Body composition and

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Body composition and metabolic complications of
antiretroviral therapy in children
Alessandra Viganò Pediatric Infectious Disease
Unit L. Sacco Hospital Milan
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Treatment with HAART has greatly improved
survival and is associated with a sustained
effect on growth in HIV-infected
children Children are more vulnerable than
adults to metabolic side-effects of therapy due
to likely greater cumulative exposure Morbidity
from long-term effects of ARV has grown in
importance
3
Adiponectin in human immunodeficiency virus-infec
ted youths relationship to body composition and
insulin resistance
Lipodystrophy Workshop 2005
4
Several molecules TNF-? Leptin Resistin Adiponec
tin are secreted by adipose tissue and they do
play a critical role on metabolism
5
Adipokines might link the changes in fat
distribution and metabolic abnormalities in
patients with HIV infection
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• Adiponectin
• increases insulin sensitivity by
• Hepatic glucose output
• Fatty acid oxidation
• in muscle and liver with overall
• of triglycerides

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Adiponectin is reduced in HIV-infected adults
with LD vs HIV-infected adults without LD and
HC
J Clin Endocrinol Metab 2003
8
Adiponectin levels were assessed in 36
HIV-infected children (aged 5.0 - 19.4 yrs) on
long-term HAART (69.4 mos) and in 171 HC (aged
4.5 - 17.9 yrs)
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Adiponectin levels in HIV-infected children were
inversely related to BMI TB fat mass Trunk fat /
total fat Fasting insulin HOMA Insulin AUC
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Age, BMI, and biochemical variables according to
LD phenotype
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Adiponectin serum concentrations in HIV and in
healthy controls of comparable ages
25 000
20 000
15 000
10 000
5 000
0
Normal fat distribution
Peripheral fat loss
Mixed lipodystrophy
Central fat accumulation
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Conclusions
Adiponectin is related to central fat
accumulation Low adiponectin levels might
induce alterations in insulin response
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EFFECTS OF RECOMBINANT GROWTH HORMONE ON
VISCERAL FAT ACCUMULATION PILOT STUDY IN
HIV-INFECTED ADOLESCENTS J Clin Endocrinol
Metab, 2005
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Aim
To evaluate the efficacy and safety of 0.028
mg/Kg daily of GH for 24 wks in HIV-infected
adolescents with visceral fat accumulation
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Methods
Inclusion criteria IAT content gt41 cm2 by
L4-MRI Exclusion criteria Abnormal glucose
tolerance Diabetes Active malignancies
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Patients
8 patients (3 boys/5 girls) Median age 15.7 yrs
(13.7-18.5) Mean BMI 21.0 Kg/cm2 (DS
2.6) D4t3TC PI exposed median 79.5 mos
(64-83) Clinically stable with undetectable
HIV-RNA Median CD4 count 706 cells/mm3
(454-1219)
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Healthy Controls
97 subjects (51 boys/46 girls) Mean age 14.5 yrs
(DS 3.0) No history of endocrine, nutritional,
growth or renal problems Mean BMI 19.7 Kg/cm2
(DS 3.0)
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Results
All patients completed the 24 weeks study GH
dosage unchanged throughout the study (1.25 -
2.20 mg/daily) GH therapy was well-tolerated
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IAT content (cm2) decreased in 8 GH-treated
children (p 0.01)
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24 Week Fat mass data Changes observed in 8
GH-Treated Patients and expected changes derived
from 97 HC
3
p 0.025
2
p 0.038
p 0.024
p 0.029
1
0
Kg
-1
-2
-3
-4
-5
Total fat
Trunk fat
Arms fat
Legs fat
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24 Week Lean mass data Changes observed in 8
GH-Treated Patients and expected changes derived
from 97 HC
p 0.02
6
5
4
p 0.019
Kg
3
p 0.02
2
1
0
Total lean
Trunk lean
Arms lean
Legs lean
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Supraphysiologic IGF-1 levels (gt upper normal
limit for age and sex)
Were detected in 5/8 (62) of the patients and
in 9/24 (37) of the measurements Ranged 2-23
over upper normal limits
Hormone Research 2003, 60 53-60
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Effects of GH treatment on fasting glucose
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Effects of GH treatment on OGTT
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Conclusions
GH 0.028 mg/Kg/daily for 24 weeks Is well
tolerated Decreases IAT and trunk fat Increases
lean mass Is not associated with worsening
of glucose metabolism
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Conclusions
GH 0.028 mg/Kg/daily for 24 weeks Increases
IGF-1 values Is associated with mild
supraphysiologic levels
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Improvement in Dyslipidemia after Switching
Stavudine to Tenofovir and Protease Inhibitor to
Efavirenz in HIV-infected Children
Antiviral Therapy, in press
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CD4 cells count
in children switching ARV
at study entry
and
after 24 weeks
1400
1200
1000
L
m
800
CD4 /
600
400
200
0
Study Entry
12 wks
24 wks
36 wks
48 wks
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Changes in cholesterol HDL levels in
children switching ARV
at study entry
and
after 24 weeks
plt0.003
plt0.003
plt0.006
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Changes in Triglycerides levels
in children switching ARV
and
at study entry
after 24 weeks
plt0.04
plt0.05
plt0.05
350
300
250
200
mg/dL
150
100
50
0
Study Entry
12 wks
24 wks
36 wks
48 wks
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Conclusions
Switching from 3TCd4TPI to 3TCTDFEFV in
HIV-infected children with long-lasting viral
suppression Is safe both virologically and
immunologically Provides a significant
improvement In lipid abnormalities
37
Long-term renal safety of tenofovir in
antiretroviral- experienced HIV-infected
children a prospective cohort study
Lipodystrophy Workshop 2005
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Background
Renal insufficiency has been associated with TDF
use and some cases were observed after as long
as 72 weeks on TDF Mitochondrial damage may be
a co-factor of TDF-induced nephrotoxicity
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Patients
We prospectively assessed (baseline, weeks 24,
48, 72 and 96) renal function parameters and
lactate levels in 27 HIV (ages, 4.9-18.0) after
replacing d4T with TDF and PI with EFV
40
27 HIV were followed up to 72 weeks and 14 of
them up to 96 weeks At baseline all HIV had SCr
values normal for age and 26/27 subjects had an
estimated GFR gt 90ml/min 1.73m2 m2
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p0.002
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Conclusions Through 96 weeks TDF use is not
associated with renal dysfunction TDF use is
associated with a significant decrease of
lactate levels
49
A 12-months Treatment with tenofovir does not
impair bone mineral accrual in HIV-Infected
Children
J Acquir Immune Defic Syndr, in press
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• A greater but non progressive decrease of lumbar
  spine BMD was observed
• in antiretroviral-naive patients
• treated with TD
• vs.
• patients treated with D4T

JAMA 2004. 292 191-201
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• Pediatric data on the effect of TDF
• on bone mass are
• Confined to ARV-experienced patients.
• Available for small number of subjetcs
• conflicting

15th IAS abs TuPeB4465, 2004
11th CROI abs 928, 2004
52
Aim
To assess the effect of substitution of
stavudine with tenofovir on bone mineral content
(BMC) and bone mineral density (BMD) in
HIV-infected children
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Patients
13 patients age range 6.4-17.3 years Clinically
stable with undetectable HIV-RNA HAART
exposed to 3TCd4T1 PI mean exposure 69 months
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Study design
DXA (12 months prior switch)
3TCD4T1 PI
DXA (at switch)
3TCTDFEFV
DXA (12 months after switch)
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Healthy Controls

• 116 subjects (92 boys / 74 girls)
• age range 5.7-19.9 years
• no history of endocrine, nutritional,
• growth and renal diseases

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Clinical data on 13 HIV
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Total Body BMC in 13 HIV
Lumbar spine BMC in 13 HIV
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Total Body BMD in 13 HIV
Total Body BMD in 13 HIV
Lumbar spine BMD in 13 HIV
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Are these changes within physiological ranges?
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Lumbar spine BMC yearly changes in 13
HIV and 166 HC
3TCTDFEFV
3TCd4T 1 PI
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Total body BMC yearly changes in 13
HIV and 166 HC
3TCd4T 1 PI
3TCTDFEFV
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Lumbar spine BMD yearly changes in 13
HIV and 166 HC
3TCd4T 1 PI
3TCTDFEFV
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Total Body BMD yearly changes in 13 HIV
and 166 HC
3TCd4T 1 PI
3TCTDFEFV
64
Conclusions
Our data indicate that a 12-months treatment
with TDF in virologically responder children is
not associated with an impairment on bone mineral
accrual
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• V. GIACOMET P. BRAMBILLA
• M. MERLO L. SCHNEIDER
• P. ERBA L. CAFARELLI
• S. BERETTA S. BORGONOVO
• Chair of Pediatrics L. Sacco Hospital
• University of Milan, Italy
• S. MORA M.T. SCIANNAMBLO
• Laboratory of Pediatric Endocrinology
• IRCCS H.S. Raffaele, Milan Italy
• G. ROMBOLA
• Department of Nephrology
• S. Andrea Hospital, LA Spezia, Italy