SEARCH

SEARCH BY CITATION

Keywords:

  • antiretroviral therapy;
  • body composition;
  • CD4;
  • children;
  • fat redistribution;
  • growth;
  • HIV;
  • viral load

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Objectives

The aim of the study was to describe growth and body composition changes in HIV-positive children after they had initiated or changed antiretroviral therapy (ART) and to correlate these with viral, immune and treatment parameters.

Methods

Ninety-seven prepubertal HIV-positive children were observed over 48 weeks upon beginning or changing ART. Anthropometry and bioelectrical impedance analysis results were compared with results from the National Health and Nutrition Examination Survey 1999–2002 (NHANES) to generate z-scores and with results for HIV-exposed, uninfected children from the Women and Infants Transmission Study (WITS). Multivariate analysis was used to evaluate associations between growth and body composition and disease parameters.

Results

All baseline lean and fat mass measures were below those of controls from NHANES. Weight, height and fat free mass (FFM) index (FFM/height2) z-scores increased over time (P=0.004, 0.037 and 0.027, respectively) and the waist:height ratio z-score decreased (P=0.045), but body mass index and per cent body fat z-scores did not change. Measures did not increase more than in uninfected WITS controls. In multivariate analysis, baseline height, mid-thigh circumference and FFM z-scores related to CD4 percentage (P=0.029, P=0.008 and 0.020, respectively) and change in FFM and FFM index z-scores to CD4 percentage increase (P=0.010 and 0.011, respectively). Compared with WITS controls, baseline differences in height and mid-thigh muscle circumference were also associated with CD4 percentage. Case–control differences in change in both subscapular skinfold (SSF) thickness and the SSF:triceps skinfold ratio were inversely associated with viral suppression. No measures related to ART class(es) at baseline or over time.

Conclusions

In these HIV-positive children, beginning or changing ART was associated with improved growth and lean body mass (LBM), as indicated by FFM index. Height and LBM related to CD4 percentage at baseline and over time. Altered fat distribution and greater central adiposity were associated with detectable virus but not ART class(es) received.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Poor growth is a common manifestation of HIV infection in children [1–5], the pathophysiology of which remains poorly understood. The importance of growth is underscored by the finding that height growth velocity predicts survival, regardless of plasma viral load [HIV-1 RNA (VL)], age and CD4 cell count [6]. The relationships among growth, VL, immune function and antiretroviral therapy (ART) remain unclear. Conflicting data exist from both pre- and post-highly active antiretroviral therapy (HAART) eras [6–13] about whether VL is associated with growth. Most, but not all [11–15], reports of children on protease inhibitor (PI) therapy note improved linear and ponderal growth. Some data suggest an association with VL that is not independent of immune function [10]. It is still unclear whether improved growth sometimes seen with treatment is primarily a result of immune restoration, improved viral control or yet another mechanism.

HIV infection and/or ART may also alter body composition, measurement of which may help differentiate starvation (preferential loss of fat resulting from inadequate energy intake) from cachexia [loss of lean body mass (LBM)], generally accepted to be cytokine mediated. Data are conflicting about preservation of LBM in HIV-infected children [2,16]. Altered fat distribution in HIV-infected persons, particularly those on ART, may also occur [17]. In particular, increased central adiposity has been reported in both HIV-infected adults and children [17,18], and is of concern because of the known association with cardiovascular morbidities [19]. Although limited information is available on associations and predictors of body composition and fat distribution in prepubertal HIV-infected children, exposure to PIs is frequently noted in association with lipodystrophy [18, 20–22]. Data regarding association with disease measures such as VL and CD4 percentage, however, are conflicting [20,21].

The objectives of this study were (a) to describe growth and body composition changes in HIV-infected children over 48 weeks after beginning or changing ART; (b) to compare these changes in HIV-infected children to both US population-based data and data for matched, HIV-exposed, uninfected children; (c) to correlate growth and body composition changes with ART class(es) and changes in VL and CD4 cell percentage. We hypothesized that there is a clinically significant inverse correlation between changes in LBM and VL and a direct correlation between changes in LBM and CD4 cell percentage in children beginning or changing ART. We further hypothesized that there would be a greater increase in central adiposity in children who started therapy containing PIs compared with those who started non-PI regimens.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Subjects and design

Pediatric AIDS Clinical Trials Group Protocol 1010 (PACTG P1010) was a multi-site, prospective 48-week cohort study of HIV-infected, prepubertal children aged 1 month to <13 years who were beginning or changing ART. The ART criteria for inclusion were one of the following scenarios: (a) beginning any ART if ART naïve, (b) beginning PI-based ART if PI naïve, or (c) changing ART for virological failure to a regimen including at least two new drugs. Exclusion criteria have been previously described but, briefly, included pubertal development, concurrent acute illness or treatment within 180 days of entry with medications known to affect growth or body composition, for example steroids [23]. Ethics committee approval was obtained from each participating institution, as was written informed consent from the parent or legal guardian and assent from the child when appropriate. Accrual began in June 2000 and continued until March 2004.

Visits were at study entry (within 72 h prior to ART initiation or change) and at 12, 24, 36 and 48 weeks thereafter. At each visit, the following evaluations were performed by trained staff: interim history and physical examination including Tanner staging; anthropometry [weight, height, circumferences (waist, hip and limb) and skinfold thicknesses (triceps, thigh and subscapular)]; single frequency tetrapolar bioelectrical impedance analysis (BIA; 50 kHz, UniQuest-SEAC BIM4 instrument; UniQuest Limited, Brisbane, Australia] of total body impedance, resistance, reactance, and phase angle; plasma VL (HIV-1 RNA) and CD4 T-lymphocyte count; and 3-day diet record (24-hour intake by recall if 3-day record not performed). Mid-arm and thigh muscle circumferences were calculated using standard equations and used as a measure of LBM. BIA measures were used to calculate total body water (TBW; L), fat free mass (FFM; kg), and fat mass (FM; kg) using equations previously validated in HIV-infected and uninfected children: TBW=25+0.475H2/R+0.140W; FFM=(3.474+0.459H2/R+0.064W)/(0.769−0.009A−0.016S); and FM=W−FFM, where H is height (cm), R is resistance (ohms), W is weight (kg), A is age (years), and S is sex (1 for male and 0 for female patients) [24]. For children <8 years of age, the resistance index (H2/R) was utilized as a measure of TBW [25]. Per cent body fat was calculated from BIA as [FM (kg)/weight (kg)] × 100, and FFM adjusted for height was calculated using the FFM index (FFM:height2 ratio) [26].

Laboratory analyses

Laboratories with approved performance in the NIAID Division of AIDS Virology and Immunology Quality Assurance Programs conducted HIV-1 RNA and CD4 cell measurements.

Sample size

A sample size of 100 was calculated to be required for the primary response variables of mid-arm muscle circumference (MAMC) and triceps skinfold thickness (TSF). Based on a pilot study, 100 subjects would allow detection of a change to within 0.5% for MAMC and 9.2% for TSF with 95% confidence. One hundred subjects would provide 99% power to detect a difference in MAMC change of 2.5% between viral responders and nonresponders and 88% power to detect a 15% difference in TSF change between the two groups.

Statistical analyses

Two distinct analytical approaches were utilized to take account of sex-, race/ethnicity- and age-related differences in measures of growth and body composition in uninfected children: (1) sex/race/ethnicity/age-adjusted z-scores were calculated using data from a large, nationally representative cross-sectional sample of children [the National Health and Nutrition Examination Survey 1999–2002 [27] (NHANES)] and (2) a case–control approach was used in which each child in this study was matched to one or more HIV-exposed, uninfected controls from another study in which the subjects were sociodemographically similar, the Women and Infants Transmission Study [28] (WITS), who were followed longitudinally.

For the first analytical approach using data from NHANES, growth and body composition z-scores at baseline were derived by selecting all available children in the NHANES database of the same sex, race/ethnicity and age (to within ±3 months) as a child in this study (the P1010 child). Then, for each growth and body composition measure, the z-score for the P1010 child was calculated as [(P1010 child's measurement)−(mean of values for matched NHANES children)]/[standard deviation (SD) of values for matched NHANES children]. This was repeated for measurements at weeks 24 and 48. Growth and body composition measures were log-transformed before calculation of z-scores, as this gave distributions of values that were more symmetric than untransformed values. The only anthropometric measures performed in our population that were not available in NHANES subjects were mid-thigh skinfold thickness and calculated mid-thigh muscle circumference. In addition, z-scores for BIA measures were only derived for children ≥8 years of age, as BIA was measured in NHANES beginning at this age. Across the growth and body composition measures, the mean (SD) number of NHANES children used in calculating a z-score for each P1010 child ranged from 34.5 (9.0) to 40.5 (12.9). A total of 6819 children from NHANES contributed data for calculating z-scores for anthropometric variables, including 2769 children aged ≥8 years for BIA variables. The weight, height and body mass index (BMI) of these children from NHANES were compared to reference Centers for Disease Control and Prevention (CDC) growth curves to obtain mean percentiles for this control population versus that reference standard.

For each growth and body composition measure, the univariate association was evaluated between the baseline z-score and each of the following measures of baseline disease status: CD4 percentage, log10 HIV RNA, CDC clinical classification, and prior ART exposure (with or without a PI in the regimen). Multivariable regression analysis was used to measure the association of baseline z-score (dependent variable) with the standard HIV-related disease predictor variables of baseline CD4 percentage, log10 HIV-1 RNA, CDC classification, and prior ART exposure, adjusting also for the log of the ratio of caloric intake to estimated caloric need at baseline (although the results changed minimally without adjustment).

Longitudinally, regression analyses were performed to evaluate the associations of change in z-score from baseline to week 48 of follow-up and change in CD4 percentage over the same period, VL at week 48 [detectable vs. undetectable HIV-1 RNA reverse transcriptase-polymerase chain reaction (RT-PCR) with sensitivity of 400 HIV-1 RNA copies/mL] and ART class initially received during study follow-up [PI-containing, nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing or both], adjusting for baseline z-score as well as baseline CD4 percentage, log10 HIV-1 RNA and CDC clinical classification. Regression analyses were also adjusted for mean caloric intake (log ratio of caloric intake to estimated caloric need) of P1010 participants over the study period to evaluate whether the associations noted were independent of diet (although the results changed minimally without adjustment). Fat, protein and caloric intake were analysed using Nutritionist IV software (Hearst Corporation, San Bruno, CA, USA).

For the second analytical approach using data from WITS, for each P1010 child (‘case’), up to three matched ‘control’ children from WITS were identified. Children were first matched on sex and race/ethnicity. In addition, as WITS followed children longitudinally, a control had to have a study visit at the same age (within ±3 months) as the case's P1010 baseline visit. As WITS evaluated the Tanner stage of female subjects ≥7 years old and male subjects ≥9 years old, WITS controls in these age ranges also had to be prepubertal at that visit. A total of 129 matched controls for 72 cases were identified (one to three matched controls per case); 22 of 38 children >8 years of age had no matches identified. WITS had very few children older than 8 years of age, limiting the utility of this control population for our older subjects.

For each growth and body composition measure, to take account of the matching in the statistical analysis, a case–control difference at baseline was calculated by subtracting the mean of the measurements for the matched controls from the case's measurement. Univariate and multivariable associations between these differences and the case's baseline disease status (CD4 percentage, log10 HIV-1 RNA and CDC classification) and prior ART exposure were evaluated using the same methods as for the analysis of z-scores described above, except that the multivariable analyses also included sex, race/ethnicity and age as predictor variables. For each case and matched WITS control, the change from baseline in a measure over 48 weeks was calculated, and then a case–control difference in that change was obtained. Multivariable associations of these differences then proceeded as for the analysis of changes in z-scores, except that the multivariable analyses also included sex, race/ethnicity and age as predictor variables; only results from multivariable analyses are presented because of the dependence of many associations on these demographic factors.

To evaluate how the 129 uninfected, control children from WITS compared with children in the general population, z-scores were also calculated using the NHANES data in the same way that z-scores were calculated for children in the P1010 study population.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

One hundred and five patients were recruited to achieve the desired sample size of 100, as five patients were found to be ineligible after study entry, because of pubarche (n=3), disallowed medication (n=1), or withdrawal of consent prior to initial data collection (n=1). Three additional patients were excluded as the entry visit occurred subsequent to the change in ART, resulting in a final sample size for analyses of 97. Six patients withdrew from the study prior to the 48-week visit. Demographic and clinical characteristics of the study population are shown in Table 1. Briefly, the mean (SD) age at entry was 5.88 (3.63) years, with 54% of subjects being female, 61% black, non-Hispanic, and 48% CDC clinical class A or N; the mean CD4 cell percentage was 24.8% (12.5%) and the mean HIV RNA was 4.55 (0.89) log10 copies/mL, corresponding to a geometric mean of 35 338 copies/mL. Nearly one-third (29%) of subjects were ART naïve and an additional 24% were PI naïve at study entry. At both 24 and 48 weeks, slightly more than half of the children had VL<400 copies/mL. During the study, all children were on treatment with a nucleoside reverse transcriptase inhibitor and 19% received an NNRTI without a PI, 20% received both an NNRTI and a PI, and 57% received a PI without an NNRTI. One child changed from a PI- to an NNRTI-containing regimen and one from an NNRTI- to a PI-containing regimen in the first 7 days; these two children were classified according to the regimen received after 7 days. Two other children started on a PI regimen but changed later in follow-up to an NNRTI-containing regimen and were classified according to the initial regimen. No other changes of drug class were reported. Twenty-five children experienced pubarche during the 48 weeks on study, 20 of whom were classified as Tanner stage 2 at the 48-week visit. Dietary intake data were available for 82 children; mean total fat intake exceeded national recommendations in only two of these children (2%) and all but one child consumed protein in quantities equal to or greater than recommended for age and weight.

Table 1.   Demographic and clinical characteristics of the Pediatric AIDS Clinical Trials Group protocol 1010 (PACTG 1010) study population
 Number of subjectsPercentage of subjects*
Age
 1 month to <18 months99.3
 18 months to <3 years1515.5
 3 years to <8 years3334.0
 8 years to <13 years4041.2
Gender
 Male4546.4
 Female5253.6
Race/ethnicity
 White, non-Hispanic1111.3
 Black, non-Hispanic5960.8
 Hispanic2626.8
 Other/unknown11.0
CDC clinical stage
 A or N4748.4
 B3233.0
 C1818.6
Prior therapy
 ART-naïve2828.9
 PI-naïve§2323.7
 PI-exposed4647.4
ART drug classes taken during study
 NRTI44.0
 NRTI/NNRTI1818.6
 NRTI/NNRTI/PI1919.6
 NRTI/PI5556.7
 NRTI/NNRTI/FI11.0
 Number of subjectsPercentage of subjects*
Entry48 weeksEntry48 weeks
  • *

    The percentage is of subjects with known status; percentages may not add up to 100 because of rounding.

  • At study entry.

  • §

    § ART exposed.

  • ART, antiretroviral therapy; CDC, Centers for Disease Control and Prevention; FI, fusion inhibitor (enfuvirtide); NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.

CD4 percentage
 0 to <15%17818.99.1
 15 to <25%291432.215.9
 ≥25%446648.975.0
 Missing79  
HIV-1 RNA (copies/mL)
 <4002462.254.1
 400 to <10 000221223.714.1
 10 000 to <30 000151116.112.9
 30 000 to <100 000261028.011.8
 ≥100 00028630.17.1
 Missing412  

All anthropometric measures and calculated TBW, FFM and percentage body fat z-scores were significantly (P<0.05) below zero in HIV-infected children at baseline (study entry), as shown in Figure 1. Similarly, in comparison to the matched HIV-exposed, uninfected children from WITS, most measures were also significantly lower at entry, with the exception of MAMC, MTSF and per cent body fat, which approached the limit of significance (0.05<P<0.1; Fig. 2). Compared with NHANES data, the uninfected control children from WITS also had z-scores that were significantly lower than zero for multiple measures of fat at both baseline and 48 weeks, including TSF, SSF and BMI, as well as for weight and waist circumference at 48 weeks (data not shown). Mean [95% confidence interval (CI)] weight, height and BMI percentiles for the NHANES controls on the CDC reference curve were 62.8 (61.0, 64.5), 56.9 (55.2, 58.5) and 65.2 (63.2, 67.0), respectively, each greater than the reference population (P<0.001).

image

Figure 1.  Difference in anthropometric and body composition z-scores in the P1010 study population compared with adjusted norms from the National Health and Nutrition Examination Survey 1999–2002 (NHANES) at study entry and week 48.

Download figure to PowerPoint

image

Figure 2.  Anthropometric and body composition differences in the P1010 study population compared with matched HIV-exposed, uninfected Women and Infants Transmission Study (WITS) controls at study entry and week 48.

Download figure to PowerPoint

Over the 48-week course of therapy, mean (SD) weight [0.16 (0.53); P=0.004], height [0.14 (0.61); P=0.037], FFM [0.27 (0.48); P=0.001] and FFM index [FFM/height2; 0.30 (0.81); P=0.027] z-scores increased significantly (Fig. 1) while the waist:height ratio z-score decreased [−0.19 (0.79); P=0.045]. At the 24-week visit, there was a significant increase in mean z-scores for MAMC [0.28 (1.22); P=0.033] and mid-thigh circumference [MTC; 0.16 (0.45); P=0.030]. The latter changes, however, were no longer significant at the 48-week visit. By contrast, there was no significant difference in change at 48 weeks between cases and matched HIV-exposed, uninfected controls from WITS (Fig. 2).

In multivariate analyses of baseline z-scores (NHANES controls), more severe stunting was associated with CDC clinical classes B and C compared with N or A (height z-score−0.56, P=0.044 and −1.06, P=0.002, respectively) and a higher waist:height ratio z-score with class C (P=0.006) (see Table 2). Baseline z-score for height, MTC and FFM were each associated with baseline CD4 percentage (z-scores 0.19, 0.38 and 0.38 higher per 10% higher CD4 percentage; P=0.029, 0.008 and 0.020, respectively), as shown in Table 2. FFM index, however, was not associated with CD4 percentage (P=0.22). VL at baseline was significantly associated only with lower peripheral fat stores, with a mean TSF z-score of −0.19 per 1 log10 RNA copies/mL higher (P=0.043). Similarly, in multivariate analysis of the differences at entry between P1010 cases and WITS controls (Table 3), case–control differences in height and MTMC were both associated with baseline CD4 percentage (compared with uninfected HIV-exposed matched controls, mean height and MTMC in infected children were higher by 1.60 and 1.32 cm, respectively, per 10% higher baseline CD4 percentage in the infected child; P=0.015 and 0.019, respectively). In addition, compared with uninfected HIV-exposed matched controls, mean BMI was higher by 3.03 kg/m2 in infected children with CDC category C disease compared with those with CDC category A/N disease (P=0.029). In the comparison with WITS controls, there were no significant associations at baseline between any growth or body composition measure and VL. Nor were significant associations seen with ART or PI exposure, although the difference in TSF in PI-exposed versus ART-naïve children approached significance (−4.54 mm; P=0.057).

Table 2.   Association of baseline growth and body composition z-scores with measures of disease status in the Pediatric AIDS Clinical Trials Group protocol 1010 (PACTG 1010) study population
Baseline valueCD4 percentage (per 10% higher)HIV RNA (per 1 log10 copies/mL higher)CDC category (vs. category A/N)
Category BCategory C
  1. Values shown are mean (95% CI). Results shown in bold are significant (P<0.05).

  2. n is the number of observations included in the analyses.

  3. Models were adjusted for the log of the ratio (caloric intake:estimated caloric need) at baseline. Prior antiretroviral therapy (ART) exposure was also included in the model but was not significant for any growth or body composition measure. z-scores were derived from data for matched children in the National Health and Nutrition Examination Survey 1999–2002 (NHANES).

  4. CDC, Centers for Disease Control and Prevention.

Weight0.04 (−0.11, 0.19)0.03 (−0.13, 0.19)−0.31 (−0.80, 0.17)−0.44 (−1.03, 0.15)
(n=96)P=0.56P=0.74P=0.20P=0.14
Height0.19 (0.02, 0.36)0.10 (−0.08, 0.28)0.56 (1.10, −0.02)1.06 (1.72, −0.39)
(n=96)P=0.029P=0.29P=0.044P=0.002
Mid-arm muscle circumference0.25 (−0.03, 0.53)0.02 (−0.26, 0.30)0.41 (−0.47, 1.30)0.54 (−0.55, 1.62)
(n=95)P=0.075P=0.89P=0.35P=0.33
Mid-thigh circumference0.38 (0.10, 0.65)−0.08 (−0.33, 0.16)0.16 (−0.58, 0.91)0.14 (−0.80, 1.08)
(n=41)P=0.008P=0.49P=0.66P=0.76
Triceps skinfold−0.08 (−0.25, 0.09)0.19 (−0.38, −0.01)−0.12 (−0.68, 0.44−0.36 (−1.04, 0.32)
(n=95)P=0.36P=0.043P=0.67P=0.29
Subscapular skinfold0.04 (−0.12, 0.21)−0.12 (−0.30, 0.05)0.06 (−0.47, 0.59)0.05 (−0.60, 0.70)
(n=96)P=0.60P=0.17P=0.82P=0.88
Subscapular/triceps skinfold ratio0.29 (−0.02, 0.60)0.09 (−0.24, 0.42)0.21 (−0.80, 1.23)−0.02 (−1.25, 1.21)
(n=95)P=0.069P=0.59P=0.68P=0.98
Fat free mass (FFM)0.38 (0.06, 0.70)0.09 (−0.19, 0.37)−0.39 (−1.25, 0.48)−0.37 (−1.46, 0.72)
(n=41)P=0.020P=0.51P=0.37P=0.49
FFM:height2 ratio0.19 (−0.12, 0.49)−0.03 (−0.30, 0.24)−0.19 (−1.02, 0.63)0.20 (−0.84, 1.25)
(n=41)P=0.22P=0.80P=0.64P=0.70
Waist:height ratio0.03 (−0.14, 0.19)−0.11 (−0.29, 0.07)0.31 (−0.23, 0.86)0.90 (0.27, 1.53)
(n=82)P=0.76P=0.23P=0.26P=0.006
Body mass index−0.08 (−0.23, 0.07)−0.02 (−0.17, 0.14)−0.18 (−0.65, 0.29)0.06 (−0.51, 0.64)
(n=96)P=0.28P=0.82P=0.46P=0.83
Body fat percentage0.22 (−0.02, 0.45)−0.02 (−0.23, 0.19)0.14 (−0.51, 0.79)0.22 (−0.60, 1.04)
(n=41)P=0.073P=0.86P=0.66P=0.59
Table 3.   Association of baseline case–control differences and measures of disease status
Baseline differences (case–control)CD4 percentage (per 10% higher)HIV RNA (per 1 log10 copies/mL higher)CDC category (vs. category A/N)
Category BCategory C
  1. Values shown are mean (95% CI). Results shown in bold are significant (P<0.05).

  2. Case–control differences were derived from matched children in the Women and Infants Transmission Study (WITS).

  3. Results are from multivariate models which also adjusted for sex, race/ethnicity, baseline age and baseline log calorie (intake/estimated need); prior ART exposure was also included in the model but was not significant for any growth or body composition measure. n is the number of observations included in the analyses.

  4. ART, antiretroviral therapy; BMI, body mass index; CDC, Centers for Disease Control and Prevention; H, height; R, resistance.

Weight (kg)1.10 (−0.43, 2.63)0.35 (−2.18, 2.88)−0.02 (−5.37, 5.33)3.26 (−2.66, 9.19)
(n=64)P=0.16P=0.78P=0.99P=0.27
Height (cm)1.60 (0.33, 2.88)0.05 (−2.06, 2.17)−2.67 (−7.15, 1.80)−3.25 (−8.23, 1.73)
(n=64)P=0.015P=0.96P=0.24P=0.20
Mid-arm muscle circumference (cm)0.07 (−0.46, 0.61)−0.09 (−0.97, 0.78)−0.63 (−2.47, 1.21)1.51 (−0.56, 3.58)
(n=64)P=0.78P=0.83P=0.49P=0.15
Mid-thigh muscle circumference (cm)1.32 (0.23, 2.41)−0.05 (−2.00, 1.89)1.04 (−2.88, 4.96)1.93 (−2.47, 6.32)
(n=57)P=0.019P=0.96P=0.60P=0.38
Mid-thigh skinfold (mm)−0.71 (−2.72, 1.30)−1.18 (−4.94, 2.58)2.15 (−5.05, 9.35)5.18 (−2.88, 13.24)
(n=63)P=0.48P=0.53P=0.55P=0.20
Triceps skinfold (mm)−0.14 (−1.29, 1.01)0.03 (−1.93, 1.20)0.41 (−3.66, 4.48)3.20 (−1.38, 7.78)
(n=66)P=0.81P=0.97P=0.84P=0.17
Subscapular skinfold (mm)0.25 (−0.83, 1.34)0.07 (−1.81, 1.94)−0.03 (−3.85, 3.79)2.98 (−1.31, 7.28)
(n=64)P=0.64P=0.94P=0.99P=0.17
BMI (kg/m2)−0.13 (−0.82, 0.57)0.34 (−0.81, 1.49)1.08 (−1.37, 3.52)3.03 (0.32, 5.74)
(n=63)P=0.72P=0.56P=0.38P=0.029
Body fat percentage−1.11 (−24.36, 22.15)−0.33 (−21.59, 20.92)−1.13 (−81.64, 79.39)1.03 (−100.59, 102.65)
(n=14)P=0.86P=0.95P=0.96P=0.97
Resistance index (H2/R) (cm2/ohm)1.02 (−0.83, 2.88)−0.62 (−3.30, 2.05)−4.47 (−10.09, 1.14)0.02 (−6.06, 6.09)
(n=47)P=0.27P=0.64P=0.12P=1.00
Waist:height ratio−0.02 (−0.03, 0.00)−0.01 (−0.02, 0.01)0.03 (−0.03, 0.08)0.04 (−0.02, 0.11)
(n=49)P=0.054P=0.53P=0.38P=0.15

Multivariate analysis of the z-score changes at 48 weeks revealed an association between change in FFM as well as the FFM index (FFM:height2 ratio) and CD4 percentage; for each 10% increase in CD4 percentage over the 48 weeks there was an associated mean (95% CI) increase in FFM z-score of 0.42 (0.11, 0.73; P=0.010) and a mean increase in FFM index z-score of 0.57 (0.14, 1.00; P=0.011). As with baseline measures, there were no differences in adjusted z-score changes for PI- versus NNRTI- versus PI and NNRTI-based HAART regimens.

Similar multivariate analysis of the difference in change between cases and matched WITS control children revealed a greater change in case–control difference in truncal fat as measured by SSF and truncal:limb fat ratio (subscapular: triceps skinfold ratio) for children whose VL was detectable at 48 weeks (4.07 mm, P=0.001 and 0.12 mm, P=0.036, respectively).

When results were not adjusted for caloric intake, all the described statistically significant associations based on z-scores or on case–control differences remained statistically significant.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Our hypothesis that increases in LBM would be directly associated with improved CD4 percentage was supported by the increase in the FFM index z-score of 0.57 for each 10% increase in CD4 percentage at 48 weeks. The associations between case–control difference in MTMC and CD4 percentage at entry in the WITS comparison and the MTC z-score and CD4 percentage at entry in the NHANES comparison lend further support to this hypothesis. There was, however, no evidence to support our hypothesis that viral suppression would relate to improvements in LBM. We did, however, find an association between higher persistent VL and fat distribution. A greater increase in truncal fat (measured by SSF) and trunk:limb fat ratio (SSF:TSF) relative to controls in the WITS comparison was seen in children who did not achieve viral suppression compared with those who did. Higher VL at baseline has been shown to predict loss of both extremity and truncal fat in HIV-infected adults [29]; the loss of extremity fat with higher viral burden is similar to the finding we noted between smaller TSF and higher VL at entry.

It is unclear how improved CD4 percentages might relate physiologically to improved muscle mass. An association between an increase in extremity muscle mass and an increase in CD4 cell count has been previously reported in adults by McDermott et al. [29] One could speculate that lower CD4 percentage may be related to intercurrent infections, and subsequent loss of LBM from catabolism as a result of these infections. McDermott et al. speculated that it may reflect ‘improved health, nutrition and mobility’ resulting from improved CD4 cell count [29]. Improved nutrition seems an unlikely explanation given that the finding persisted after adjustment for caloric intake in our study, but, again, reducing intercurrent infections could reduce nutritional needs.

The children in this study had similar mean gains in height z-score (0.14), but greater gains in weight z-score (0.16), compared with those previously described for children on PI therapy [12]. These improvements occurred in the first 48 weeks on therapy and were independent of viral suppression, in contrast to a previous report that improved growth was delayed until 96 weeks on therapy, and only for virological responders [11]. Height increases appeared to be greater than those seen with PI therapy in a study by Miller et al., [15] although they presented only adjusted z-scores; our populations differ in that the P1010 children were receiving a variety of different HAART regimens, which may have resulted in greater overall effect. Growth and body composition changes in our study were independent of class(es) of ART begun at study entry. Additionally, there was no evidence that there was an increase in central adiposity in the study population as a whole, as reflected by mean waist:height ratio z-score, which actually decreased over the 48 weeks, or by SSF. Nor was there evidence to support our hypothesis that PI therapy would be associated with a greater increase in central adiposity.

Our findings on body composition at baseline do not concur with those of Fontana et al. [16] in that the per cent body fat z-score was significantly lower than that of the comparison children in NHANES at entry, and there was a similar trend in comparison to the HIV-exposed children in WITS [mean (SD) z-score=−0.51 (0.69) and case–control difference vs. WITS –5.6% (11.5), P<0.001 and P=0.09, respectively], suggesting that FM was more diminished in these children than was lean mass. This suggests that there may be a component of relative ‘starvation’ in addition to the impaired anabolism demonstrated by lower measures of LBM. Alternatively, it could be that the NHANES controls had greater relative body fat than Fontana's controls. The latter possibility is supported by the mean BMI percentile of matched NHANES controls used in this study of 65.2%.

In our study population, both FFM and FFM index z-scores increased significantly, suggesting that greater lean mass in the population as a whole was not entirely a result of greater linear growth, but rather there was also a relative increase in muscle mass. Per cent body fat and BMI did not change, however; apparently a corresponding appropriate gain in FM also occurred. Unfortunately, the significant increase of arm muscle circumference seen in our population at 24 weeks was not sustained. Nor was there greater gain in arm or thigh muscle circumference (or any anthropometric or BIA measure) in our population when compared with control children from WITS, despite the children in our population entering the study with lower measures of both muscle and fat stores. Apparently the anabolic response that may result in improved linear growth does not result in significantly greater muscle circumference in the children as a group, at least over 48 weeks. Miller et al. [15] reported that PI treatment was independently associated with improvements in LBM as measured by arm muscle circumference, a finding we did not corroborate either looking at differences between PI-exposed and -naïve children at baseline or comparing those receiving PI-based HAART to those receiving non-PI-based HAART regimens during the study. Results to date in WITS also demonstrate a trend towards decreased arm and thigh muscle masses in infected versus uninfected children, with no evidence that this is changing in the era of HAART [30].

There are several limitations to this study. It is likely that the HIV-infected children in our study differed from the overall US population represented in the NHANES data in ways for which we could not adjust; differences between the WITS uninfected children and the NHANES population in several anthropometric measures support this speculation. Furthermore, BIA measures were only available in children >8 years of age in NHANES, limiting the utility of BIA in this comparison. NHANES itself consists of cross-sectional data which are not ideal for comparison with data from subjects followed longitudinally. The HIV-exposed, uninfected cohort in WITS is likely to be more similar to our study population than the overall population in NHANES, but the case–control method did not allow generation of z-scores; there were also few matches for the older children. Results of the two comparisons are discrepant in some cases; it is likely that some of these differences are attributable to the different ages represented, as age was significantly associated with multiple measures at both baseline and over the 48 weeks. Other differences may be the result of fewer available matched children in the WITS cohort, resulting in less power to detect changes in case–control differences over time that may be clinically significant. The subjects in our study also began diverse ART regimens, limiting the power to detect changes that may be associated with specific ART class(es). Although we did not find an association with specific ART classes, all children were on treatment, so it is not possible to sort out the contribution that treatment per se may have to growth and body composition changes. The lack of associations at entry with PI therapy compared with ART or PI naivety suggests that there may not be substantive effects of ART per se on growth or body composition. There were also many comparisons such that some findings of borderline significance may have occurred by chance. Finally, we did not have a comparison group of HIV-infected children who were not beginning or changing therapy, so clearly the associations noted may be different in children on long-term therapy. The major strengths of the study include a sample size larger than in most prospective studies evaluating body composition changes in this population, a homogenously prepubertal population at study entry, evaluation before and after ART initiation or change, and collection of both anthropometric and BIA measures.

In summary, in this population of HIV-infected children predominantly with mild-to-moderate disease, initiation or change in ART was followed by improvements in linear and ponderal growth as well as improved FFM index, when compared with population-based norms, but not when compared with matched HIV-exposed, uninfected children. These differences in results according to comparison group may primarily be related to age, as younger children were disproportionally represented in the comparison to exposed, uninfected children, or power, as there were fewer matched children in the latter group. Limb muscle mass circumferences did not improve significantly nor were there changes in lean:fat ratios as measured by body fat percentage over time in the group as a whole. Height and other measures of LBM were associated with CD4 percentage at study entry and over time, and greater truncal fat is associated with failure to achieve viral suppression. Further investigation is required to understand the physiological relationships underlying these associations.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The authors would like to acknowledge the children who participated in this study and their families, the entire protocol 1010 team for their contributions and support and Jie Chin for statistical support. We are also grateful to the Women and Infant Transmission Study for sharing data on matched, uninfected children. This study was supported in part by the Pediatric AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases and the Pediatric/Perinatal HIV Clinical Trials Network of the National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD.

The following sites and individuals have contributed to this study: Howard University: S. Rana, P. Yu, S. Dangol, J. Roa; Bronx Lebanon Hospital Center; St. Jude Children's Hospital: M. Donohoe, K. Knapp, N. Patel, J. Utech; Baylor Texas Children's Hospital: K. Owl, M. Dobmeier, M. Paul, C. Hanson; Children's Hospital of Boston; Harlem Hospital: E. Abrams, D. Calo, M. Fere, S. Champion; North Broward Hospital District; Jacobi Medical Center: A. Wiznia, M. Chin, K. Dorio, J. Abadi; University of Florida: J. Sleasman, R. Lawrence, C. Delany; Children's Hospital LA: T. Dunaway, L. Heller; University of Maryland: J. Farley, M. MacFadden; State University of New York at Stony Brook: S. Nachman, M. Davi, C. Seifert, S. Muniz; Metropolitan Hospital Center: M. Bamji, I. Pathak, S. Manwani; Children's Hospital, Oakland: A. Petru, T. Courville, K. Gold, S. Bessler; Harbor-UCLA Medical Center: M. Keller, K. Zangwill, J. Hayes, A. Gagajena; Columbia Presbyterian Medical Center: A. Higgins, M. Foca; University of Miami: C. Goldberg, M. Bissainthe, C. Mitchell, G. Scott; New York University School of Medicine: T. Hastings, M. Mintor, N. Deygoo, W. Borkowsky; University of Illinois: K. Rich; K. Hayani, J. Camacho; Children's Hospital University of Colorado, Denver: E. McFarland, M. Levin, C. Salbenblatt, E. Barr; Medical College of Georgia: W. Foshee, C. Mani, C. White, B. Kiernan; Johns Hopkins University: S. Marvin, A. Ruff; Duke University: R. McKinney, Y. Choi, L. Ferguson, J. Swetnam; Children's National Medical Center; San Juan City Hospital: M. Acevedo, M. Gonzales, C. Martinez Betancoult, F. Pabon; Yale University School of Medicine: D. Schroeder, S. Romano, M.J. Aquino-de Jesus; Los Angeles County Medical Center: J. Homans, Y. Rodriquez, A. Kovacs; University of Puerto Rico: I. Febo Rodriquez, L. Lugo, I. Heyer, C. Martinez; University of Massachusetts Medical School: K. Luzuriaga.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  • 1
    McKinney RE, Robertson WR. Effect of human immunodeficiency virus infection on the growth of young children. J Pediatr 1993; 123: 579582.
  • 2
    Miller TL, Evans S, Orav EJ et al. Growth and body composition in children with human immunodeficiency virus-1 infection. Am J Clin Nutr 1993; 57: 588592.
  • 3
    Moye J Jr., Rich KC, Kalish LA et al. Natural history of somatic growth in infants born to women infected by human immunodeficiency virus. J Pediatr 1996; 128: 5867.
  • 4
    Saavedra JM, Henderson RA, Perman JA et al. Longitudinal assessment of growth in children born to mothers with human immunodeficiency virus infection. Arch Pediatr Adolesc Med 1995; 149: 497502.
  • 5
    Lindegren ML, Steinberg S, Byers RH. Epidemiology of HIV/AIDS in children. Pediatr Clin N Am 2000; 47: 120.
  • 6
    Chantry C, Byrd R, Englund J et al. Growth, survival and viral load in childhood HIV infection. Pediatr Infect Dis J 2003; 22: 10331039.
  • 7
    Arpadi SM, Cuff PA, Kotler DP et al. Growth velocity, fat-free mass and energy intake are inversely related to viral load in HIV-infected children. J Nutr 2000; 130: 24982502.
  • 8
    Pollack H, Glasberg H, Lee E et al. Impaired early growth of infants perinatally infected with human immunodeficiency virus: correlation with viral load. J Pediatr 1997; 130: 915922.
  • 9
    Miller TL, Easley KA, Zhang W et al for the Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2 HIV) Study Group, National Heart, Lung, and Blood Institute, Bethesda, MD. Maternal and infant factors associated with failure to thrive in children with vertically transmitted human immunodeficiency virus-1 infection: the prospective, P2C2 human immunodeficiency virus multicenter study. Pediatrics 2001; 108: 12871296.
  • 10
    Hilgartner MW, Donfield SM, Lynn HS et al for the Hemophilia Growth and Development Study. The effect of plasma human immunodeficiency virus RNA and CD4+T lymphocytes on growth measurements of hemophilic boys and adolescents. Pediatrics 2001; 107: e56.
  • 11
    Nachman SA, Lindsey JC, Pelton S et al. Growth in human immunodeficiency virus-infected children receiving ritonavir-containing antiretroviral therapy. Arch Pediatr Adolesc Med 2002; 156: 497503.
  • 12
    Buchacz K, Cervia JS, Lindsey JC et al for the Pediatric AIDS Clinical Trials Group 219 Study Team. Impact of protease inhibitor-containing combination antiretroviral therapies on height and weight growth in HIV-infected children. Pediatr 2001; 108: e72.
  • 13
    Verweel G, Van Rossum AM, Hartwig NG et al. Treatment with highly active antiretroviral therapy in human immunodeficiency virus type-1-infected children is associated with a sustained effect on growth. Pediatrics 2002; 109: e25.
  • 14
    Van Rossum AC, Gaakeer MI, Verweel G et al. Endocrinologic and immunologic factors associated with recovery of growth in children and human immunodeficiency virus type 1 infection treated with protease inhibitors. Pediatr Infect Dis J 2003; 22: 7076.
  • 15
    Miller TL, Mawn BE, Orav EJ et al. The effect of protease inhibitor therapy on growth and body composition in human immunodeficiency virus type 1-infected children. Pediatrics 2001; 107: E77.
  • 16
    Fontana M, Zuin G, Plebani A et al. Body composition in HIV-infected children: relations with disease progression and survival. Am J Clin Nutr 1999; 69: 12821286.
  • 17
    McDermott AY, Shevitz A, Knox T et al. Effect of highly active antiretroviral therapy on fat, lean, and bone mass in HIV-seropositive men and women. Am J Clin Nutr 2001; 74: 679686.
  • 18
    Brambilla P, Bricalli D, Sala N et al. Highly active antiretroviral-treated HIV-infected children show fat distribution changes even in absence of lipodystrophy. AIDS 2001; 15: 24152422.
  • 19
    Verkauskiene R, Dollfus C, Levine M et al. Serum adiponectin and leptin concentrations in HIV-infected children with fat redistribution syndrome. Pediatr Res 2006; 60: 225230.
  • 20
    Arpadi SM, Cuff PA, Horlick M et al. 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 2001; 27: 3034.
  • 21
    Sánchez Torres AM, Munoz Muniz R, Madero R et al. Prevalence of fat redistribution and metabolic disorders in human immunodeficiency virus-infected children. Eur J Pediatr 2005; 164: 271276.
  • 22
    Melvin AJ, Lennon S, Mohan KM et al. Metabolic abnormalities in HIV type 1-infected children treated and not treated with protease inhibitors. AIDS Res Hum Retrovir 2001; 17: 11171123.
  • 23
    Chantry CJ, Hughes MD, Alvero C et al. Lipid and glucose alterations in HIV-infected children beginning or changing antiretroviral therapy. Pediatrics 2008; 122: e129e138.
  • 24
    Horlick M, Arpadi SM, Bethel J et al. Bioelectrical impedance analysis models for prediction of total body water and fat-free mass in healthy and HIV-infected children and adolescents. Am J Clin Nutr 2002; 76: 991999.
  • 25
    Kushner RF, Schoeller DA, Fjeld CR et al. Is the impedance index (ht2/R) significant in predicting total body water? Am J Clin Nutr 1992; 56: 835839.
  • 26
    Wells JC, Cole TJ, ALSPAC study team. Adjustment of fat-free mass and fat mass for height in children aged 8 y. Int J Obes Relat Metab Disord 2002; 26: 947952.
  • 27
    National Center for Health Statistics. National Health and Nutrition Examination Survey, 1999–2000 and 2001–2002 Public use data files. Center for Disease Control and Prevention Home Page. Available at http://www.cdc.gov/nchs/about/major/nhanes/NHANES99-00.htm and http://www.cdc.gov/nchs/about/major/nhanes/NHANES01-02.htm (accessed 15 March 2006).
  • 28
    Paul ME, Chantry CJ, Read JS et al. Morbidity and mortality during the first two years of life among uninfected children born to human immunodeficiency virus type 1-infected women: the women and infants transmission study. Pediatr Infect Dis J 2005; 24: 4656.
  • 29
    McDermott AY, Terrin N, Wanke C et al. CD4+cell count, viral load, and highly active antiretroviral therapy use are independent predictors of body composition alterations in HIV-infected adults: a longitudinal study. Clin Infect Dis 2005; 41: 16621670.
  • 30
    Moye J, Frederick M, Chantry C et al. 10-year follow-up of somatic growth in children born to women infected by human immunodeficiency virus. 8th Conference on Retroviruses and Opportunistic Infections. Chicago, IL, February 4–8, 2001 [Abstract no. 514].