Serum lipids, glucose homeostasis and abdominal adipose tissue distribution in protease inhibitor-treated and naive HIV-infected children
Bitnun, Aria; Sochett, Etienneb; Babyn, Paulc; Holowka, Stephaniec; Stephens, Derekd; Read, Stanleya; King, Susan Ma
From the Divisions of aInfectious Diseases and bEndocrinology and Diabetes, Department of Pediatrics; and the Departments of cRadiology and dPopulation Health Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
Requests for reprints to: Susan M. King, MD CM, FRCP(C), Associate Professor, Division of Infectious Diseases, Department of Pediatrics, the Hospital for Sick Children, Toronto, Ontario, Canada.
Correspondence to: Ari Bitnun, MD, Division of Infectious Diseases, Department of Pediatrics, the Hospital for Sick Children, Toronto, Ontario, Canada. E-mail: email@example.com
Received: 26 September 2002; revised: 16 January 2003; accepted: 22 January 2003.
Objective: To determine the extent and degree of abnormalities of serum lipids, glucose homeostasis and abdominal adipose tissue distribution in protease inhibitor (PI)-treated and PI-naive HIV-infected children.
Design: A cross-sectional study involving HIV-infected children, 3–18 years of age, in a paediatric tertiary care centre.
Main outcome measures: Total, HDL and LDL-cholesterol, triglycerides, glucose, insulin, proinsulin and C-peptide were determined in the fasting state. Insulin resistance was assessed using the homeostatic model assessment–insulin resistance (HOMA–IR). Abdominal adipose tissue distribution was determined by single-slice computed tomography at the umbilical level.
Results: Thirty PI-treated and 20 PI-naive children were evaluated (76% prepubertal). PI-treated children had significantly higher total cholesterol (P = 0.0021), LDL-cholesterol (P = 0.019) and triglycerides (P = 0.0018). Serum glucose, insulin, proinsulin and C-peptide, the insulin : glucose ratio, HOMA–IR and abdominal adipose tissue distribution were similar in the two groups. Clinical and immunological HIV categories, viral load, CD4 cell count and stavudine therapy were not significantly associated with serum lipids, insulin resistance or abdominal adipose tissue distribution. The predictor variable most strongly associated with fasting serum insulin and HOMA–IR was the Tanner stage. Age was the most significant predictor variable of the visceral : subcutaneous adipose tissue ratio.
Conclusion: In this cohort of predominantly prepubertal HIV-infected children, PI therapy was associated with an atherogenic dyslipidemia but not with insulin resistance or abnormal abdominal adipose tissue distribution. The results suggest that children, particularly prepubertal children, are less susceptible than adults to PI-induced changes in glucose homeostasis and abdominal adipose tissue distribution.
The morbidity and mortality associated with HIV infection has been dramatically reduced since the introduction of highly active antiretroviral therapy into routine clinical use [1–3]. Unfortunately, in HIV-infected adults, such therapy has been linked to the development of a variety of metabolic abnormalities that include peripheral lipoatrophy, visceral adipose tissue accumulation, hypercholesterolemia, hypertriglyceridemia, insulin resistance, impaired glucose tolerance and diabetes mellitus [4–6]. Collectively, these metabolic abnormalities have been referred to as the HIV-associated lipodystrophy syndrome [4,5]. The protease inhibitors (PI) [7–11], and to a lesser extent, the nucleoside reverse transcriptase inhibitors (NRTI) [12,13] have been implicated as possible causes of the HIV-associated lipodystrophy syndrome.
There is currently a paucity of data pertaining to the HIV-associated lipodystrophy syndrome in children. Of the six paediatric studies published to date, three were cross-sectional analyses [14–16], two were longitudinal observational studies [17,18] and one was a physician survey . Only two of the studies compared PI-treated children with PI-naive children with respect to various aspects of the HIV-associated lipodystrophy syndrome [16,18]. In the present report, we compare the glucose homeostasis and serum lipid profiles of PI-treated and PI-naive HIV-infected children and the abdominal adipose tissue distribution of PI-treated HIV-infected children, PI-naive HIV-infected children and HIV-uninfected children.
Subjects were recruited from among HIV-infected children followed by the Division of Infectious Diseases at the Hospital for Sick Children, Toronto, between August 1999 and September 2001. Children were eligible for inclusion if they were between 3 and 18 years of age and if there had been no change in their clinical or immunological HIV classification status during the preceding 6 months . A minimum of 3 months of PI therapy was required for inclusion in the PI-treated group. Exclusion criteria included any of the following: (i) the presence of a chronic illness in addition to HIV, such as familial hypercholesterolemia, which could significantly affect serum lipids, glucose homeostasis or adipose tissue distribution; (ii) the inability of the family or patient to comply with the study protocol because of difficult social circumstances, general unreliability of the patient or guardian with respect to medical care, or a significant underlying clinical illness in the child, such as HIV encephalopathy, which would compromise his/her ability to cooperate with study requirements; (iii) high-dose or prolonged glucocorticoid therapy during the 30 days before the performance of the study investigations; (iv) birth control pill administration; (v) substantial non-compliance with antiretroviral therapy based on history and prescription renewal information. A group of 52 randomly selected children not infected with HIV who underwent abdominal computed tomography (CT) scanning in the context of trauma served as an additional comparison group with respect to abdominal adipose tissue distribution.
Ethical approval for this study was obtained from the Research Ethics Board at the Hospital for Sick Children, Toronto, Canada. Written informed consent was obtained from all children 16 years of age or older. For younger children, written informed consent was obtained from the child's legal guardian. Written assent was obtained for all children between 6 and 16 years of age deemed capable of reasonably providing such assent.
Study investigations were carried out during a single regular clinic visit. The age, sex, ethnicity (Caucasian, Black, other), clinical and immunological HIV disease category, CD4 cell count, viral load, past and current antiretroviral medications, height, weight, Tanner stage, waist–hip circumference ratio and blood pressure were recorded. In those receiving PI therapy, the duration of such therapy was documented. Height was measured to the nearest millimeter using a wall-mounted stadiometer and weight to the nearest 100 g using a standard balance scale. Body mass index (BMI) was calculated in standard fashion (weight in kilograms divided by the square of the height in meters). The pubertal developmental stage was evaluated using standard criteria by a single study investigator [21,22]. Waist and hip circumference were measured in duplicate to the nearest millimeter by a single study nurse using a plastic tape measure. The measurement of waist circumference was performed at the level of the umbilicus and that of the hip at the level of the greater trochanter and symphysis pubis.
Blood was drawn for the measurement of serum glucose, insulin, proinsulin, C-peptide, total, HDL and LDL-cholesterol and triglyceride levels after a 10 h overnight fast. Samples for the measurement of serum glucose, insulin, proinsulin and C-peptide were transported on ice to the laboratory, centrifuged and the serum was stored at −20°C for measurement at a later date. Serum glucose was determined using the glucose oxidase method (Synchron CX7/CX3 and Glucose 2 Analyser; Beckman Coulter Canada Inc., Canada). Serum insulin and proinsulin were determined by double antibody radioimmunoassays (Insulin RIA 100; Pharmacia Upjohn, Uppsala, Sweden and LINCO Research Inc., St Charles, MO, USA, respectively) and serum C-peptide was determined using a competitive radioimmunoassay (Diagnostic Products Corporation, CA, USA). Insulin resistance was estimated by the homeostatic model assessment–insulin resistance (HOMA–IR) using the following equation :
Equation (Uncited)Image Tools
Samples for the measurement of fasting serum total cholesterol, HDL-cholesterol, LDL-cholesterol and triglyceride levels were transported immediately to the laboratory for analysis. Serum total cholesterol and triglyceride levels were measured using a Kodak Ektachem 700 analyser (Eastman Kodak Company, Rochester, NY, USA). Serum HDL-cholesterol was measured using the VITROS 950/950AT Chemistry System (Johnson and Johnson Ortho-Clinical Diagnostics, Inc., Rochester, NY, USA). Serum LDL-cholesterol was calculated in the standard fashion [LDL (mmol/l) = total cholesterol (mmol/l) − HDL-cholesterol (mmol/l) − serum triglyceride levels (mmol/l)/2.2].
Abdominal adipose tissue distribution was assessed using a single-slice (10 mm thickness) abdominal CT scan at the level of the umbilicus. This methodology has been shown to provide reliable estimates of total abdominal adipose tissue distribution [24–26]. CT scans were performed with the patient in the supine position using a General Electric HiSpeed Advantage or a General Electric HiLight Advantage CT scanner (General Electric Medical Systems, Milwaukee, WI, USA). Exposure parameters were kVp 120 and mAs 200. The total body radiation dose per patient was 9.55 milliGray/cm. The analysis of CT scans was performed using the Image Masking Program by a single investigator who was blinded to the treatment category. The cross-sectional area of total, visceral and paraspinal/intraspinal adipose tissue were each determined by summing the area of pixels in the range of −150 to −50 Hounsfield units in the corresponding compartments of the CT image. The area of subcutaneous adipose tissue was determined by subtracting visceral and paraspinal/intraspinal adipose tissue areas from those of the total adipose tissue area. The ratio of visceral to subcutaneous adipose tissue was then calculated.
Statistical analysis was performed using SAS statistical software (SAS Institute, Inc., Cary, NC, USA). The PI-treated and PI-naive HIV-infected cohorts were compared with respect to baseline characteristics and outcome variables using the two-sided Student's t-test for continuous variables and the χ2 statistic for dichotomous variables. Two-way analysis of variance (ANOVA) was used to examine the impact of PI therapy on serum total cholesterol, triglyceride and insulin levels, HOMA–IR and the visceral to subcutaneous adipose tissue ratio, adjusted for pubertal stage. Multiple regression analysis was used to determine the independent effects of various predictor variables on serum total cholesterol, triglyceride and insulin levels, HOMA–IR and the visceral to subcutaneous adipose tissue ratio. The outcome variables examined by multiple regression analysis were selected a priori to encompass the three areas of interest: serum lipids, glucose homeostasis and abdominal adipose tissue distribution. Logarithmic transformations were used on potential predictor variables and outcome variables with skewed distributions. In the multiple regression analyses, the level of significance for an independent effect was set at 0.01 as an adjustment for multiple testing. In a separate analysis, the visceral adipose tissue area, subcutaneous adipose tissue area and visceral to subcutaneous adipose tissue ratio of PI-treated HIV-infected children, PI-naive HIV-infected children and HIV-uninfected children was compared using ANOVA.
Thirty PI-treated and 20 PI-naive HIV-infected children were enrolled in the study for an overall recruitment rate of 90%. Nine PI-naive subjects consented to serum lipid and glucose homeostasis assessment, but not to abdominal CT scanning; all PI-treated subjects and the remaining 11 PI-naive subjects completed all investigations. The mean duration of PI therapy in the PI-treated group was 22.4 ± 8.9 months (range 8–46 months). All PI-treated subjects were receiving highly active antiretroviral therapy that included a PI and at least two other non-PI antiretroviral drugs. PI therapy consisted of ritonavir (n = 12), nelfinavir (n = 13), indinavir (n = 2), lopinavir (n = 1), ritonavir plus nelfinavir (n = 1) and nelfinavir plus saquinavir (n = 1). In the PI-naive group, four were antiretroviral naive, 14 were on two NRTI and two were on two NRTI and a non-nucleoside reverse transcriptase inhibitor.
HIV infection was perinatally acquired in 25 of the PI-treated and 19 of the PI-naive subjects. Five PI-treated children were infected during infancy through the receipt of contaminated blood products before 1985. One PI-naive subject was infected through sexual activity at 15 years of age. Among PI-treated subjects, four were classified as asymptomatic (class N; 13.3%), seven as mildly symptomatic (class A; 23.3%), four as moderately symptomatic (class B; 13.3%) and 15 as severely symptomatic (class C; 50%) in accordance with the revised paediatric clinical classification system of the Center for Disease Control and Prevention . In the PI-naive group there were seven asymptomatic (class N; 35%), five mildly symptomatic (class A; 25%), five moderately symptomatic (class B; 25%) and three severely symptomatic (class C; 15%) children.
The baseline characteristics of PI-treated and PI-naive HIV-infected children are depicted in Table 1. The two groups were similar with respect to age, sex, Tanner stage and ethnicity. In the PI-treated group, 53% were black, 30% were Caucasian, and 17% belonged to other ethnic groups. The corresponding proportions in the PI-naive group were 70, 25 and 5%, respectively. Eighty per cent of PI-treated children and 70% of PI-naive children were prepubertal (Tanner 1). Those receiving PI therapy were more likely to have a more advanced HIV clinical stage (P = 0.026) and to be receiving stavudine therapy (P = 0.043). PI-treated subjects tended to have experienced a more advanced degree of immunosuppression based on CD4 cell count nadir (P = 0.073), but their current CD4 cell count tended to be higher than those of PI-naive subjects (P = 0.067).
Serum lipids and glucose homeostasis
Fasting serum total cholesterol, LDL-cholesterol and triglyceride levels were significantly higher in PI-treated than PI-naive HIV-infected children in the unadjusted analysis (Table 2). These differences were maintained after adjusting for other variables (Table 3). Total cholesterol levels above 5.44 mmol/l (210 mg/dl) were seen in 20% of PI-treated and 0% of PI-naive children. Thirty-three per cent of PI-treated and 15% of PI-naive children had LDL-cholesterol levels above 3.37 mmol/l (130 mg/dl). Five of the PI-treated children had a total cholesterol level above 6.22 mmol/l (240 mg/dl); the LDL-cholesterol level of four of these children was greater than 4.40 mmol/l (170 mg/dl). Serum triglyceride levels of 1.64 mmol/l (145 mg/dl) or greater were seen in 40% of PI-treated and 5% of PI-naive subjects.
Fasting hyperglycemia or hyperinsulinemia was not observed in any of the PI-treated or PI-naive children. The degree of insulin resistance, as determined by fasting serum insulin, proinsulin and C-peptide, the insulin to glucose ratio and HOMA–IR were similar in PI-treated and PI-naive HIV-infected children (Table 2). Factors that did correlate with serum insulin on univariate analysis included age (R = 0.61, P < 0.0001), Tanner stage (R = 0.64, P < 0.0001), BMI (R = 0.62, P < 0.0001), visceral adipose tissue area (R = 0.67, P < 0.0001), total adipose tissue area (R = 0.46, P = 0.0025) and serum triglyceride levels (R = 0.40, P = 0.0036). Similar univariate associations were seen for serum proinsulin, C-peptide, the insulin to glucose ratio and HOMA–IR. The viral load, CD4 cell count, clinical and immunological HIV categories and stavudine exposure were not significantly associated with serum insulin, proinsulin and C-peptide, the insulin to glucose ratio or HOMA–IR on univariate analysis.
The impact of PI therapy on serum total cholesterol, triglyceride and insulin levels, HOMA–IR and the visceral to subcutaneous adipose tissue ratio, adjusted for pubertal stage, was examined using two-way ANOVA. In this analysis, the pubertal stage was dichotomized as Tanner 1 or Tanner 2–5. The PI therapy category remained significant with respect to serum total cholesterol (P = 0.005) and triglyceride levels (P = 0.003), and remained non-significant with respect to serum insulin (P = 0.45), HOMA–IR (P = 0.94) and the visceral to subcutaneous adipose tissue ratio (P = 0.18). In each of these five analyses, the PI category–Tanner stage interaction term was not significant.
Multiple regression analyses for serum total cholesterol, triglyceride and insulin levels, HOMA–IR and the visceral to subcutaneous adipose tissue ratio were performed using the potential predictor variables listed in Table 1; the final regression models for these variables are depicted in Table 3. Explanatory variables significantly associated with total cholesterol included PI therapy, age and BMI. With respect to serum triglyceride levels, PI therapy was the only significant predictor variable. Tanner stage was the only significant predictor variable with respect to serum insulin and HOMA–IR, and age was the only significant predictor variable with respect to the visceral to subcutaneous adipose tissue ratio. Clinical and immunological HIV categories, viral load, CD4 cell count, sex and stavudine therapy were not significantly associated with serum total cholesterol, triglyceride or insulin levels, HOMA–IR or the visceral to subcutaneous adipose tissue ratio.
In PI-treated children, the duration of PI therapy was not significantly associated with total, HDL or LDL-cholesterol, triglyceride levels, glucose, insulin, proinsulin, C-peptide, the insulin to glucose ratio, HOMA–IR, visceral, subcutaneous or total adipose tissue areas or the visceral to subcutaneous adipose tissue ratio. Stavudine-exposed and unexposed children did not differ significantly with respect to serum lipids, glucose homeostasis or abdominal adipose tissue distribution.
Abdominal adipose tissue distribution
Abdominal adipose tissue distribution was determined for 30 PI-treated HIV-infected, 11 PI-naive HIV-infected and 52 HIV-uninfected children. The age and sex of PI-treated HIV-infected children (8.6 ± 4.4 years, 40% female), PI-naive HIV-infected children (9.2 ± 4.1 years, 55% female) and HIV-uninfected children (9.9 ± 4.2 years, 31% female) were similar (ANOVA; P = 0.29 and P = 0.54, respectively). The mean visceral to subcutaneous adipose tissue ratio in these three groups was 0.312 ± 0.179, 0.247 ± 0.108 and 0.295 ± 0.178, respectively (Fig. 1). The corresponding mean visceral adipose tissue area was 1562 ± 1989, 1500 ± 802 and 1250 ± 972 mm2 and the mean subcutaneous adipose tissue area was 5098 ± 3942, 8090 ± 6834 and 5857 ± 7101 mm2 for PI-treated HIV-infected, PI-naive HIV-infected and HIV-uninfected children, respectively. There were no significant differences between the three groups with respect to the visceral to subcutaneous adipose tissue ratio, visceral adipose tissue area or subcutaneous adipose tissue area.
The most striking finding of our study was the high prevalence of hypercholesterolemia and hypertriglyceridemia among PI-treated HIV-infected children. Similar findings have been noted in several previously published paediatric studies [16,18]. In children, hypercholesterolemia has been associated with increased carotid artery intima-media thickness [27,28], increased coronary artery calcification scores , abnormal endothelial function [30,31], and more extensive fatty streaks and fibrous plaques in the coronary arteries and aorta . In adults, elevated levels of total and LDL-cholesterol and triglycerides as well as low levels of HDL-cholesterol are well recognized as important risk factors for the development of coronary artery disease, stroke and peripheral vascular disease. Preliminary data involving PI-treated HIV-infected adults suggest that those who develop dyslipidemia and other manifestations of the HIV-associated lipodystrophy syndrome may be at increased risk of premature coronary artery disease . Clearly, the possibility that premature coronary artery disease, stroke and peripheral vascular disease will occur in dyslipidemic PI-treated HIV-infected children and adolescents is of great concern.
The lack of effect of PI therapy on glucose homeostasis observed in our cohort is consistent with findings of previously published paediatric studies [15,16,18]. In the two studies that compared PI-treated with PI-naive children [16,18], no significant differences in fasting serum glucose or insulin levels were observed. In the third study , glucose tolerance, determined by a standard oral glucose tolerance test, was normal in all 39 children studied, including 13 with clinically apparent lipodystrophy; 31 (79%) of these children were receiving PI therapy. Taken together, these results suggest that clinically significant increases in insulin resistance are relatively uncommon in HIV-infected children irrespective of antiretroviral therapy.
The lack of effect of PI therapy on abdominal adipose tissue distribution observed in our cohort is consistent with some [15,16], but not all , previously published studies. In the only study addressing this issue that specifically compared PI-treated with PI-naive subjects, no significant differences in BMI, waist–hip ratio, percentage trunk adipose tissue and the trunk to limb adipose tissue ratio were detected between groups using anthropometric measurements and dual-energy X-ray absorptiometry . In another cross-sectional study , neither the proportion of subjects receiving PI therapy nor the duration of such therapy were significantly different in those with compared with those without clinically apparent lipodystrophy. On the other hand, in a longitudinal observational study of prepubertal children, PI therapy was found to be one of several risk factors for dual-energy X-ray absorptiometry-defined lipodystrophy . Unfortunately, because of the small numbers of subjects enrolled, it was not deemed possible to adjust for potential confounding variables such as age, Tanner stage and HIV-related virological and immunological factors.
The apparent lack of effect of PI therapy on glucose homeostasis and, to a lesser extent, on abdominal adipose tissue distribution observed in our cohort and other paediatric studies contrasted with published data pertaining to HIV-infected adults in which such abnormalities are substantially more common in PI-treated than PI-naive subjects [7–11]. This apparent discrepancy may be related, at least partly, to normal physiological changes that occur during childhood. Prepubertal children are inherently more insulin sensitive and tend to have proportionally more subcutaneous and less visceral adipose tissue than pubertal children and adults [34–36]. The transition from the prepubertal state of relative insulin sensitivity and the lower visceral to subcutaneous adipose tissue ratio to the more insulin resistant and higher visceral to subcutaneous adipose tissue ratio state of adulthood occurs principally during puberty and is mediated, at least partly, by hormonal changes that occur during this period . It is possible that PI-treated HIV-infected prepubertal children are able to maintain a state of normal glucose homeostasis, as determined by fasting insulin, proinsulin and C-peptide and HOMA–IR, by virtue of their relatively high insulin sensitivity. Hyperinsulinemia has been linked to visceral adipose tissue excess, and it may be that in the absence of hyperinsulinemia visceral adipose tissue accumulation does not occur or occurs only to a minimal degree.
In our PI-treated cohort, serum insulin, proinsulin, C-peptide, the insulin to glucose ratio and HOMA–IR correlated positively with age, Tanner stage, BMI, visceral and total abdominal adipose tissue area and serum triglyceride levels. There was no significant association between these outcomes and the duration of PI therapy, stavudine therapy, clinical or immunological HIV categories, viral load or CD4 cell count. In the multiple regression analysis, Tanner stage was the only significant predictor variable with respect to serum insulin and HOMA–IR, and age was the only significant predictor variable with respect to the visceral to subcutaneous adipose tissue ratio. Taken together, these results suggest that in prepubertal HIV-infected children, glucose homeostasis and abdominal adipose tissue distribution are primarily affected by normal physiological changes that occur during childhood rather than by exposure to antiretroviral medications or HIV-related virological or immunological factors.
In evaluating adipose tissue distribution we elected to focus on the abdominal cavity because of the importance of the visceral adipose tissue depot in relation to insulin resistance, dyslipidemia and atherosclerotic cardiovascular disease [38,39]. Visceral adipose tissue accumulation has been demonstrated in a substantial proportion of PI-treated HIV-infected adults, and has been associated, in these patients, with insulin resistance, impaired glucose tolerance and dyslipidemia [7,8]. In contrast, the results of our study suggest that the excess accumulation of visceral adipose tissue does not occur, or occurs at relatively low frequency and severity in prepubertal PI-treated HIV-infected children. Unfortunately, with the exception of one study , none of the previously published paediatric studies utilized imaging techniques capable of discerning between visceral and subcutaneous adipose tissue. In this study of predominantly pubertal and post-pubertal children, the visceral adipose tissue area was significantly higher in those with than in those without clinically apparent lipodystrophy . The findings of that study as well as our own are consistent with those of another paediatric study that demonstrated less severe clinical lipodystrophy changes in prepubertal compared with pubertal children . These data suggest that prepubertal children are less susceptible to PI-induced adipose tissue distribution changes than pubertal children and adults.
The NRTI, particularly stavudine, and more advanced HIV disease have also been associated with the development of the HIV-associated lipodystrophy syndrome in adults as well as children [4,5,12,13,17]. In the study by Arpadi et al. , the presence of lipodystrophy in prepubertal HIV-infected children was associated with a lower baseline CD4 cell count, higher baseline viral load and treatment with stavudine as well as PI. In our cohort, there was no significant correlation, on univariate analysis, between the severity of HIV disease, as determined by clinical and immunological HIV categories, viral load and CD4 cell count, or stavudine therapy with serum lipids, glucose, insulin, proinsulin C-peptide or measures of abdominal adipose tissue distribution. In the multiple regression analyses, there were trends suggesting an inverse association between viral load and serum insulin, viral load and total cholesterol, and CD4 cell count and serum insulin. Although these results must be interpreted with caution, they do suggest that HIV-related virological and immunological factors may have some effect on glucose homeostasis, serum lipids and adipose tissue distribution in HIV-infected children.
The principal limitations of our study were its cross-sectional design and small sample size. Although we attempted to adjust for the potential confounding effects of age, Tanner stage, race, BMI, HIV clinical and immunological disease categories and stavudine therapy, it is possible that the two groups differed systematically in other important ways. With regard to sample size, it is conceivable that differences in glucose homeostasis and adipose tissue distribution between groups could have been detected with a larger sample size. However, our study was sufficiently powered to detect differences in glucose homeostasis parameters had the prevalence of and degree of insulin resistance of PI-treated children been similar to those observed in adults. With regard to abdominal adipose tissue distribution, given the small number of subjects in the PI-naive group and the wide variation in the visceral to subcutaneous adipose tissue ratio among subjects of all three groups, the power to detect a significant difference was limited.
Several other limitations deserve mention. First, our choices of glucose homeostasis and adipose tissue distribution outcomes although appropriate, were not without flaw. Fasting serum insulin, proinsulin and C-peptide and HOMA–IR may not be measures of sufficient sensitivity to allow the detection of small, but nevertheless physiologically important changes in insulin resistance. With regard to adipose tissue distribution, our study was designed solely to investigate the distribution of adipose tissue within the abdomen. As such, we are unable to comment on the potential effects of the PI on total body and peripheral adipose tissue distribution. Second, the incomplete application of CT scanning to the PI-naive group of children may have led to recruitment bias. However, we believe this is unlikely, as failure to perform CT scanning was not the result of a selection bias on the part of study investigators. Third, the findings of our study may not be generalizable to all PI, as the majority of children in our cohort were receiving either ritonavir or nelfinavir.
In conclusion, in this cross-sectional study of predominantly prepubertal HIV-infected children, PI therapy was associated with the development of an atherogenic dyslipidemia, but not insulin resistance or visceral adipose tissue accumulation. Whether insulin resistance, adipose tissue redistribution and premature atherosclerosis become more prevalent in PI-treated HIV-infected children during puberty is unknown at the present time. Our results suggest that routine monitoring of serum lipids in all HIV-infected children, particularly in those receiving PI therapy, is warranted. Children found to be persistently dyslipidemic may benefit from dietary intervention and should be counselled regarding the benefits of regular exercise .
The authors would like to thank the children and parents who participated in this study as well as the nurses, Cheryl Arneson, Debra Louch and Jennifer Ponsonby, who assisted in the performance of study investigations. We also thank the Positive Action Fund, GlaxoSmithKline in partnership with Shire BioMed, the Ministry of Health, Ontario, and Agouron Pharmaceuticals for providing funding for the study, and the Canadian HIV Trials Network for providing the funding for Dr Ari Bitnun's Clinical Associateship.
Sponsorship: Dr Ari Bitnun's Clinical Associateship was funded by the Canadian HIV Trials Network. The study was supported by the Positive Action Fund, GlaxoSmithKline in partnership with Shire BioMed, the Ministry of Health, Ontario, and Agouron Pharmaceuticals.
1.Lindegren ML, Steinberg S, Byers RH Jr. Epidemiology of HIV/AIDS in children
. Pediatr Clin North Am
2.de Martino M, Tovo PA, Balducci M, Galli L, Gabiano C, Rezza G, et al. Reduction in mortality with availability of antiretroviral therapy for children with perinatal HIV-1 infection. Italian Register for HIV Infection in Children and the Italian National AIDS Registry
3.Gortmaker SL, Hughes M, Cervia J, Brady M, Johnson GM, Seage GR III, et al. Effect of combination therapy including protease inhibitors on mortality among children and adolescents infected with HIV-1
. N Engl J Med
4.Shevitz A, Wanke CA, Falutz J, Kotler DP. Clinical perspectives on HIV-associated lipodystrophy syndrome: an update
5.Carr A, Cooper DA. Adverse effects of antiretroviral therapy
6.Dube MP. Disorders of glucose metabolism in patients infected with human immunodeficiency virus
. Clin Infect Dis
7.Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, Cooper DA. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors
8.Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor- associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study
9.Walli R, Herfort O, Michl GM, Demant T, Jager H, Dieterle C, et al. Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients
10.Mulligan K, Grunfeld C, Tai VW, Algren H, Pang M, Chernoff DN, et al. Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection
. J Acquir Immune Defic Syndr
11.Behrens G, Dejam A, Schmidt H, Balks H-J, Brabant G, Korner T, et al. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors
12.Mulligan K, Tai VW, Algren H, Abrams DI, Leiser RJ, Lo JC, et al. Altered fat distribution in HIV-positive men on nucleoside analog reverse transcriptase inhibitor therapy
. J Acquir Immune Defic Syndr
13.Mallal SA, John M, Moore CB, James IR, McKinnon EJ. Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection
14.Brambilla P, Bricalli D, Sala N, Renzetti F, Manzoni P, Vanzulli A, et al. Highly active antiretroviral-treated HIV-infected children show fat distribution changes even in absence of lipodystrophy
15.Jaquet D, Levine M, Ortega-Rodriguez E, Faye A, Polak M, Vilmer E, Levy-Marchal C. Clinical and metabolic presentation of the lipodystrophic syndrome in HIV-infected children
16.Melvin AJ, Lennon S, Mohan KM, Purnell JQ. Metabolic abnormalities in HIV type 1-infected children treated and not treated with protease inhibitors
. AIDS Res Hum Retroviruses
17.Arpadi SM, Cuff PA, Horlick M, Wang J, Kotler DP. Lipodystrophy in HIV-infected children is associated with high viral load and low CD4+-lymphocyte count and CD4+-lymphocyte percentage at baseline and use of protease inhibitors and stavudine
. J Acquir Immune Defic Syndr
18.Vink NM, van Rossum AM, Hartwig NG, de Groot R, Geelen S. Lipid and glucose metabolism in HIV-1-infected children treated with protease inhibitors
. Arch Dis Child
19.Babl FE, Regan AM, Pelton SI. Abnormal body-fat distribution in HIV-1-infected children on antiretrovirals
20.Centers for Disease Control and Prevention. 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age
1994, 43 (No. RR-12)
21.Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls
. Arch Dis Child
22.Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys
. Arch Dis Child
23.Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man
24.Miller KD, Jones E, Yanovski JA, Shankar R, Feuerstein I, Falloon J. Visceral abdominal-fat accumulation associated with use of indinavir
25.Borkan GA, Gerzof SG, Robbins AH, Hults DE, Silbert CK, Silbert JE. Assessment of abdominal fat content by computed tomography
. Am J Clin Nutr
26.van der Kooy K, Seidell JC. Techniques for the measurement of visceral fat: a practical guide
. Int J Obes Relat Metab Disord
27.Pauciullo P, Iannuzzi A, Sartorio R, Irace C, Covetti G, Di Costanzo A, et al. Increased intima-media thickness of the common carotid artery in hypercholesterolemic children
. Arterioscler Thromb
28.Tonstad S, Joakimsen O, Stensland-Bugge E, Leren TP, Ose L, Russell D, et al. Risk factors related to carotid intima-media thickness and plaque in children with familial hypercholesterolemia and control subjects
. Arterioscler Thromb Vasc Biol
29.Mahoney LT, Burns TL, Stanford W, Thompson BH, Witt JD, Rost CA, et al. Coronary risk factors measured in childhood and young adult life are associated with coronary artery calcification in young adults: the Muscatine Study
. J Am Coll Cardiol
30.Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis
31.Clarkson P, Celermajer DS, Powe AJ, Donald AE, Henry RM, Deanfield JE. Endothelium-dependent dilatation is impaired in young healthy subjects with a family history of premature coronary disease
32.Berenson GS, Srinivasan SR, Bao W, Newman WP III, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study
. N Engl J Med
33.Passalaris JD, Sepkowitz KA, Glesby MJ. Coronary artery disease and human immunodeficiency virus infection
. Clin Infect Dis
34.Cook JS, Hoffman RP, Stene MA, Hansen JR. Effects of maturational stage on insulin sensitivity during puberty
. J Clin Endocrinol Metab
35.Travers SH, Jeffers BW, Bloch CA, Hill JO, Eckel RH. Gender and Tanner stage differences in body composition and insulin sensitivity in early pubertal children
. J Clin Endocrinol Metab
36.Goran MI, Kaskoun M, Shuman WP. Intra-abdominal adipose tissue in young children
. Int J Obes Relat Metab Disord
37.de Ridder CM, Thijssen JH, Bruning PF, Van den Brande JL, Zonderland ML, Erich WB. Body fat mass, body fat distribution, and pubertal development: a longitudinal study of physical and hormonal sexual maturation of girls
. J Clin Endocrinol Metab
38.Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease
39.Reaven GM. Pathophysiology of insulin resistance in human disease
. Physiol Rev
40.McCrindle BW. Screening and management of hyperlipidemia in children
. Pediatr Ann
Adipose tissue; cholesterol; HIV; insulin resistance; lipodystrophy; protease inhibitor
© 2003 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.