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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e31824330cb
Epidemiology and Prevention

Body Fat Abnormality in HIV-Infected Children and Adolescents Living in Europe: Prevalence and Risk Factors

Alam, Naufil MSc*; Cortina-Borja, Mario PhD*; Goetghebuer, Tessa MD; Marczynska, Magdalena MD, PhD; Vigano, Alessandra MD§; Thorne, Claire PhD*; For the European Paediatric HIV and Lipodystrophy Study Group in EuroCoord

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*MRC Centre of Epidemiology for Child Health, University College London Institute of Child Health, London, United Kingdom

Paediatric Department, CHU St Pierre, Brussels, Belgium

Pediatric Department of Infectious Diseases, Medical University of Warsaw, Wolska, Warszawa, Poland

§Department of Pediatrics, Università di Milano, Luigi Sacco Hospital, Milan, Italy.

Correspondence to: Naufil Alam, MSc, MRC Centre of Epidemiology for Child Health, University College London Institute of Child Health, 30 Guilford Street, London, United Kingdom, WC1N 1EH (e-mail: naufil.alam@ucl.ac.uk).

Supported in part by a grant (40H1) from Istituto Superiore di Sanità, Progetto Nazionale di Ricerca sull “AIDS 2009-10.” N. Alam is supported by a Medical Research Council PhD studentship. C. Thorne is supported by a Wellcome Trust Research Career Development Fellowship. Great Ormand Street Hospital/University College London: UK DoH National Institute for Health Research Biomedical Research Centers funding scheme. The ECS was a coordination action of the European Commission (PENTA/ECS 018865), and the research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under EuroCoord grant agreement no. 260694 (www.eurocoord.net).

The members of the European Paediatric HIV and Lipodystrophy Study Group are as follows. Belgium: Dr T. Goetghebuer, Dr M. Hainaut, Dr A. Vanderfaeillie, Dr C. Epalza, E. Van der Kelen, and Prof. J. Levy (Hospital Universitaire St. Pierre, Brussels), Dr B. Brichard and H. Waterloos (Hospital Universitaire St Luc, Brussels), and Dr V. Schmitz (Centre Hospitalier Regional La Citadelle, Liege); Italy: Dr R. Badolato (University of Brescia), Prof. L. Galli (University of Florence), Dr R. Rosso, Dr G. Secondo, and Prof. C. Viscoli (University of Genoa), Dr F. Salvini (San Paolo Hospital Milan), Dr A. Vigano, Dr V. Giacomet, Dr V. Fabiano, and Prof. G.V. Zuccotti (Luigi Sacco Hospital Milan), DR. A. Lo Vecchio and Dr E. Nicastro (University Frederico II, Naples), Dr C. Giaquinto and Dr O. Rampon (Univeristy of Padua), Dr S. Bernardi, Dr G. Pontrelli, and Dr H. Tchidjou (Bambino Gesù Hospital, Rome), Dr C. Gabiano, Dr E. Silvestro, and Dr F. Mignone (University of Turin), and Prof. A. Maccabruni (University of Pavia); Poland: Dr M. Marczynska, Dr M. Kaflik, Dr S. Dobosz, Dr J. Popielska, and Dr A. Oldakowska (Medical University Warsaw/Regional Hospital of Infectious Disease).

The authors C. Thorne and A. Vigano contributed to study concept and C. Thorne, A. Vigano, and T. Goetghebuer contributed to study design. A. Vigano, T. Goetghebuer, M. Marczynska, and members of the European Paediatric HIV and Lipodsytrophy Study were involved in the acquisition of data. N. Alam performed the data management and statistical analyses, with support from M. Cortina Borja. N. Alam drafted the manuscript, which all authors critically revised for important intellectual content. All authors read and approved the final manuscript.

The authors have no conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jaids.com).

Received July 6, 2011

Accepted November 18, 2011

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Abstract

Objectives: To estimate the prevalence of and identify risk factors for lipodystrophy syndrome (LS) and body fat abnormality in a population of HIV-infected children and adolescents.

Design: Cross-sectional observational study.

Methods: HIV-infected subjects aged 2–18 years were recruited from 15 HIV centers in Belgium, Italy, and Poland between January 2007 and December 2008. Standardized assessments by the patient's long-term clinician were performed to establish the presence of abnormality. Risk factors were explored in logistic regression models for fat abnormality outcomes and LS (abnormality plus dyslipidemia).

Results: Among 426 subjects (70% white), median age was 12.2 years (interquartile range: 9.0–15.0 years) and median duration of antiretroviral therapy was 5.2 years (interquartile range: 2.2–8.8 years). Prevalence was 57% (n = 235) for LS and 42% (n = 176) for fat abnormality; 90 subjects with abnormality were affected in ≥3 locations. Lipoatrophy occurred in 28% (n = 117) of subjects and lipohypertrophy in 27% (n = 115), most commonly in the face and trunk, respectively. In multivariable analysis, white ethnicity, body mass index, ritonavir/lopinavir, and nonnucleoside reverse transcriptase inhibitors were each associated with an increased risk of LS (P < 0.05). White ethnicity, history of Centers for Disease Control and Prevention–defined disease, and stavudine were associated with risk of lipoatrophy (P < 0.05). Increased risk of lipohypertrophy was associated with body mass index and prior HIV disease.

Conclusions: Fat abnormality was prevalent in close to half of children and adolescents, who had accumulated long treatment durations. Risk of fat abnormality was associated with specific drugs, including stavudine and ritonavir, and other variables. Our results underline the importance of continued surveillance of children treated with antiretroviral therapy.

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INTRODUCTION

Lipodystrophy syndrome (LS), characterized as body fat abnormality and/or metabolic disturbances, has been associated with antiretroviral therapy (ART) in HIV-infected adults1–7 and children.8–11 Less is known about LS in children and adolescents than in adults because most pediatric studies have been cross-sectional and/or of limited size.11–15 Furthermore, investigation of LS in children is hampered by the lack of a consensus definition as that exists for adults.16

Investigation of LS in childhood and its relationship with ART is increasingly important given the continued high prevalence and incidence of pediatric HIV worldwide17 and the increasing availability and use of ART,18 resulting in substantially improved AIDS-free survival and reduced morbidity.19–21 The recommendation that all HIV-infected infants start ART and the fact that therapy is usually life-long22,23 will result in children receiving ART for increasingly long durations, being exposed to drugs at critical points in physiological development, and accumulating exposures to multiple regimens; the impact of this on LS pathogenesis is unknown.

The European Paediatric HIV and Lipodystrophy Study Group has established a cohort of HIV-infected children and adolescents to investigate LS. Our objectives here are to characterize the cohort to estimate the prevalence of LS, lipoatrophy and lipohypertrophy, and to identify risk factors, in cross-sectional analysis conducted at baseline.

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METHODS

HIV-infected children and adolescents were recruited between January 2007 and December 2008, in 15 pediatric HIV centers in Belgium (3), Italy (11) and Poland (1). Most sites were concurrently participating in the European Collaborative Study8 and/or the Italian Register of HIV Infection in Children.24,25 All HIV-infected children older than 2 years and adolescents 18 years or younger who were under care were invited to participate, regardless of ART history. Patients treated with anabolizing steroids in the previous 6 months were excluded. Ethical approval was obtained according to local procedures. At recruitment, a screening questionnaire for each subject was completed by their clinician to collect baseline demographic and clinical characteristics.

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Variables and Definitions

Subjects were classified by age at enrollment (2–6, 7–11, and 12–18 years) and by pubertal stage using the Tanner scale (I, pre-pubertal; II–III, intermediate stages; and IV–V, completion of puberty).26 Degree of immunosuppression was assessed using CD4 percentages according to the Centers for Disease Control and Prevention (CDC) classification.27,28 Nadir and recruitment CD4 cell counts were recorded. Similarly, maximum and recruitment HIV clinical status, according to the CDC classification,29 were collected. Viral load (undetectable defined as HIV RNA <50 copies per milliliter) at enrollment was recorded. Complete ART history was collected. Highly active antiretroviral therapy (HAART) was defined as at least 3 ART drugs, including ≥1 nucleoside reverse transcriptase inhibitors (NRTIs), with ≥1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) or ≥1 protease inhibitors (PIs). Triple-class therapy was defined as ART including at least 1 PI, 1 NRTI, and 1 NNRTI.

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Outcomes

Body fat abnormality was assessed after clinical examination and classified as none, mild, moderate, or severe. “Mild” abnormality symptoms were defined as those only noticeable when specifically inspected, “moderate” as those readily obvious to the child/carer and physician, and “severe” as those obvious to a casual observer. This assessment was made by the child's principal clinician, who had usually provided long-term care. Specific body locations were inspected. Lipoatrophy was defined as fat loss in one or more of the following sites: face (sunken cheeks/eyes, or prominent zygomatic arch), arms and legs (skinny with prominent veins, muscularity, or bones), and buttocks (loose skin folds, prominent muscles, or loss of contour and fat, or hollowing). Lipohypertrophy was defined as fat gain in one or more of the following sites: trunk (increased abdominal girth), base of neck/back (“buffalo hump”), or breast enlargement. Hypercholesterolemia and fasting hypertriglyceridemia were defined according to age and sex thresholds.30 The definition of LS incorporated fat abnormality (lipoatrophy and/or lipohypertrophy) and/or metabolic disturbance (hypercholesterolemia and/or fasting hypertriglyceridemia and/or impaired fasting glucose: defined as fasting plasma glucose ≥100 mg/dL). Outcomes investigated were any fat abnormality, lipohypertrophy, lipoatrophy, combined phenotype of both lipohypertrophy and lipoatrophy, and LS.

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Statistical Methods

Associations between body fat abnormality and demographic and clinical characteristics were investigated using χ2 tests. ART use, both individual and class, was assessed as dichotomous variables (current/noncurrent; ever/never use at enrollment). Duration of cumulative ART exposure was estimated as the difference between earliest start date and enrollment date. Comparisons of median values of continuous measures [eg, body mass index (BMI), serum cholesterol] between groups used Kruskal–Wallis tests.

Risk factors for outcomes were identified using logistic regression models. The final multivariable models were selected using a backward stepwise approach. All multivariable models retained age and duration of ART at recruitment and contained a random effect for clinical site as potential confounders a priori. Tanner score was not included in the models to prevent overadjustment for puberty. Variables were systematically removed from the saturated model containing all explanatory variables until those remaining were significant at the 5% level. Discarded variables were then methodically reintroduced to investigate any influence on effect size and statistical significance. All possible variable combinations were investigated in nested models; reintroduced variables were retained, and the process was repeated if reintroduction resulted in a change in effect size >10% in other variables or was itself statistically significant. The final optimal models were those where all variables were significant at 5%. Models were investigated to ensure that missing data had no impact. For each outcome, multivariable models were constructed using specific ART drugs and using ART class. Additional multivariable models were used to estimate the association of current regimen (NRTI monotherapy, PI/NNRTI-based HAART, and triple-class ART) with each outcome. All statistical analyses were conducted using STATA 11.1 (STATA Corp).

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RESULTS

The study population included 426 children and adolescents, with median age of 12.2 years [interquartile range (IQR): 9.0–15.0 years], and 70% (285/409) of white ethnicity (Table 1). Ninety-eight percent of the study population (n = 400) was vertically infected. Overall, 6% (25/416) of the study population was coinfected with hepatitis C virus. At recruitment, most subjects were either asymptomatic or had mild symptoms (>85% across all age groups), showed no immunosuppression (>75%), and had undetectable viral load (>58%). However, 23% of subjects 12 years or older had previously experienced severe immunosuppression, with 23% of these having experienced severe clinical symptoms.

Table 1
Table 1
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Table 1
Table 1
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Twenty-nine participants were not receiving ART at recruitment (Table 1), all were ART-naive, and a further 33 had ART history missing. More than 90% of the 364 participants on ART at enrollment were receiving HAART. The most common NRTI in current use was lamivudine (n = 247) and the most common NNRTI was efavirenz (n = 94). Ninety percent (n = 197) of the 218 subjects receiving PIs were on ritonavir-boosted regimens. Median duration of ART was 5.2 years (IQR: 2.2–8.8 years). Median ART duration was higher in subjects with body fat abnormalities and/or metabolic abnormalities compared with those without: none of these differences reached statistical significance (see Table, Supplemental Digital Content 1, http://links.lww.com/QAI/A242). Median age at treatment initiation was 5.8 years (IQR: 2.6–9.9 years), with the youngest children starting ART earlier compared with the oldest age group (P < 0.001) (Table 1).

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Prevalence of Body Fat Abnormality and LS

Prevalence of body fat abnormality was 42% (176/422) and that of lipohypertrophy and lipoatrophy was 27% (n = 115) and 28% (n = 117), respectively (Fig. 1); 4 subjects were excluded due to missing information. High prevalence of fat abnormality was reported in the following groups: those currently receiving stavudine (30/44; 68%), efavirenz (49/93; 53%), or triple-class ART (9/13; 69%) as illustrated in Supplemental Digital Content 2 (see Table, http://links.lww.com/QAI/A243). Prevalence was also high in hepatitis C virus–positive subjects (16/24; 67%) and in children with experience of CDC stage C disease (45/87; 52%). Children aged 2–6 years at enrollment had the lowest prevalence of body fat abnormality (7/43; 16%).

Figure 1
Figure 1
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Median BMI was 18.6 kg/m2 (IQR: 16.4–21.4) and differed according to the presence or absence of body fat abnormality [19.4 (IQR: 17.1–22.5) vs 17.8 (16.1–20.2), respectively, P < 0.001] and of lipohypertrophy [21.3 (18.5–23.7) vs 17.6 (16.2–19.9), P < 0.001]. Significant differences in waist–hip ratio were seen among 12- to 18-year-olds by the presence or absence of LS, fat abnormality, lipohypertrophy in male population, and of lipoatrophy in female population (P < 0.05, data not shown). Prevalence of metabolic disturbance in subjects with fat abnormality was 28% (49/174): 24 (14%) had hypercholesterolemia, 30 (17%) had fasting hypertriglyceridemia, and 6 (3%) had impaired fasting glucose (metabolic data unavailable for 2 subjects).

Figure 2 highlights severity of abnormality by body site among the 176 subjects with fat abnormality: 53% had lipoatrophy in the face, 50% in the arms, 51% in the legs, and 40% in the buttocks, whereas 59% had lipohypertrophy in the trunk, 21% in the neck, and 29% in the breasts. Eighty-seven (74%) of the 117 subjects with lipoatrophy and 53 (46%) of the 115 subjects with lipohypertrophy were affected in ≥2 locations. More than 51% (n = 90) of subjects with fat abnormality showed ≥3 signs of abnormality, with 15% (n = 27) and 28% (n = 50) having 2 signs or 1 sign, respectively. More than half (62%) of those with 1 sign had mild (n = 25) or moderate (n = 6) truncal lipohypertrophy, whereas 22% (n = 11) had mild facial lipoatrophy. There were significant differences in patterns of fat abnormality by sex (see Table, Supplemental Digital Content 3, http://links.lww.com/QAI/A244), with more lipohypertrophy in females versus males in the trunk [30% (63/212) vs 19% (38/199), P < 0.05] and in the neck [11% (24/212) vs 6% (24/212), P < 0.05]. Overall, there was greater prevalence of lipoatrophy in the arms, legs, and buttocks in the age group of 12–18 and 7–11 years compared with the age group of 2–6 years (P < 0.05) (see Table, Supplemental Digital Content 4, http://links.lww.com/QAI/A245).

Figure 2
Figure 2
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Prevalence of LS was 56.5% (235/416) [95% confidence interval (CI): 51.7 to 61.3]; most LS cases were defined on the basis of fat abnormality with (n = 49) or without (n = 127) metabolic disturbance rather than metabolic disturbance alone (n = 59); 10 children were excluded from this analysis due to missing data on metabolic disturbance or fat abnormality. Among the 108 subjects with metabolic disturbance, 47 (45%) had isolated fasting hypertriglyceridemia, 29 (28%) had isolated hypercholesterolemia, 4 (4%) had impaired fasting glucose only, 22 (21%) had combined hypercholesterolemia and fasting hypertriglyceridemia, and 1 (1%) each having either hypercholesterolemia with fasting hypertriglyceridemia, hypercholesterolemia with impaired fasting glucose, or all 3 metabolic outcomes; 3 subjects excluded due to missing data.

Six of the 29 ART-naive participants had body fat abnormalities, significantly fewer than among those nonnaive [20.7% vs 43.3% (170/393), χ2 test: P < 0.05]: 1 had mild buttock lipoatrophy; 3 had moderate trunk or mild neck lipohypertrophy; 1 had severe trunk, moderate breast, and mild neck lipohypertrophy; and 1 had the combined phenotype (moderate lipoatrophy in face, arms, and legs, mild buttock lipoatrophy, and mild breast lipohypertrophy).

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Factors Associated With Body Fat Abnormality and LS

In univariable analyses (Table 2), white ethnicity and history of moderate or severe HIV symptoms were associated with an increased risk of all outcomes. Older age was associated with all outcomes except LS. Subjects experiencing or with completed puberty were more likely to have fat abnormality than prepubescent children, but this association was not seen for LS. Current and ever use of NRTI, and specifically stavudine, was associated with a 2- to 5-fold increased risk of LS, fat abnormality, and lipoatrophy (Table 2; see Table, Supplemental Digital Content 5, http://links.lww.com/QAI/A246). In contrast, current use of zidovudine was associated with a 40%–75% decreased risk of fat abnormality, lipoatrophy, and the combined phenotype. Use of efavirenz was associated with significant increased risk of all fat abnormality outcomes, whereas current PI use was associated with a 60% increased LS risk and ever use of PI with a 2-fold increased risk of all outcomes.

Table 2
Table 2
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Table 2
Table 2
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In multivariable models including specific drugs as explanatory variables (Table 3), white ethnicity was associated with a 3–4 times increased risk of LS, fat abnormality, lipoatrophy, and the combined phenotype. Subjects with past CDC stage B/C disease were twice as likely to have fat abnormality, lipoatrophy, and lipohypertrophy compared with other subjects. Prior severe immunodeficiency was significantly associated with a reduced risk of lipoatrophy. Current stavudine was associated with a 5-fold increased risk of fat abnormality (3.5-fold for ever use) and a 3-fold increased risk of lipoatrophy (5-fold for ever use) and LS (Table 3; see Table, Supplemental Digital Content 6, http://links.lww.com/QAI/A247). Current efavirenz was associated with a 2- to 3-fold increased risk of both LS and body fat abnormality and nevirapine with a 3-fold increased risk of LS. Current lamivudine and zidovudine use was associated with a reduced risk of the combined phenotype; although no current drugs were associated with an increased risk of this phenotype, ever use of efavirenz, didanosine, lopinavir, and indinavir were associated with a 2- to 4-fold increased risk.

Table 3
Table 3
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In refitted models including current ART class, current NNRTI use was associated with an increased risk of fat abnormality [adjusted odds ratio (AOR), 1.97; 95% CI: 1.11 to 3.50], lipohypertrophy (AOR, 2.49; 95% CI: 1.08 to 5.78), combined phenotype (AOR, 6.45; 95% CI: 1.62 to 25.71), and LS (AOR, 2.78; 95% CI: 1.20 to 5.45), whereas current PI use was associated with an increased risk of LS (AOR, 2.56; 95% CI: 1.26 to 6.11) and combined phenotype (AOR, 5.41; 95% CI: 1.36 to 24.48).

To explore the association between triple-class therapy and body fat abnormality, new models adjusted for age, ART duration, and site were tested. Triple-class therapy was a significant risk factor for fat abnormality (AOR, 4.68; 95% CI: 1.07 to 20.5), lipohypertrophy (AOR, 3.67; 95% CI: 1.07 to 12.65), lipoatrophy (AOR, 5.13; 95% CI: 1.0 to 22.0), and the combined phenotype (AOR, 4.35; 95% CI: 1.11 to 17.03).

Repeating the model selection procedure with the inclusion of an interaction between age and sex demonstrated a lack of significance for any outcome. Sensitivity analyses were conducted using the outcome of moderate/severe versus no/mild fat abnormality. Similar directions of association were found although not all risk factors reached statistical significance (data not shown).

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DISCUSSION

More than half of this cohort of HIV-infected children and adolescents (56%) presented with LS and 42% with body fat abnormality: 1 in 2 with moderate or severe abnormalities. Among the subjects with fat abnormality, the proportions with lipohypertrophy-only, lipoatrophy-only, and the combined phenotype were roughly equal at approximately one third each. Factors associated with risk of body fat abnormality included white ethnicity, history of symptomatic HIV disease, and use of specific ART.

The prevalence of fat abnormality in this study was substantially higher than the 18%–33% reported in other pediatric studies,8,10–12,31–33 reflecting variations in LS definitions and methodology, and underlying population differences. However, restricting the definition to moderate and severe cases, resulted in a prevalence of 19%. LS development may be a graded progressive process; furthermore, the natural development of adipose tissue in childhood may have a protective effect against LS, which wanes during and after puberty.31 Thus, the comparatively older age of our participants (median age of 12.2 years compared to the mean of 7.5–11.0 years in the cited studies) may also partly explain the greater prevalence we observed.

In our unadjusted analysis, subjects undergoing puberty or with completed puberty had a 2- to 3-fold increased risk of fat abnormality. We excluded Tanner score from our adjusted models as sex and age were included, and we did not want to overadjust for puberty. In separate analyses where Tanner score was included in our stepwise modeling, it remained significantly associated with fat abnormality in the final model, giving credence to the role of puberty in LS (data not shown). In analyses adjusting for ever-use of ART, there was a significant 17% and 13% increased risk of lipoatrophy and of the combined phenotype per year of age. The similar associations with age reported in adults are generally of a smaller magnitude: In the Swiss HIV Cohort, there was an 18% increased risk of fat abnormality per decade increase in age at baseline.34 It is not certain to what extent such changes are the result of “normal” age-associated fat gain unrelated to HIV in adults.34 The pattern of body fat abnormalities here, with the trunk the most and the neck the least common location, is similar to reports from adult studies2,35 but somewhat dissimilar to that reported in children,8 possibly reflecting the older age of our population.

Lipohypertrophy in the trunk reported in a HIV-seronegative individual undergoing postexposure prophylaxis36 together with animal studies37–39 indicate that ART may be central in LS pathogenesis. However, our finding that some ART-naive children develop fat abnormalities is consistent with a multifactorial process, including possible direct action of HIV itself.40 We demonstrated an increased risk of LS and/or the combined lipoatrophy/lipohypertrophy phenotype associated with current and past PI use. PI use has been inconsistently shown to be associated with lipoatrophy in adults,2,41,42 with data from cross-sectional pediatric studies similarly conflicting.8,11,12,32 Postulated mechanisms behind PI use and lipoatrophy include inhibition of proteins involved in lipid metabolism43–45 and insulin dysregulation.44,46

NRTI use has been strongly implicated in the pathogenesis of fat abnormalities, particularly lipoatrophy,41 with potential mechanisms including mitochondrial damage in adipocytes47 and inhibition of adipogenesis.48 Our findings with respect to stavudine are consistent with previous reports8,11,32,34,42,49–53; more than 10% of our subjects were currently receiving stavudine, despite current guidelines.22

One third of our subjects had both lipoatrophy and lipohypertrophy. Increasing age and BMI and past use of some specific drugs (from all 3 classes) were associated with an increased risk of this combined phenotype, whereas current lamivudine and zidovudine use was associated with a significantly reduced risk. In subgroup analysis, this latter association seemed to be driven by males and children older than 11 years (data not shown). The associations of the combined phenotype with age and past drug exposure suggest that its emergence may be progressive and associated with cumulative ART exposure over time.

Current nevirapine use was associated with an increased risk of LS, whereas associations between LS and fat abnormalities were demonstrated with past and/or current use of efavirenz. Although the association of NNRTIs with fat abnormality has not been investigated in child/adolescent studies, our results are consistent with adult studies.54–56 Pediatric reports have described associations between longer treatment duration and increased risk of fat abnormality in body fat abnormality11,24 unlike in our investigation.

Experience of more serious HIV disease was associated with body fat abnormality, lipohypertrophy, and lipoatrophy, in accordance with an earlier multisite European pediatric study.8 Several studies have identified immunosuppression as an independent risk factor for lipoatrophy42,57 and fat abnormality.58 Indeed, results from the prospective HIV Outpatients Study demonstrating association between low CD4 counts and lipoatrophy independent of ART led to the hypothesis that factors associated with more advanced HIV disease predispose individuals to later develop LS.42

Reports in children and adults8,10,11,31,34,50,51,59,60 demonstrated that females were more likely to have fat abnormality, lipohypertrophy, and the combined phenotype than males, possibly due to hormonal or pharmacokinetic differences.61 We found no association between female sex and increased risk of lipohypertrophy in adjusted analyses, although there was a significant association between sex and lipohypertrophy in the trunk or neck.

Around two thirds of our cohort was of white ethnicity, associated with 3 to 4 times increased risk of lipoatrophy and fat abnormality, consistent with other studies.49,59,62 Underlying genetic differences between ethnic groups may explain these findings, the metabolic syndrome having been shown to occur less frequently in individuals of black compared with white ethnicity in non–HIV-infected populations.63

Several studies have reported a negative impact of body fat changes on self-esteem and psychological profile in HIV-infected adults,64–66 which has been linked to nonadherence to ART.67,68 Little is known about the impact in children or adolescents,69 but this is likely to be an issue for adolescents, given that this is a time when self-image is important. Our study did not collect information on self-reported body image, but the fact that approximately 7% of children and adolescents had severe and potentially stigmatizing fat loss or gain demonstrates the need for further research.

A limitation of our study is its observational nature and the potential for confounding. Some previous studies have relied on self-reported changes potentially leading to over-reporting of body shape changes.65 Our approach, with fat abnormality assessed according to strictly defined criteria using a scale of severity by the child's established clinician, avoids such misclassification but remains a subjective measure. A minority (28%; 50/176) of body fat abnormality cases were based on abnormality in a single body site; only 31 subjects (7% of all participants) were categorized as having fat abnormality on the basis of trunk lipohypertrophy alone (26 mild and 5 moderate). Furthermore, risk factors identified in our main analyses were confirmed by sensitivity analyses investigating moderate/severe fat abnormality (although not necessarily reaching statistical significance). However, given that the clinician would be aware of the ART status of the patient when making the assessment of fat abnormality, the potential for bias cannot be discounted. Our multisite design provided us with a large sample size compared with previous pediatric studies, resulting in a diverse study sample and good generalizability. We addressed potential systemic differences in clinical practice by incorporating a random effect for clinical site within our models. Finally, the analyses presented here are based on recruitment data and thus limited by their cross-sectional nature. We are collecting longitudinal data on our cohort and will be able to address issues including incidence and progression or regression of fat abnormality in the future.

Our study suggests that body fat abnormality occurs in almost half of HIV-infected children and adolescents, with the same complex range of phenotypes as seen in adults. Moreover, associated risk factors in this population are similar to those seen in adults, with both ART-related and demographic/clinical factors identified. In our cohort of HIV-infected children, most will have accumulated at least a decade of exposure to multiple drugs by the time they become adults. This underscores how important it is to monitor and investigate the long-term implications of life-long HIV and ART use.

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Keywords:

children; adolescents; lipodystrophy syndrome; fat abnormality; antiretroviral therapy

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