LS in these children, and long term studies are needed to evaluate the consequences of these metabolic abnormalities.
We thank the Diabetes Research Laboratory at Baystate Medical Center and the Pediatric Immunology Laboratory at University of Massachusetts Memorial Medical Center for evaluating the laboratory samples, Xianming Zheng, Ph.D. for assistance with statistical analysis and Edward O. Reiter, M.D. for support and helpful comments in preparing the manuscript. This study was supported in part by a grant from Pharmacia/Upjohn, Inc.
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