The Effect of Antiretroviral Therapy (ART) on Body Composition and Clinical Markers of Lipodystrophy in HIV-Infected Children Assessed in Follow-Up Study

doi:10.4236/wja.2012.23033

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World Journal of AIDS, 2012, 2, 252-258

doi:10.4236/wja.2012.23033 Published Online September 2012 (http://www.SciRP.org/journal/wja) 249

The Effect of Antiretroviral Therapy (ART) on Body

Composition and Clinical Markers of Lipodystrophy in

HIV-Infected Children Assessed in Follow-Up Study

Agnieszka B. Dzwonek1, Vas Novelli1, C. Smith2, Margaret Lawson3

1Clinical Infectious Diseases Unit, Great Ormond Street Children’s Hospital NHS Trust, London, UK; 2Research Department of In-

fection and Population Health, University College London Medical School, London, UK; 3Childhood Nutrition Research Centre,

Institute of Child Health, University College London, London, UK.

Email: Vas. [email protected]

Received April 16th, 2012; revised May 16th, 2012; accepted June 1st, 2012

ABSTRACT

Objectives: An tiretroviral therapy (ART) has been associated with lipodystrophy in childr en. We evaluated chang es in

various anthropometric measurements for the assessment of lipodystrophy and assessed whether there was an associa-

tion with use of protease inhibitors (PI), non-PI containing ART and/or stavudine (d4T). Methods: Eighty-five

HIV-infected children attending the HIV clinic at Great Ormond Street Hospital (GOSH) were included. The average

follow-up was 8.4 months (range 3 - 12 months). Body fat redistribution was assessed by anthropometric measurements

including skinfold thickness and circumferences of upper and lower limbs. Measurements were converted to age- and

sex- adjusted z-scores through development stages including puberty. Results: Sixty children had taken ART; 37 re-

ceived PI-containing; 38 received d4T; 25 had never been treated. In the studied population, clinically important

changes with decreases in biceps (BSF), subscapular skinfolds and total body fat (4SFT) over period of 12 months were

observed. Some increase was noticed in triceps skinfolds (TSF). Limbs circumferences remained at the same level.

Further we looked at 4 months basis changes in anthropometric measurements stratified by baseline ART. Generally

z-scores of anthropometric measurements were lower in therapy naive children when compared to ART groups.

PI-based ART regimens resulted in significant increases in BSF with a trend towards increases in TSF, suprailiac and

4SFT. Mid-arm and thigh circumferences were higher in PI compared to naive group. Similarly, significant changes in

BSF z-scores were associated with d4T use. Increases were seen in TSF and mid-arm circumference and decreases were

observed in subscapular skinfolds and calf circumference z-scores. Conclusions: Body fat redistribution in HIV-in-

fected children with sub-clinical lipodystrophy could be detected by anthropometric measurements, particularly when

PI or d4T is included in ART. Over time, changes with increase in arm and trunk fat, and no change or decrease in leg

fat were more pronounced among ART-receiving children.

Keywords: Body Fat Redistribution; Anthropometric Measurements; HIV; Children; Art

1. Introduction

Although survival in HIV-infected children has greatly

improved with the introduction of antiretroviral therapy

(ART), a lipodystrophy syndrome has emerged [1-6].

This encompasses abnormal distribution of adipose tissue,

peripheral wasting, insulin-resistance and dyslipidaemia.

Children may be more vulnerable than adults because of

the potential impact of growth, as well as children’s

likely greater cumulative exposure [7].

The lipodystrophy syndrome has been mostly studied

via cross-sectional studies [2-6,8,9 ]. Determination of the

prevalence of lipodystrophy has b een compli cated by the

lack of an objective case definition for use in children.

Further, assessment of lipodystrophy is complicated by

the different methodologies used to assess its components

across studies.

The recent European Collaborative Study estimated a

42% prevalence of body fat abnormality in 426 HIV-

infected children and adolescents based on clinical ob-

servation (peripheral lipoatrophy and/or central lipo-

hypertrophy) [8]. A prevalence of fat abnormality in this

study was substantially higher than the proportion of

about 25% reported in other previous paediatric studies

[2-4,6,10].

Clinical lipodystrophy, metabolic changes and insu-

lin-resistance have been reported to worsen at puberty.

Some studies have shown that ethnicity, clinical condi-

tion, duration of HIV infection, nucleoside reverse tran-

The Effect of Antiretroviral Therapy (ART) on Body Composition and Clinical Markers of Lipodystrophy

in HIV-Infected Children Assessed in Follow-Up Study 253

scriptase inhibitor (NRTI) and protease inhibitor (PI)

treatment were associated with lipodystrophy [9-12].

The objectives of this observational follow up study

were to investigate changes in anthropometric measure-

ments in a cohort of HIV-infected children on different

ART regimens over study period and to assess whether

there was an association between PI and d4T use with

these measurements.

2. Methods

2.1. Patients Population

We studied HIV-infected children older than three years

attending the HIV Family Clinic at Great Ormond Street

Children’s Hospital (GOSH) NHS Trust, London, UK

between 2002 and 2004. Relevant ethical approval was

granted by the Institute of Child Health and GOSH Re-

search Ethics Committee and Informed consent was ob-

tained. Recent steroid therapy or wasting from other

causes (e.g. disuse atrophy) were criteria for exclusion.

Of the 128 HIV-infected children identified as eligible

during the study period, 113 (88%) participated but only

those with follow-up visits (n = 85) were included in the

analysis. Clinical details and drug history were extracted

from the Collaborative HIV Paediatric Study (CHIPS)

database. The HIV clinic at GOSH follows Paediatric

European Network for Treatment of AIDS (PENTA)

guidelines for initiating antiretroviral therapy [13]. Gen-

erally, ART is started in p atients with persistently low or

declining CD4 counts, or with clinical deterioration.

2.2. Anthropometric Measurements

After study enrolment, measurements were taken at clinic

visits scheduled every three to four months. Trained phy-

sician for taking anthropometric measurements (AD)

collected data over 3 year’s period and all children who

attended HIV Family Clinic and who agreed on that par-

ticular visit to participate in the study were included in

the analysis. Before anthropometric measurements were

obtained, all children had a general physical examination,

including observation for clinical features of peripheral

lipoatrophy and central lipohypertrophy. Weight and

height were recorded, and body mass index (BMI: kg/m2)

was calculated. Skinfold thickness, triceps (TSF), biceps

(BSF), subscapular and suprailiac, were measured using

the Harpenden Skinfold Calliper (Holtain Ltd., Crymych

UK). The sum of these four skinfold sites was calculated

as an indication of total body fat. Peripheral adiposity

was assessed by measuring midupper arm (MAC), thigh

and calf circumferences using a narrow one-metre tape

(Chasmors Ltd., London UK). Triplicate skinfold and

circumference measurements were undertaken by the

same trained researcher (AD). The mean value of the

three measurements was used in the analysis. Skinfold

and circumference measurements were converted to age-

and sex-adjusted z-scores (the distance of the value from

the age- and sex-appropriate mean) using Dutch refer-

ence data and a SPSS programme developed at the Insti-

tute of Child Health, UCL, described previously [9,14].

2.3. Statistical Analyses

The dates of the first anthropometric measurements per-

formed on each child were defined as baseline. The 4-

month measurements of the anthropometric markers

were found by creating a window 2 months either side

(i.e. from 2 - 6 months), and the nearest measurement

that took place within this window was taken as the four

month measurement. Similar approach was used for 8

and 12 months. The median and interquartile range val-

ues at baseline, 4, 8 and 12 months for each anthro-

pometric measurement were calculated. Furthermore, the

change from baseline at 4, 8 and 12 months was also

calculated. This analysis was then repeated stratified by

antiretroviral regimen at baseline and compared using a

Kruskall Wallis test. Analyses were performed using

SAS version 9.0 (SAS Institute Inc., Cary, NC, USA).

3. Results

Amongst 113 children enrolled in the study between

2002 and 2004, 85 children had follow up anthropomet-

ric measurements. Their median (range) age was 9.7

years (3.0 - 15.7 years). All had vertically acquired HIV-

1 infection and 90% were of black Sub-Saharan African

origin. Eighty five children included in analyses had two

or more visits. The majority (n = 38) had three visits,

with 34 children having 2 visits and 13 having four or

more. These resulted in total of 237 clinic visits when

measurements were taken over study period. The average

time of observation was 0.7 years ranging from 3 to 12

months. Characteristics of the studied group are pre-

sented in Table 1. At enrolment, 51 children (60%) were

receiving ART therapy. Of these, 24 children (47%) were

receiving a protease inhibitor (PI) based regimen. Forty

one per cent of currently treated (21/51) children with

ART at the entry to the study received d4T, including 8

children who were receiving both a PI-s and d4T therapy.

Thirty-four children (40%) were not on any treatment at

enrolment, including 9 who had been previously treated,

but had stopped therapy in the 6 months before entry.

Twenty five children had never been treated with ART.

In the past, 37 children had been exposed to PI-based

ART and 38 children to d4T.

3.1. Study Population

The median (range) age- and sex-adjusted z-scores at the

The Effect of Antiretroviral Therapy (ART) on Body Composition and Clinical Markers of Lipodystrophy

in HIV-Infected Children Assessed in Follow-Up Study

254

Table 1. Characteristics of children included in the analysis at time of the first measurements.

N (%)

Number 85

Gender Male 37 (43.5%)

Female 48 (56.5%)

Age (years) Median (range) 9.7 (3.0 - 15.7)

CD4 T cells percentage <15% 17 (20.0%)

15% - 25% 27 (31.8%)

>25% 36 (42.3%)

Unknown 5 (5.9%)

Weight (kg) Median (range) 29.9 (14.8 - 68.4)

Height (cm) Median (range) 130.8 (93.7 - 181.9)

BMI (kg/m2) Median (range) 17.4 (13.6 - 25.8)

CDC stage A 23 (27.0%)

B 42 (49.4%)

C 20 (23.6%)

ART use Current 51 (60.0%)

Previous 9 (10.6%)

Never 25 (29.4%)

Total period of ART use (years) Median (range) 4.6 (0.0 - 13.9)

PI use Current 24 (28.25%)

Previous 37 (43.5%)

Never 24 (28.25%)

Total period of P I use (years) Median (range) 3.8 (0.0 - 5.5)

D4T use Current 21 (24.7%)

Previous 38 (44.7%)

Never 26 (30.6%)

Total period of d4T use (years) Median (range) 2.7 (0.0 - 5.4)

first visit when baseline anthropometric measurements

were taken for the 85 children for biceps, triceps, sub-

scapular, suprailiac skin folds and sum of four skin folds

were 1.22 (+0.22 - +2.5), +0.21 (–0.61 - +1.56), +1.34

(+0.12 - +3.14) , –0.43 (–1.00 - +0 .41) and +0.58 (–0 .37 -

+1.93), respectively. For mid arm, thigh and calf cir-

cumferences, these z-scores were –0.76 (–1.73 - +0.35),

–0.83 (–1.92 - –0.11) and -1.26 (–2.28 - –0.22). These

data are presented in Table 2. Clinically important

changes were observed in biceps skinfold thickness (BSF)

and subscapular skinfolds z-scores, with decrease in

z-scores measured over period of 12 months. Triceps

skinfolds (TSF) z-score showed some increase in 12

months, in comparison to baseline measurements. Mid-

arm (MAC), thigh and calf circumferences z-scores in-

creased over studied time when compare to baseline

z-scores measurements. Sum of four skinfolds z-scores

measurements did not appear to change over 12 months

observation period.

3.2. PI-s vs Naive Group 4-Month Changes

Table 3 shows changes in body skinfolds measurements

at 4 months stratified by baseline ART regimen. There

are some changes in regional fat measured by skinfolds

The Effect of Antiretroviral Therapy (ART) on Body Composition and Clinical Markers of Lipodystrophy

in HIV-Infected Children Assessed in Follow-Up Study 255

Table 2. Changes in body fold measurements at 4, 8 and 12 months.

Baseline 4 months 8 months 12 months

Median (IQR) value N Median (IQR)

change N Median (IQR)

change

Biceps SKF +1.22

+0.22 - +2.50 37 +0.50

–0.22 - +1.26 29 +0.95

–0.65 - +1.21 21 +0.72

–0.36 - +1.67

Triceps SKF +0.21

–0.61 - +1.56 41 +0.25

–0.31 - +0.56 37 –0.11

–0.42 - +0.32 24 +0.55

+0.09 - +1.92

Subscapular SKF +1.34

+0.12 - +3.14 39 +0.36

–0.16 - +1.10 37 +0.20

–0.52 - +1.29 23 +0.71

–0.21 - +2.21

Suprailiac SKF –0.43

–1.00 - +0.41 40 +0.10

–0.24 - +0.38 37 –0.21

–0.45 - +0.10 23 +0.24

–0.15 - +0.56

Sum of 4 skinfolds +0.58

–0.37 - +1.93 34 +0.14

–0.20 - +0.60 29 –0.14

–0.57 - +0.57 21 +0.44

–0.17 - +1.38

Mid-arm

Circumference –0.76

–1.73 - +0.35 41 +0.07

–0.08 - +0.44 37 +0.29

–0.26 - +0.76 24 +0.25

–0.28 - +1.07

Thigh

circumference –0.83

–1.92 - –0.11 40 +0.01

–0.25 - +0.38 34 0.00

–0.36 - +0.37 24 +0.25

–0.09 - +0.80

Calf circumference –1.26

–2.28 - –0.22 40 +0.08

–0.26 - +0.54 34 +0.07

–0.49 - +0.44 24 +0.17

–0.03 - +0.94

Table 3. Changes in body fold measurements at 4 months stratified by baseline ART regimen

Non-PI or no cur rent ART, ART

experienced PI ART naive p-value

N Median (IQR) change N Median (IQR) change N Median (IQR)

change

Biceps SKF 14 +0.80

+0.14 - +1.57 15 +0.74

+0.05 - +1.51 8 –0.84

–1.92 - –0.03 0.016

Triceps SKF 17 +0.28

–0.17 - +0.45 15 +0.34

–0.25 - +0.77 9 –0.05

–0.53 - +0.25 0.19

Subscapular SKF 16 +0.32

–0.41 - +1.30 15 +0.37

–0.15 - +1.23 8 +0.36

–0.37 - +0.58 0.69

Suprailiac SKF 16 +0.08

–0.23 - +0.43 15 +0.18

–0.11 - +0.39 9 –0.16

–0.40 - +0.25 0.24

Sum of 4 skinfolds 12 +0.18

–0.19 - +0.96 15 +0.37

+0.07 - +0.77 7 +0.11

–0.80 - +0.14 0.26

Mid-arm

circumference 17 +0.07

–0.26 - +0.44 15 +0.17

0.00 - +0.72 9 0.00

–0.13 - +0.46 0.11

Thigh

circumference 17 +0.24

–0.12 - +0.47 14 –0.04

–0.27 - +0.27 9 –0.18

–0.23 - +0.19 0.64

Calf circumference 17 +0.05

–0.21 - +0.66 14 +0.11

–0.29 - +0.44 9 +0.11

–0.54 - +0.65 0.76

and limbs circumferences as well in total body fat as-

sessed by 4 SKFs. There are differences in skinfolds

changes in arm measurements i.e. BSF and TSF, an in-

crease over 4 months period, with marked increase in

BSF (p < 0.05) whereas TSF changed +0.34 z-scores

when compared to negligible change of –0.05 z-score in

naive group of patients. Arm measured by MAC changed

+0.17 z-score, whereas no difference was observed in

naive group of patients. Overall, three anthropometric

measurements (biceps, triceps skinfolds and mid-arm

circumference) assessing arm fat distribution increased

over period of 4 months when compared to naive group.

This observation may suggest increased upper limbs fat

accumulation in PIs treated group. Potential lower limb

extremities fat was estimated by thigh and calf circum-

ferences z-scores measurements. There were no differ-

ences in changes observed in calf circumference z-scores

in both groups (+0.11 z-score). Thigh circumference

measurements did not change over time in PIs groups

whereas in naive group some decrease in z-scores was

observed (–0.18 z-score). Central trunk fat can be as-

sessed by measuring of subscapular and suprailiac skin-

folds. Subscapular skinfold changed equally in both

groups and remained the same with some increase over

time +0.37 z-score. There was no difference in sub-

scapular skinfold z-scores changes between PIs receiving

and naive group of patients. In contrast, suprailiac skin-

folds increased over time (+0.18 z-score) in PIs group

while it decreased (–0.16 z-score) in naive group. This

may suggest some central fat accumulation in PIs treated

The Effect of Antiretroviral Therapy (ART) on Body Composition and Clinical Markers of Lipodystrophy

in HIV-Infected Children Assessed in Follow-Up Study

256

group. Interestingly, in children on other than PIs therapy,

suprailiac skinfold did not change over time. Overall,

total body fat as measured by sum of four skinfolds

showed an increase of +0.37 z-score in PIs group, with

changes of +0.11 z-score in naive group.

3.3. D4T vs Naive Group 4-Month Changes

Table 4 shows changes in body skinfolds measurements

at 4 months stratified by baseline d4T regimen. An in-

crease in all anthropometric z-scores measurements was

observed in therapy groups, both d4T containing and no

d4T therapy group, when compared to therapy naive

children, except for subscapular skinfolds z-scores ch ange

which was comparable in no-d4T therapy group and na-

ive (+0.38, + 0.36 z-scores, respectively). Changes in

z-scores were clinically important in no-d4T therapy

group with significant changes in biceps skinfold (BSF)

z-scores with an increase in d4T therapy group and de-

crease in therapy naive group. In naive group z-score

decreased to –0.84 whereas in d4T therapy groups in-

creased to +0.19 and to +0.81 z-score in no-d4T group.

Remaining anthropometric z-scores measurements ch an g ed

in therapy group s with an increase in z-scores except calf

circumference z-score which changed to decrease to

–0.13 when compared to naive group z-score change to

+0.11 over 4 months period. Although increase in z-

scores changes were observed for remaining anthropom-

etric measurements these positive changes in z-scores

were more clear/ pronounced in no-d4T group of chil-

dren than in d4T therapy based regimen. This may sug-

gest that children on d4T are exposed to fat wasting

rather than accumulation.

4. Discussion

The most significant effect of ART therapy in our study

was on upper limbs as measured by BSF. In the whole

group of children, total (n = 85), BSF and subscapular

skinfolds decreased over period of observation indicating

a decrease in peripheral adiposity. The remaining body

fat measurements increased or remained unchanged

when compared with baseline measurements. Analyses

of changes were rather presented as degree of increase in

anthropometric measurements z-scores to assess potential

body fat dep osition.

Since the groups were ethnically similar, these differ-

ences could be associated with the treatment given. Nor-

mally, all anthropometric measurements increase through-

out the growth period, and a plateauing or decrease in

circumferences is likely to be clinically important which

was observed in our cohort of patients analysed as a

whole. Although changes in skinfold thickness meas-

urements were noticed these measurements are difficult

to make accurately and are prone to error. Therefore an-

thropometric assessments should be done by one trained

health practitioner. Evaluation of skinfold measurement

is less straightforward than for circumference data since

values vary throughout childhood and centile charts are

required. Biceps skinfold thickness centile charts are not

generally available and normal values also vary accord-

ing to age. We recommend that baseline and regular rou-

tine anthropometric measurements should be recorded

for all HIV-infected children.

Table 4. Changes in body fold measurements at 4 months stratified by baseline d4T use.

No d4T/Other d4T Naive P-value

N Median (IQR) change N

Median (IQR)

change N Median (IQR) change

Biceps SKF 19 +0.81

+0.49 - +1.96 10 +0.19

–0.90 - +1.26 8 –0.84

–1.92 - –0.03 0.0036

Triceps SKF 20 +0.15

–0.34 - +0.45 12 +0.53

+0.10 - +0.77 9 –0.05

–0.53 - +0.25 0.07

Subscapular

SKF 19 +0.38

–0.24 - +2.01 12 +0.25

–0.08 - +0.84 8 +0.36

–0.37 - +0.58 0.78

Suprailiac SKF 19 +0.18

–0.25 - +0.44 12 +0.10

–0.10 - +0.40 9 –0.16

–0.40 - +0.25 0.25

Sum of 4

skinfolds 17 +0.38

–0.11 - +0.82 10 +0.20

–0.09 - +0.77 7 +0.11

–0.80 - +0.14 0.28

Mid-arm

circumference 20 +0.13

–0.06 - +0.50 12 +0.19

0.00 - +0.49 9 0.00

–0.13 - +0.05 0.22

Thigh

circumference 19 +0.14

–0.29 - +0.47 12 0.00

–0.18 - +0.26 9 –0.18

–0.23 - +0.19 0.91

Calf

circumference 19 +0.21

–0.04 - +0.82 12 –0.13

–0.36 - +0.36 9 +0.11

–0.54 - +0.65 0.30

The Effect of Antiretroviral Therapy (ART) on Body Composition and Clinical Markers of Lipodystrophy

in HIV-Infected Children Assessed in Follow-Up Study 257

In order to compare growth in a heterogeneous group

of children it is necessary to derive z-scores, which

compare measurements with the age and sex-specific

population mean. Th ere is no reference group with which

to compare our group of mainly sub-Saharan African

children. The WHO growth charts only include children

up to the age of 5 years so European charts were used to

calculate z-scores [14]. As we were comparing growth

velocity rather than growth itself comparing with ART-

naive group of the same ethnic original, we felt this ap-

proach wa s re asonabl e .

This study is an extension of a previously published

cross-sectional analysis and confirmed our earlier find-

ings that although physical features of lipodystrophy

were seen in only 5% of patients in our cohort, children

with no clinical evidence of lipodystrophy had altered

body fat distribution [9]. Up to date, two longitudinal

studies in HIV-infected children estimated that 25% -

54% have changes in body fat distribution [10,11].

Clinical diagnosis of lipodystrophy is subjective, espe-

cially in a paediatric population where growth hormones

and pubertal effects may play a role. Therefore, use of

more objective measures, such as anthropometric meas-

urements, may be particularly useful in this population.

In an American study significant fat redistribution was

described in pubertal children receiving PI based therapy,

although duration of PI therapy and the length of expo-

sure to ART did not appear to be risk factors for lipodys-

trophy [12]. Clinical signs of lipodystrophy appear to be

less common in children compared to adults and it may

be that factors such as growth hormone and insulin sensi-

tivity mitigate the dev elopment of the lipodystrophy syn-

drome in pre-pubertal children.

There were some limitations of the current study. The

study was purely observational looking at the signs of

lipodystrophy in cohort of HIV-infected children above 3

years of age attending the HIV family clinic at GOSH,

and who fulfilled the inclusion criteria. Patients received

ART therapy according to national guideline at the time

[13]. Some patients received ART therapy for varying

lengths of time prior to the study. However, we com-

pared ART treated patients with ART naive. Anthro-

pometric measurements were taken during regular visits

at the HIV clinic. Some children only had one time point

measurements due to parental refusal for further assess-

ment therefore were not included in the follow up study.

Duration of follow up varied from 3 to 12 months. Al-

though the number of visits varied (2 - 6), most children

were followed up for 3 visits with 4 months period be-

tween visits. Longer observation period is required. This

is one of the limitations of the study; short observation

period which maybe not long enough to show persisted

pattern of changes over time.

The average time of observation in our study was 0.7

years which may not be long enough to de tect changes in

other parts of the body. Computed tomography (CT),

nuclear magnetic imaging (MR) and dual-energy X-ray

absorptiometry (DEXA) are objective reference methods

but are expensive for routine follow-up and diagnosis.

Therefore, anthropometry and other non-invasive bedside

methods should be evaluated. There is evidence of cor-

relation between fat mass measured by anthropometric

skinfolds thickness and DEXA in HIV-infected patients

with lipodystrophy [15]. Therefore anthropometry meth-

ods can be used in healthcare services as one of validated

methods for estimating body fat in HIV-infected patients.

In conclusion, our study supports previously reported

evidence of body fat changes in children receiving PI or

d4T. Although d4T is no longer used as a routine th erapy

in Europe it does still form part of first- and second-line

regimens in some countries and clinicians should be

aware of this association in children. Further long-term

observational studies over a longer time period, with dif-

ferent ART regimens, are required to fully evaluate the

long term effects of ART therapy on growth and body

composition in HIV-infected children.

To our knowledge this is the first follow-up observa-

tional study looking at the effects of ART therapy on

body composition in HIV-infected children in the UK

using anthropometric assessment. These methods could

be used worldwide particularly where access to more

advanced radiological methods CT, MR or DEXA scan is

limited. Early intervention by altering ART can make a

difference in management of HIV-infected children [16].

5. Acknowledgements

Dr Agnieszka Dzwonek received an unrestricted educa-

tional grant from Ovita Nutricia Research Foundation,

Warsaw, Poland. The authors would like to thank Pro-

fessors T. Cole and N. Klein, Specialist HIV nurse: M.

Clapson, and statistician K. Drew.

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