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Antiviral Therapy 12:1247–1254
Lipodystrophy and metabolic changes in
HIV-infected children on non-nucleoside reverse
transcriptase inhibitor-based antiretroviral therapy
Linda Aurpibul1, Thanyawee Puthanakit1, Benjamin Lee1, Ampica Mangklabruks1, Thira Sirisanthana1 and
Virat Sirisanthana2*
1
Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand
Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
2
*Corresponding author: Tel: +6 653 946 471; Fax: +6 653 946 470; E-mail: [email protected]
Background: Highly active antiretroviral therapy (HAART)
has recently been implemented in Thailand. Its long-term
effects have not been clearly evaluated. The objective of
this study was to estimate the prevalence of lipodystrophy (LD) and other metabolic changes in HIV-infected
children receiving HAART.
Methods: Ninety children who began HAART (either nevirapine or efavirenz, together with lamivudine and
stavudine) were prospectively followed. LD was assessed by
waist-to-hip ratio and LD checklist. Hypercholesterolaemia
was defined as total cholesterol >200 mg/dl and lowdensity lipoprotein cholesterol >130 mg/dl. Low levels of
high-density lipoprotein cholesterol (HDL-c), hypertriglyceridaemia and hyperglycaemia were defined as HDL-c
<40 mg/dl, triglyceride >200 mg/dl and plasma glucose
>110 mg/dl, respectively.
Results: The mean age at entry was 7.6 (SD 2.9) years.
Fifty-three children received nevirapine- and 37 received
efavirenz-based HAART. The prevalence of LD was 9%,
47% and 65% at 48, 96 and 144 weeks after HAART
initiation, respectively. Patterns of LD at week 144 were
central lipohypertrophy (46%), peripheral lipoatrophy
(20%), and combined type (34%). A higher prevalence of
LD was found among females (61% versus 39%; P=0.04)
and those with more advanced disease (CDC category B
or C) at baseline (73% versus 51%; P=0.04). There was
no difference in prevalence of LD between the two regimens. At 144 weeks, fasting hypertriglyceridaemia was
detected in 12%, hypercholesterolaemia in 11%, and
increased plasma glucose in 4% of children. Low HDLcholesterolaemia decreased from 94% at baseline to 12%
at week 144 (P<0.01).
Conclusions: More than half of the children developed LD
at 144 weeks after HAART. Dyslipidaemia occurred in
11–12% of children.
Introduction
Human immunodeficiency virus (HIV) infection is one of
the major global health challenges, with nearly 40
million persons currently infected worldwide, including
2.3 million children [1]. Highly active antiretroviral
therapy (HAART) has dramatically reduced the
morbidity and mortality in HIV-infected adults and children in developed countries and certain developing countries, including Thailand [2–4]. Long-term adverse effects
of HAART, including lipodystrophy (LD) and other
metabolic disturbances, have been documented in adults,
but are rarely reported in children.
LD, a change in body shape owing to redistribution
of body fat, has been well described in HIV-infected
adults, particularly those treated with protease
inhibitors (PIs) or nucleoside reverse transcriptase
inhibitors (NRTIs), especially stavudine [5–7]. The
real pathogenesis remains obscure. Three phenotypes
© 2007 International Medical Press 1359-6535
of LD have been described: central fat accumulation
(lipohypertrophy), peripheral wasting (lipoatrophy),
and a combination of these. Some workers in the field
think that ‘lipodystrophy’ is a vague term and have
avoided using the word. They divided the metabolic
body changes in these patients into i) lipoatrophy, ii)
lipohypertrophy, and iii) combined form.
LD has been described in paediatric populations but
is more poorly understood than among adults. A case
definition has not yet been validated. Prevalence estimates in children are about 25% but range widely
from 1% to 33% because of a lack of diagnostic
criteria, which also complicates comparisons between
studies [8–18]. Identification of LD is difficult in children due to the changes in body shape that naturally
occur with growth. The lack of objective methods to
distinguish lipodystrophic patients and to monitor
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those at high risk for developing LD limits opportunities
for intervention before obvious LD has occurred.
Techniques such as dual-energy X-ray absorptiometry
(DEXA) and magnetic resonance imaging (MRI) help to
detect changes in body fat distribution before profound
signs of LD are seen [19], but are too expensive to be
performed in most clinics, especially those in resourcelimited settings. Owing to the necessity for lifelong
therapy over many decades, HIV-infected children may
be more vulnerable to LD and metabolic disturbances
than HIV-infected adults. In addition, maintaining
adherence to therapy among HIV-infected adolescents
is typically extremely difficult because of age-related
psychosocial issues. Stigma related to LD may lead to
low self esteem and decreased quality of life, further
compounding the adherence problem.
Disorders of lipid metabolism have been observed in
HIV-infected adults receiving antiretroviral therapy,
especially PI-based HAART [20]. The most common
dyslipidaemias seen among these patients have been
hypercholesterolaemia and hypertriglyceridaemia.
Fewer data exist regarding the prevalence of dyslipidaemia in HIV-infected children. Several crosssectional studies reported the prevalence of increased
cholesterol in HIV-infected children to range from 15%
to 66% and increased triglyceride to range from 13%
to 71% [9,11,13,14,16,18]. This disturbance in lipid
metabolism predisposes affected patients to premature
cardiovascular diseases [21]. In contrast to that in
adults, disturbance in glucose metabolism appears to
be relatively uncommon in children [16,17,22].
The purpose of this study was to estimate the
prevalence of LD and metabolic disturbances in HIVinfected children receiving lamivudine, stavudine, and
either nevirapine or efavirenz. A secondary aim was
to identify potential predictors of LD. We also propose
the use of clinical information and simple physical
measurements as an objective method to aid physicians
in the early identification of LD in HIV-infected children
receiving HAART.
Methods
Patients
The study population was HIV-infected children
starting HAART between August 2002 and October
2004 at Chiang Mai University Hospital, Chiang Mai,
Thailand. Inclusion criteria were: i) age 5–15 years, ii)
symptomatic HIV infection with severe immunosuppression, defined as a baseline CD4+ T-cell
percentage ″15%, and iii) receiving a treatment regimen
consisting of either nevirapine or efavirenz with lamivudine and stavudine. Exclusion criteria were: i) steroid
therapy, ii) abnormal body figure prior to HAART, and
iii) <95% adherence to antiretroviral treatment.
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Study design
This was part of a prospective longitudinal study to
assess clinical, immunological and virological
outcomes after HAART initiation [2,4]. Briefly, we
prospectively followed HIV-infected children who
started receiving HAART in the National Access to
Antiretroviral Programme for People Living with
HIV/AIDS at Chiang Mai University Hospital between
August 2002 and October 2004. All children were
followed at 3-month intervals. Baseline clinical assessment prior to HAART was used for classification of
CDC clinical category [23]. The study was approved by
the research ethics committee of Chiang Mai
University. Informed consent was obtained from each
child’s parent or legal guardian.
Antiretroviral regimen
Patients received either a nevirapine- or efavirenzbased regimen at the discretion of the attending
physician. Details of drug administration were previously reported [2]. Briefly, a fixed-dose combination
tablet GPO-vir (30 mg of stavudine, 150 mg of
lamivudine and 200 mg of nevirapine) was used for
the nevirapine-based regimen. The dosage was calculated to deliver a nevirapine dose of 150–200 mg/m2
every 12 h. The formulation used for the efavirenzbased regimen was stavudine (30 mg/capsule),
lamivudine (150 mg/tablet) and efavirenz (50 mg
and 200 mg capsules; Bristol-Myers Squibb). The
stavudine and lamivudine dose ranged from
0.9–1.3 mg/kg/dose and 4.0–6.3 mg/kg/dose, respectively. The dosage of efavirenz was 200 mg, 250 mg,
300 mg, 350 mg, 400 mg or 600 mg every 24 h in the
evening for children with body weights of 10 to
<15 kg, 15 to <20 kg, 20 to <25 kg, 25 to <32 kg, 32
to <40 kg or ≥40 kg, respectively.
Assessment
Anthropometric measurements. Weight and height
measurements were taken at each visit.
Measurements of waist and hip circumferences were
added in November 2003 and were measured every 6
months. Mid-waist circumference was measured at
the level of the umbilicus after exhalation. Maximum
hip circumference was measured at the widest lateral
hip diameter, across the maximal protuberance of the
buttocks, and perpendicular to the cranial-caudal
axis of the body. Because these values vary with age,
they were converted to age- and sex-adjusted Z
scores based on normal ranges among healthy Thai
children [24,25].
Clinical assessment. Clinical assessment was performed
by the same researcher (V Sirisanthana) for the duration of the study using serial photography and an LD
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Lipodystrophy in HIV-infected children on HAART
checklist, modified from that of the European
Paediatric Lipodystrophy study group [13]. Body sites
assessed for LD included the cheeks, the muscles and
veins of the arms and the abdomen. A clinical rating
scale of 0–3 was used to assess for evidence of atrophy:
grade 0, absent; grade 1, mild (noticeable on close
inspection); grade 2, moderate (readily noticeable);
grade 3, severe (readily noticeable to other observers).
Additional sites assessed included the buttocks, leg
muscles and veins, breasts and dorso-cervical neck, but
these data were not used to define LD. Puberty was
assessed using Tanner stages.
Definition. The definition of lipoatrophy was adapted
from that previously described in adults by Carr et al.
[26]. It was defined as the presence of at least one of
four criteria: i) atrophy of the cheeks at any grade, ii)
grade 2 or 3 prominent arm muscles, iii) grade 2 or 3
prominent arm veins or iv) grade 1 prominent arm
muscles plus grade 1 prominent arm veins.
Lipohypertrophy was defined as i) age- and sexadjusted waist-to-hip ratio Z score of >3.5 [25] or ii)
grade 2 or 3 increased abdominal girth if waist-to-hip
ratio was not available. Children satisfying both the
lipoatrophy and lipohypertrophy criteria were assigned
as cases with the combined type. Only cases in which
changes persisted on at least two or more physical
examinations 3 to 6 months apart were included.
Laboratory procedures
At 6-month intervals, blood specimens were collected
after a minimum of 8 h of fasting. Hyper-cholesterolaemia was defined as total cholesterol >200 mg/dl and
low-density
lipoprotein
cholesterol
(LDL-c)
>130 mg/dl [27–29]. Low high-density lipoprotein
cholesterol (HDL-c) was defined as HDL-c <40 mg/dl
and hypertriglyceridaemia as triglyceride >200 mg/dl
[27–29]. A total cholesterol-to-HDL-c ratio cut-off
value of >6.5 was used [30]. Impaired fasting plasma
glucose was defined as fasting plasma glucose
>110 mg/dl [29].
Statistics
Statistical analyses were performed using Statistical
Package for Social Science version 11.5 software (SPSS
Inc, Chicago, Illinois, USA). Comparisons of continuous variables were performed using paired t-test for
repeated measurement and independent sample t-test
for group variables. Independent categorical variables
were analysed by χ2 test. Paired categorical variables
were analysed by McNemar χ2 test. Correlation
between two continuous variables was studied using
bivariate correlations. Statistical significance was set at
two-tailed P-value <0.05.
Antiviral Therapy 12:8
Results
Demographic and clinical characteristics
Of the 101 HIV-infected children who began HAART
between August 2002 and October 2004, 90 met eligibility criteria while 11 were excluded. Five had been on
steroid therapy, five had abnormal body figures prior to
or not related to HAART (three cachexia and protruded
abdomen from mycobacterial infection, one cachexia
from cerebral toxoplasmosis, and one pregnancy while
on HAART), and one had <95% adherence to HAART.
Baseline characteristics of the children are shown in
Table 1. At 144 weeks after treatment, mean weight-forage and height-for-age Z scores were -1.08 (SD ±0.95)
and -1.52 (SD ±0.99), respectively. The average body
mass index (BMI) was 16.3 kg/m2 (SD ±2.2, range
12.9–23.6). Only one child was overweight at 144
weeks after HAART initiation (11-year-old boy,
BMI=23.6 kg/m2) [31]. Mean CD4+ T-cell percentage
was 25% (SD ±7), mean CD4+ T-cell count was 680
(SD ±260) cells/μl, and 85% of children had an undetectable plasma HIV RNA level.
Lipodystrophy
All three types of LD were seen. The prevalence of LD
was 9%, 16%, 47%, 57% and 65% at weeks 48, 72,
96, 120 and 144 of HAART initiation, respectively.
The percentage of children with LD increased over time
(Table 2). The severity of LD also increased over time
(data not shown). Lipohypertrophy was more common
than lipoatrophy at all time points. Enlarged breasts in
boys and/or prominent dorso-cervical neck were
observed in four adolescents; all had age- and sexmatched waist-to-hip ratio Z score of ≥3.5. One third
(13/39) of the children who developed LD had the
combined type at 144 weeks after HAART initiation.
Of the 31 children who had lipohypertrophy, 28 met
the definition using age- and sex-adjusted waist-to-hip
ratio Z score of ≥3.5 and three who did not have waist
and hip measurements had grade 2 or 3 increased
abdominal girth.
The prevalence of LD was significantly higher
among females than males (61% versus 39%; P=0.039)
(Table 1). No children reached complete puberty
(Tanner stage V) either at entry or while on study.
There was no significant difference between the 85
children who were prepubertal (Tanner stage I) at entry
and the five who had ongoing puberty (Tanner stage
II–IV) (58% versus 100%; P=0.06; Table 1). There was
no significant difference between nevirapine- and
efavirenz-based regimens. A greater proportion of children who were CDC clinical category B or C prior to
HAART developed LD compared with children who
were category N or A (73% versus 51%; P=0.036).
After 96 weeks of HAART, BMI among the group with
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Table 1. Baseline characteristics and risk factors of lipodystrophy
Characteristic
Gender
Male, n (%)
Female, n (%)
HAART regimen
d4T+3TC+NVP, n (%)
d4T+3TC+EFV, n (%)
Mean age, years (±SD)
Age groups
<10 years, n (%)
≥10 years, n (%)
Tanner stage*
Prepubertal (I), n (%)
Ongoing puberty (II–IV), n (%)
CDC clinical classification
N or A, n (%)
B or C, n (%)
Mean body mass index (SD)
Mean weight for age z score (SD)
Mean height for age z score (SD)
Mean CD4+ T-cell count, cells/μl (SD)
Mean CD4+ T-cell percentage, % (SD)
CD4+ T-cell percentage group
<5, n (%)
5–10, n (%)
10–15, n (%)
Mean HIV RNA level, log10 copies/ml (SD)
All children
n=90
Lipodystrophy
n=54
Non-lipodystrophy
n=36
P-value†
43 (48)
47 (52)
21 (39)
33 (61)
22 (61)
14 (39)
0.04
–
53 (59)
37 (41)
7.6 (2.9)
30 (56)
24 (44)
7.9 (3.1)
23 (64)
13 (36)
7.2 (2.4)
0.43
–
0.28
63 (70)
27 (30)
36 (67)
18 (33)
27 (75)
9 (25)
0.40
–
85 (94)
5 (6)
49 (91)
5 (9)
36 (100)
0
0.06
–
53 (59)
37 (41)
14.78 (1.77)
–1.95 (1.06)
–2.47 (1.3)
159 (173)
6 (5)
27 (50)
27 (50)
14.88 (1.74)
–2.04 (1.13)
–2.67 (1.37)
176 (191)
6 (5)
26 (72)
10 (28)
14.63 (1.82)
–1.82 (0.93)
–2.17 (1.03)
133 (141)
5 (5)
0.04
–
0.53
0.32
0.05
0.21
0.37
51 (57)
19 (21)
20 (22)
5.32 (0.45)
22 (43)
8 (42)
6 (30)
5.27 (0.48)
29 (57)
11 (58)
14 (70)
5.38 (0.38)
0.58
–
–
0.25
*No patient had reached Tanner stage V (complete puberty). † Lipodystrophy versus non-lipodystrophy. d4T, stavudine; EFV, efavirenz; HAART, highly active antiretroviral
therapy; NVP nevirapine; 3TC lamivudine.
Table 2. Incidence of lipodystrophy classified by phenotype
Total number of children, n*
Prevalence of lipodystrophy
Total, n (%)
Atrophy, n
Hypertrophy, n
Combined type, n
Week after HAART
96
48
72
90
88
8 (9)
0
8
0
14 (16)
3
10
1
120
144
83
74
60
39 (47)
8
27
4
42 (57)
9
25
8
39 (65)
8
18
13
*The number of children followed up during weeks 96–144 decreased because of staggered enrolment.
LD was significantly higher than among those without
LD (data not shown).
Metabolic disturbances
Lipid profiles at each time point are shown in Table 3.
The proportion of children with hypertriglyceridaemia (triglyceride >200 mg/dl) and hypercholesterolaemia (cholesterol >200 mg/dl with LDL-c
1250
>130 mg/dl) increased from zero at baseline to 12%
and 19% of children, respectively, at 48 weeks of
HAART (P=0.09 and <0.01, respectively). After week
48 of HAART, the proportion of children with hypertriglyceridaemia and hypercholesterolaemia remained
at 8–12% and 10–15%, respectively. The proportion
of children with low HDL-c decreased from 94% at
baseline to 12% at week 144 on HAART (P<0.01).
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Lipodystrophy in HIV-infected children on HAART
Table 3. Lipid profiles and fasting glucose level in HIV-infected children receiving HAART
Week during HAART
72
96
Lipid profile
0
24
48
120
144
Triglyceride, mg/dl (SD)*
Triglyceride >200, n (%)†
Triglyceride >150, n (%)†
Cholesterol, mg/dl (SD)*
Cholesterol >200 with
LDLc >130, n (%)†
Cholesterol >200, n (%)†
LDLc, mg/dl (SD)*
LDLc >130, n (%)†
HDLc, mg/dl (SD)*
HDLc <40, n (%)†
Total cholesterol:
HDLc ratio (SD)*
Total cholesterol:
HDLc ratio >6.5, n (%)†
Fasting plasma glucose
Glucose, mg/dl (SD)*
Glucose >110 μg/dl, n (%)†
100 (39)
0/52 (0)
5/53 (9)
133 (30)
0/52 (0)
115 (55)
7/82 (9)
19/82 (23)
164 (35)
9/82 (11)
112 (75)
10/86 (12)
18/86 (21)
173 (35)
16/86 (19)
106 (72)
6/78 (8)
13/78 (17)
177 (38)
12/78 (15)
123 (93)
8/77 (10)
19/77 (26)
177 (33)
8/77 (10)
126 (99)
8/72 (11)
19/72 (26)
174 (37)
8/72 (11)
129 (84)
7/57 (12)
15/57 (26)
177 (36)
6/57 (11)
1/52 (2)
87 (33)
2/52 (4)
27 (8)
49/52 (94)
5.1 (1.5)
11/82 (13)
101 (31)
14/82 (17)
41 (14)
43/82 (52)
4.2 (1.1)
20/86 (23)
103 (33)
18/86 (21)
48 (13)
22/86 (26)
3.8 (1.0)
23/78 (29)
104 (32)
13/78 (17)
53 (17)
16/78 (21)
3.6 (1.3)
20/77 (26)
99 (27)
8/77 (10)
53 (15)
10/77 (13)
3.6 (1.2)
18/72 (25)
96 (28)
8/72 (11)
54 (18)
13/72 (18)
3.5 (1.0)
13/57 (23)
97 (29)
6/57 (11)
54 (19)
7/57 (12)
3.6 (1.8)
8/52 (15)
3/82 (4)
1/86 (1)
2/78 (3)
4/77 (5)
1/72 (1)
1/57 (2)
N/A
N/A
N/A
N/A
N/A
N/A
88 (14)
2/46 (4)
88 (9)
0/54 (0)
88 (10)
2/70 (3)
88 (9)
2/56 (4)
P-value
0 versus 48
P-value
0 versus 144
0.30
0.04
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01
N/A
N/A
*Data are mean values (±SD). †Number of children with unfavorable value/total children tested. NA, not available. HAART, highly active antiretroviral therapy;
HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol.
No significant difference was seen in mean lipid
profile values at weeks 48 and 144 when compared by
gender (male versus female), age group (≥10 years
versus <10 years), and CD4+ T-cell percentage (<5 or
higher) using independent sample t-test for comparison. At week 48 the mean triglyceride level was significantly higher among children in CDC category B or C
than N or A (135 versus 95 mg/dl; P=0.02). No correlations were seen between BMI, CD4+ T-cell
percentage or HIV RNA level at baseline and lipid
profile values at weeks 48 and 144 of HAART.
The group of children with LD had significantly higher
mean triglycerides than the non-LD group from week 48
of HAART (LD group 129 mg/dl [SD 85] and non-LD
group 86 mg/dl [SD 45]; P<0.01) and thereafter (data not
shown). At 144 weeks of HAART, 19% of children with
LD had hypertriglyceridaemia (versus none in the nonLD group). There was no statistical difference in mean
total cholesterol between the LD and non-LD groups.
Mean HDL-c level was significantly lower in the LD than
non-LD groups at weeks 96 and 120 of treatment.
When compared by HAART regimen, those
receiving the nevirapine-based regimen had significantly higher HDL-c (from week 24, 44 versus
38 mg/dl; P=0.04) and lower total cholesterol-to-HDLc ratio (from week 72, 3.2 versus 4.1; P<0.01). These
differences persisted through week 120 of treatment.
There were no significant differences in triglyceride or
cholesterol levels between the nevirapine-based and
efavirenz-based regimens.
Antiviral Therapy 12:8
The mean fasting plasma glucose levels at each time
point are shown in Table 3. At 144 weeks of treatment
it was 88 mg/dl (range 69–122). Two of 56 (4%) had
impaired fasting plasma glucose (>110 mg/dl), one
from the LD group receiving efavirenz another from
the non-LD group receiving the nevirapine-based
regimen. None had increased fasting plasma glucose in
the diabetic range (>126 mg/dl) at any time point. No
significant differences in fasting plasma glucose were
seen when compared by gender (male versus female),
age group (≥10 years versus <10 years), and CDC
category (N or A versus B or C).
Discussion
Our study was a prospective longitudinal study that
included the largest number of HIV-infected children
from a single centre to date. All received an NNRTIbased regimen containing the same two NRTIs (stavudine and lamivudine) and one of two NNRTIs
(nevirapine or efavirenz). Clinical assessment of LD
was performed by the same researcher (V
Sirisanthana) using serial photography, an LD checklist and waist and hip circumference measurements.
These characteristics made this study unique and
greatly reduce the presence of multiple confounding
variables found in other studies.
The prevalence of LD in our study was 9%, 16%,
47%, 57% and 65% at 48, 72, 96, 120 and 144 weeks,
respectively, after initiation of NNRTI-based HAART.
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The pattern of LD was 46% central lipohypertrophy,
21% peripheral lipoatrophy and 33% combined.
The prevalence of LD in our study was 9% at 48
weeks after HAART initiation. This time-point is
comparable in duration to the previous US study by
Amaya et al., [11] when LD was documented in 18%
of HIV-infected children who were stable on antiretroviral treatment for 12 months. By 96 weeks on
HAART, the prevalence of LD in our study increased to
47%, which is higher than the prevalence reported in
two French studies of comparable duration. One was
the study by Jaquet et al. [9], which reported a 33%
prevalence of LD. Another study by Beregszaszi et al.
[16] reported a 24.6% prevalence of LD. Most children
in the two French cohorts had been receiving antiretroviral drugs for ≥2 years. Our prevalence of LD was
65% at 144 weeks after HAART initiation. A Belgian
study reported a lower prevalence of LD: 23% of HIVinfected children aged 3–19 years (42% were on antiretroviral treatment for >5 years) [18]. In a study by
Vigano et al. [12] among HIV-infected Italian children
on HAART for 39.3–50.9 months, LD was seen in
16% of children at study entry and increased to 22%
in the next 12 months.
PI therapy has been implicated as the most likely
cause of LD in the past, but more recent studies have
shifted the focus to NRTIs as the cause, particularly
stavudine [32]. In most published studies, the majority
of HIV-infected children have been treated with a PIcontaining regimen [9–14,16–18]. Unlike in developed
countries where patients typically receive PI-based
regimens, our cohort was treated with two NRTIs
(stavudine and lamivudine) and one NNRTI
(nevaripine or efavirenz). These regimens were recommended by the World Health Organization as first-line
HAART regimens. Our study was the only study that
reported prevalence of LD in HIV-infected children
taking these NNRTI-based HAART regimens. Two
studies reported this prevalence in adults. The
reported prevalence of LD among HIV-infected adults
in India was 46%, with a higher prevalence among
those taking regimens containing stavudine than
among those on zidovudine-containing regimens [33].
In another study among Thai HIV-infected adults
treated with lamivudine, stavudine and nevirapine,
17% were reported to have LD by subjective assessment by the patient and/or physicians within 2 years of
initiating treatment [34]. All children in our cohort
received more stavudine than is generally recommended, either in a fixed-dose combination tablet or
in an adult capsule (0.9–1.3 mg/kg/dose versus recommended dose of 1 mg/kg/dose). Universal treatment
with stavudine, and the high stavudine doses used,
may have contributed to the higher incidence of LD
seen in our study.
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LD is more difficult to define in HIV-infected children
because of normal body changes with age.
Questionnaire survey was used by Babl et al. [8] and
showed very low prevalence of LD (in 1% of those
surveyed). Arpadi et al. [10] used DEXA to measure
total and regional body fat mass (29%). Viagno et al.
[12] used DEXA and MRI studies to document
increased intra-abdominal tissue (22%). These techniques had two limitations – namely the restricted
availability of the tools and the lack of reference values
in children. Skinfold thickness measurements were used
in the two French studies, where French reference
values for gender and age were available in children
(33% and 25%, respectively) [9,16]. Most studies in
children used clinical grading assessment by researchers
(9–26%) [11,13–15,17,18]. The variety of methods
used complicates estimation of the true prevalence of
LD. Unlike lipoatrophy, which is usually noticeable,
lipohypertrophy is difficult to detect clinically. We
found that the use of a persistent increase in waist-tohip ratio Z score of ≥3.5 is a useful tool in defining
lipohypertrophy. This measure should be included at
the initiation of HAART in order to enable early
detection of lipohypertrophy.
Lipohypertrophy was the most common phenotype
of LD seen in our study, supporting others’ findings in
HIV-infected children, most of whom were on PI-based
HAART [9,14]. We detected cases of lipohypertrophy
within the first 48 weeks after the initiation of HAART,
while cases of lipoatrophy were detected later (Table
2). Our results are in contrast with those from Indian
HIV-infected adults treated with stavudine, lamivudine
and nevirapine, where lipohypertrophy was found
slightly less frequently than lipoatrophy [33].
In our study, a significantly higher prevalence of LD
was found among females and those with more
advanced disease (CDC category B or C) at baseline.
These findings are similar to those reported by the
European Paediatric Lipodystrophy Group [13]. Torres
et al. [14] reported that an increased prevalence of LD
was associated with older age or puberty, but we did
not see that relationship in our study. This may be
because the children in our study were generally
younger (mean age 7.6 years).
Our study showed that HAART containing stavudine, lamivudune and either nevirapine or efavirenz
was accompanied by a significant increase in the
proportion of children with hypertriglyceridaemia
(12%) and hypercholesterolaemia (11%). Plasma
triglyceride levels in healthy children and adolescents
vary widely [35]. The National Cholesterol Education
Programme (NCEP) states that the risk for pancreatitis
occurs in patients with triglyceride ≥500 mg/dl, and
triglyceride levels <200 mg/dl are considered acceptable
[28]. Thus, we chose the level of >200 mg/dl to define
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Lipodystrophy in HIV-infected children on HAART
hypertriglyceridaemia. Several studies used a lower
cut-off point at >150 mg/dl and found a prevalence of
13–22% [9,13,16,18]. Using this lower cut-off point,
the prevalence of hypertriglyceridaemia in our study
would be 26% (Table 3). Similar to the case of hypertriglyceridaemia, the 11% prevalence of hypercholesterolaemia in our study would increase to 23% by
using a cholesterol level of >200 mg/dl in defining
hypercholesterolaemia (Table 3). This prevalence was
comparable to those in other studies of HIV-infected
children (15–27%) [9,13,16,18]. The majority of these
studies employed PI-based HAART regimens. The
significant increase of HDL-c seen in our study was
not noted in other studies in children. However, it has
been noted in studies in adults receiving NNRTI-based
HAART regimens [30,36]. We found that children on
the nevirapine-based regimen had significantly higher
HDL-c and lower total cholesterol-to-HDL-c ratio than
those on efavirenz-based regimens. This is similar to a
previous report in HIV-infected adults [36]. The
increased HDL-c fraction may have led to a decreased
LDL-c fraction. Both findings result in reduced risk of
coronary heart disease. Our study found more hypertriglyceridaemia in the LD group versus the non-LD
group, while the study by Jaquet et al. [9] reported no
significant difference in triglycerides and cholesterol
between children with and without LD.
We found only a few cases with increased plasma
glucose, which was consistent with previous studies in
HIV-infected children. One study reported that all HIVinfected children, on a variety of treatment regimens,
had fasting glucose values within the normal range,
while 9% had evidence of insulin resistance [18].
Another study found no children with diabetes or
impaired fasting plasma glucose, while impaired
glucose tolerance was seen in 3% of children tested
after oral glucose tolerance test [16]. Measurement of
fasting plasma glucose may not be sensitive enough to
detect early disturbance in glucose metabolism.
Glucose tolerance tests or measurement of insulin or
c-peptide levels may have roles in the detection of
insulin resistance. The use of NNRTI-based, but not PIbased, HAART regimen was reported to be associated
with a reduction of insulin resistance in HIV-infected
children [22]. This could possibly explain the low
prevalence of glucose abnormalities in our study.
Glucose metabolism in children might be different to
that in adults, as 12% of HIV-infected Indian adults
taking the same regimen as used in our study had
fasting hyperglycaemia (>110 mg/dl) [33].
This study has several limitations. It was not
designed to compare the incidence of metabolic changes
among various antiretroviral treatment regimens. Thus,
there was no comparison group. Specifically, there were
no comparisons with PI-based regimens. Secondly, all
Antiviral Therapy 12:8
our patients received stavudine treatment. Therefore
our results may not be generalized to patients whose
treatment regimen does not include stavudine.
Our study demonstrates a high prevalence of LD, but
few metabolic complications among HIV-infected children taking World Health Organization-recommended
first-line HAART regimen containing stavudine,
lamivudine and either nevirapine or efavirenz. The risk
of morbidity from coronary artery disease and strokes
seems small but may increase in adulthood. Of greater
concern are the psychological and social consequences
of LD in adolescents. These emotional adverse events
pose a particular problem toward non-compliance
with long-term therapy. It inevitably leads to treatment failure and the emergence of drug-resistant viral
strains. Stavudine was the most likely drug to blame
for LD in our study. If available, other drugs from the
NRTI class should be substituted for stavudine in the
first-line HAART regimen.
Acknowledgements
This study was supported by the Thailand Research
Fund of the Royal Thai Government and NIH research
grant R01 TW006187. BL was supported by the
Fogarty Aids International Training and Research
Program of the Johns Hopkins University.
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Accepted for publication 11 August 2007
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