Long Term
Complications of
Treatment in
Children
By
Kulkanya Chokephaibukit, MD
Professor of Pediatrics
Faculty of Medicine Siriraj Hospital
Mahidol University, Bangkok, Thailand
Lecture at HIVNAT 25 July 2013
HIV is an acceptable virus
to live with!
Emily, 7 year-old girl
with ALL cured by
using HIV gene therapy
A disabled form of HIV deliver
the gene to make chimeric
antigen receptor T-cell
(CTL019)of the patient that
recognize the and destroy
cancer cells
Concerning Long Term Complications of Treatment
in HIV-Infected Children and Adolescents
• Lipodystrophy, esp. facial lipoatrophy
• Metabolic complications that may result in
cardiovascular diseases/coronary heart
diseases/stroke, DM
• Kidney dysfunction
• Fractures risk/osteopenia/vitamin D
deficiency
• Neuro/psychiatric problems
A 9 year-old boy with perinatal HIV
Chief Complaint: Hyperpigmentation of neck and armpit
for 2 years
History:
• Maternal HIV without perinatal treatment
• Diagnosis of HIV infection by serology at 18 month-old ,
CD4: 256 cell/mm3 (12.39%)
• He was started on AZT+3TC (in 1998), then changed to
HAART
• At 7 year-old, started to gain weight, very good
appetite, and noticed hyperpigmentation
Familial Hx: Mom died from AIDS. Live with grandparents,
both had DM
The 9 year-old boy with dark neck
for 2 years
Age
%CD4
CD4 count
VL
ART
18 mo
12.39
256
-
AZT+3TC
3Y
2.03
48
-
d4T+ddI+EFV
4.5 Y
2.79
72
504,000
d4T+3TC+EFV
M41L, D67N
K101E, V179D
5.5 Y
-
-
-
AZT+3TC+IDV/
r
5.6 Y
3.04
137
<40
AZT+3TC+IDV/
r
The 9 year-old boy with dark
neck for 2 years
Date
%CD4
CD4
VL
ART
count
5.6 Y
3.04
137
<40
AZT+3TC+IDV/r
8.5 Y
19.63
930
-
AZT+3TC+IDV/r
9Y
19.35
592
-
AZT+3TC+LPV/r
9.5 Y
23.86
679
<40
AZT+3TC+LPV/r
The 9 year-old boy
with dark neck
Physical Examination:
• Wt 46.9 kg (>P97), Ht 140.8 cm (P97), 146% Ideal BW, BMI
23.9 kg/m2, WC 76.5 cm, HC 73.7 cm
W/H ratio 1.04
• GA: loss of pad of fat/ lower limbs, dorsocervical hump
• Chest: gynecomastia
• GU: testes 5 cc, PH Tanner II
• Normal findings for heart, lungs, abdomen, and neuro
examinations
Hyperpigmentation
of the neck and
armpits,
dorsocervical hump
What is your diagnosis of his
skin hyperpigmentation?
A. genetic
B. Acanthosis nigricans
C. poor hygeine
What is the common condition
associated with this skin
hyperpigmentation?
A. Insulin resistance and diabetes
B. Dyslipidemia
C. Malignant melanoma
Acanthosis nigricans
A clue for IR
• Hyperpigmented velvety macules and patches
and progress to palpable plaques. Mostly
observed at the intertriginous areas of the
axilla, groin, and posterior neck
• Causes:
- Obesity, particularly with darker skin
color. Children BMI>98th tile have AN in 62%.1
- Diabetes and Insulin resistance.2
- Polycystic ovarian syndrome
- Malignancy: adenocarcinomas of the GI tract
(70-90%), and others
1.Krawczyk M. Pol Arch Med Wewn. Mar 2009;119(3):180-3. 2. Sadeghian G. J Dermatol. Apr 2009;36(4):209-12
Problem Lists
• Obesity
• Acanthosis nigricans
• Lipodystrophy (mild facial
lipoatrophy)
• FBS = 159mg/dl (Provisional DM)
• Metabolic syndrome?
Lipodystrophy in HIV-infected children
 Incidence vary 10-50%1-4 due to lack of
consensus for definition
 Associated with PI and stavudine
 PI: Predominate with truncal obesity, buffalo
hump, and less periheral lipoatrophy
 d4T: Predominate with facial, associated with
HLA-B*40015 and Fas gene6
 Likely to appear in early adolescence1,7
1.Lapphra K. J Med Assoc Thai. 2005. 2. Taylor P. Pediatrics 2004 3. Amaya RA. Pediatr Infect Dis J. 2002.
4. Sawawiboon N. Int J STD AIDS 2012, 5. Wangsomboonsiri W. CID 2010;50(4):597-604, 6. Likanonsakul
S, AIDS Res Hum Retroviruses. 2012 Jul 9., 7. Alam NM. J Acquir Immune Defic Syndr. 2012; 59(3): 314–
324
Characteristics of Lipodystrophy
from Protease Inhibitors
• Fat gain on abdomen, breast, and
dorsocervical hump
• Fat loss from peripheral extremities
• Fat gain in visceral organs
Lipodystrophy
from d4T
Facial and peripheral lipoatrophy following >6 months of
stavudine treatment, found in 38% of d4T Rx, occur around early
adolescence
Sawawiboon N. International Journal of STD & AIDS 2012; 23: 497–501
Body fat abnormality in HIV-infected children
and adolescents: The difference of regions
Study Population
Lipoatrophy
23%
Lipohypertrophy
or combine
2.5%%
No fat maldistribution 75%
Europe (N= 426, LD = 42%
Receiving PI 60%,
Received d4T 10%
Alam NM. J Acquir Immune Defic Syndr. 2012
March 1; 59(3): 314–324
Thailand, N=202, LD = 25%
Receiving PI 41%,
Received d4T 60%
Sawawiboon N. International Journal of STD & AIDS
2012; 23: 497–501
Facial lipoatrophy
Is it reversible?
Facial Lipoatrophy
may improve after
stopping d4T
Improvement found in 23%,
at mean duration of 45
months after stopping d4T,
around early adolescence
Need to stop d4T
before reaching
adolescence
Sawawiboon N. International Journal of STD & AIDS 2012; 23: 497–501
What about high FBS once?
What would you do?
A. Control sugar intake and repeat FBS
B. Perform OGTT
C. It’s mostly transient, repeat FBS
in 6 months
Interpretation of Fasting Blood Sugar
Normal FBS
Provisional DM
Impaired FBS
FBS 100 mg/dl
126 mg/dl
Oral Glucose Challenge Test:
Must be done in all cases of impair FBS
Normal OGTT
Provisional DM
Impaired OGTT
2 hr PG 140 mg/dl
200 mg/dl
Why do we need to worry about DM?
A. A lot of treatment and complication
of DM to follow, interrupt normal life
B. DM increased risk of ART associated
CVD
C. Early intervention (exercise and
metformin) may prevent or delayed
DM and complications
Diagnosis of Diabetes Mellitus
 Symptoms of DM plus casual BG ≥200 mg/dL
(polyuria, polydipsia, and unexplained weight
loss) or
 FBS ≥126 mg/dL or
 2-hr BS ≥200 mg/dL during an OGTT or
 HbA1C ≥ 6.5%
Pre-diabetes
• Impaired FBS 100-125 mg/dL
• Impaired OGTT: 2 hr glucose 140-199 mg/dL
• HbA1c 5.7-6.4%
American Diabetes Association. Diabetes Care 2010
9 yo. boy with acanthosis nigricans
Oral Glucose Tolerance Test
0
30
60
90
120
BS
58
134
181
165
188
Insulin
88.7
842.3
>1000
>1000
>1000
Diagnosis: Impaired OGTT with hyperinsulinemia>>Pre-diabetes
Normal fasting lipid profile
Chol
LDL-C
HDL-C
TG
174
120
51
140
Insulin Resistance and Type 2 Diabetes
in HIV-Infected Children
 Prevalence in adults 10-20%
 Increase prevalence in patients receiving
HAART with lipodystrophy1
 Incidence in children is much lower
 However, 19% of children receiving PI had
impair OGTT2
1.Vigouroux C. Diabetes & Metabolism 1999
2. Bitnun A. J Clin Endocrinol Metab 2005
Insulin Resistance and HIV
Classical T2DM risk
HIV-associated risk factors
factors
 Peripheral lipoatrophy
 Obesity (abdominal)
 Physical inactivity
 Increased liver or muscle
fat
 Genetic
 Inflammatory cytokines
 Family history
 Race
 Older age
 Dyslipidemia
 Low testosterone
 Oxidant stress
 HCV infection
 PIs therapy
How can we prevent DM in
this patient?
A. Diet and exercise
B. Diet and exercise and metformin
C. Control other factor:
dyslipidemia
Exercise and Metformin can prevent DM
Reduction in the Incidence of
T2 DM with Lifestyle
Intervention or Metformin
• 3234 patients with IFG or IGT
• Treatment; placebo,
metformin, lifestylemodification program
• Lifestyle-modification
program: 7% weight loss and
150 mins of physical activity
per week
• Average follow-up was 2.8 yr
Diabetes Prevention Program. N Engl J Med 2002:346:393-403
Exercise and Metformin can prevent DM
At 3 years
28.9%
21.7%
14.4%
Lifestyle gr.: reduced the risk of converting to
DM by 58%
Metformin gr.: reduced the risk of converting
to DM by
31%
Diabetes Prevention
Program.
N Engl J Med 2002:346:393-403
Drugs that may delay or prevent the
development of Type2 DM
None is approved in children
Troglitazone (TRIPOD) (withdrawn due to rare hepatitis)
Hispanic women with GDM  56% risk reduction
Buchanan TA et al. Diabetes 2002
Acarbose (STOPP-NIDDM)
Subject with IGT 32% decreased conversion to T2DM
Chiasson JL et al. JAMA 2003
Xenical (XENDOS)
Subject with BMI >29, lifestyle plus xenical vs
placebo 
37% risk reduction
Torgerson JS et al. Diabetes care 2004
A 9 Year-Old Boy with Perinatal HIV
and Insulin-Resistance
Treatment: Metformin (500) 1 tab oral bid
Encourage healthy life style, exercise
Continue ART: AZT/3TC/LPV/r
Outcomes: 4 mo after treatment
 Wt 44.4 kg (-2 kg),
 Ht 142 cm, BMI 22 kg/m2 (-1.9)
 WC 76.2 cm (-0.3 cm)
After 4 months of Metformin Rx and
exercise: Improved hyperinsulinemia and BS
OGTT 8/11/06
0
30
60
90
120
58
88.7
134
842.3
181
>1000
165
>1000
188
>1000
0
30
60
90
120
58
13.19
95
130.9
116
249.4
99
139.3
99
161.1
BS
Insulin
OGTT 12/1/07
BS
Insulin
6 Months later…He
developed
hyperlipidemia
Fasting lipid profile
Date
Chol
LDL-C HDL-C
TG
7/25/06
12/7/07
174
232
120
138.4
140
113
51
71
NCEP Definition for Dyslipidemia in
Children and Adults
TG was not established by NCEP; a TG level of 125 mg/dL approximates the mean 95th
percentile for TGs in boys and girls during childhood and adolescence.
Why do we need to care about dyslipidemia?
Should we just leave it for the adult doctors to take care of the
business when the child grown-up!
 It is an important risk factor for CVD in adults
 Atherosclerosis starts in childhood, esp. if TC>200 and
LDL-C >130 mg/dl
 Very common, found 60%-80% in children receiving HAART,
particularly PI1-3, found more in patients with lipodystrophy
 Some PI cause less dyslipidemia: ATV, DRV
1.Lapphra K. J Med Assoc Thai. 2005. 2. Taylor P. Pediatrics 2004. 3. Amaya RA. Pediatr Infect Dis J. 2002
Metabolic complications:
>>Start from lipodystrophy,
>>dyslipidemia, insulin resistance
End up with cardiovascular diseases,
stroke, DM
Dyslipidemia found 40%-80% in children,
associated with receiving PI and lipodystrophy1-3
Prevalence of Dyslipidemia in a European cohort of HIV-infected
children and adolescents (N=426), 60% receiving PI4
Fasting Hypertriglyceridemia
66%
45%
21%
Hyper-cholesterolemia
49%
28%
1%
Glucose intolerance
5%
4%
1.Lapphra K. J Med Assoc Thai. 2005. 2. Taylor P. Pediatrics 2004. 3. Amaya RA. Pediatr Infect Dis J.
2002, 4. Alam NM. J Acquir Immune Defic Syndr. 2012 March 1; 59(3): 314–324
Frequency of abnormal lipid profile in
Thai adolescents
Siriraj, Bangkok, 2013
HIV-infected Healthy
N = 100
Total = 50
P value
CHOL > 200
mg/dl
LDL > 130 mg/dl
25 (25%)
12 (24%)
0.867
16 (16%)
8 (16%)
0.733
HDL < 35 mg/dl
8 (8%)
0 (0)
0.017
TG > 150 mg/dl
37 (37%)
49%
receiving PI
1 (2%)
<0.001
V. Poomlek. 7th IAS 2013, KL, MOPE047
Risk of Myocardial Infarction in Patients Exposed to Specific
Individual Antiretroviral Drugs : The Data Collection on
Adverse Events of Anti-HIV Drugs (D:A:D)
Worm SW. JID 2010;201:318-30.
What else can we do other
than even more encouraging
lifestyle modification?
A: Change ARV
B: Start statin
C. Start fibrate
Treatment of dyslipidemia in children
• Exercise at least 1 hr per day
• Modified diet (<30% total fat and <7% of sat fat, <200 mg of
cholesterol/day)
• Statin only in those with persistent TC>200 mg/dl and LDL-C
>130 mg/dl, not for < 8 yo, unknown long-term effect.
• Fibrate for hypertriglyceridemia (>400 mg/dl)
• ARV modification
Intervention in this patient:
• Educate for life style modification: Low fat diet and exercise
• Change LPV/r to ATV/r
Lipid Changes at Week 48 with
Baseline in PI Studies
He started to be uneasy to take ARV
Date
%CD4
CD4 count
VL
Medication
1/6/2010
(12 Y)
20.58
572
-
AZT+3TC+ATV/
r
7/9/2010
(12 Y)
-
-
-
TDF+3TC+ATV/
r
18/3/2011
(13 Y)
22.88
510
**Once daily
regimen
<40
TDF+3TC+ATV/
r
Fasting Blood Sugar : 138mg/dl
Cholesterol 155 mg/dl
Triglyceride 159 mg/dl LDL 74 mg/dl
HDL 50 mg/dl
Diet education for dyslipidemia
High
Cholesterol
Diet
High Triglyceride Diet
Diabetic diet education
5 Years after starting treatment
And became a teenager
He becomes an uneasy adolescent and start to have poor
compliance to metformin and diet and weight control
- He continue to gain more weight
BP: 130/90 mmHg
TG = 202 mg/dl, HDL 52 mg/dl, Cholesterol 224 mg/dL
Follow-up
• FBS
• HbA1C
400 mg/dl
Dx: DM
Start Insulin SC
13.8 %
Does he meet the criteria
for metabolic syndrome?
…..Yes or No
Metabolic Syndrome
A Cluster of
 Abdominal obesity
 Increased triglyceride levels
 Decreased HDL-cholesterol levels
 Hyperglycemia
 Hypertension
A meta-analysis of the prospective
studies has shown that the presence of
metabolic syndrome increases the risk of
Type2 DM and CVD
Galassi A. Am J Med. 2006
Metabolic Syndrome in children and adolescents:
The clusters of metabolic risk factors
(International Diabetes Federation)
Presence of
metabolic
syndrome
increases risk of
- CVD (RR 1.53;
1.26-1.87)
- CHD(RR 1.52;
1.37-1.69)
- Stroke (RR 1.76;
1.37-2.25).
Galassi A. Am J Med 2006;119:812-9
International Diabetes Federation
(IDF) Criteria for MS in Children
Age
group
Obesity (WC)
TG
(mg/dl)
HDL-C
(mg/dl)
BP (mmHg)
BG (mg/dl)
6<10
≥90th% tile
10<16
≥90th% tile or
adult cut-off
≥150
<40
Sys≥130 or
Dias≥85
FBG ≥100
or T2DM
≥16
≥90 cm in
male,
≥80 cm in
female
≥150
<40 in male,
<50 in female
Sys≥130 or
Dias≥85
FBG ≥100
or T2DM
Central obesity plus any two of other criteria
Zimmet P et al on Behalf of the International Diabetes Federation Task Force on
Epidemiology and Prevention of Diabetes. Lancet 2007:369:2059-2061
Criteria Dx Metabolic
syndrome in this patient
BW > P97
 Triglyceride > 150 mg/dl
 FBS > 100 mg/dl
 BP 120/80-128/80 mmHg
 HDL 45-50 mg/dl
Metabolic syndrome among HIV-infected
patients: related factors
Incidence 5.1% in <30 yo., 27% in 50-59 yo.
Jerico C. Diabetes Care. 2005 Jan;28(1):132-7.
Pathogenesis of Metabolic Complications
in HIV-infected Patients
 HIV infection increase inflammatory cytokines
 TNF inhibits the uptake of FFA by adipocyte, increase
lipogenesis
 IL-6 and adipocytokines cause dyslipidemia and lipodystrophy
 May directly induce insulin resistance
 Protease inhibitor
 Effect several steps causing dyslipidemia, IR, and
lipodystrophy
 NRTI
 Cause mitochondrial dysfunctionlactic acidosis adipocyte
death
Development of HIV and PI associated
lipodystrophy/ IR
11β-HSD1, 11βhydroxysteroid
dehydrogenase
type 1; FFA, free
fatty acids;
ROS, reactive
oxygen species;
Anuurad E. Curr Opin Endocrinol Diabetes Obes. 2010 Oct;17(5):478-85.
Screening and
intervention for metabolic
complications in
HIV-Infected Patients
is needed especially
for patients at risk
Contribution of risks factors for CAD in
HIV-Positive Persons
1.04
1.25
1.47
Estimated effect (95%CI)
on the odds ratio of a first
CAD event for:
- genetic risk score quartile
(black dots),
- HIV-related variables
(gray triangles)
- traditional CAD risk
factors (gray squares).
Rotger M. CID 2013 Jul;57(1):112-21.
Physical exam/wt/ht/wc
Check FBS, Lipid q 6 mo.
Impaired
FBS
Oral Glucose Tolerance Test (OGTT)
Dyslipidemia
• Glucose 1.75g/kg/dose (Max 75g)
• Blood for Blood sugar and insulin
• (at 0, 60, 120 min)
• Life style modification
• ART modification
• Lipid lowering agent if
not response
Impaired
OGTT
Hyperinsuline
mia
• Start Metformin
• DM education
• Life style modification
• ART modification
normal
•F/U FBS q 3-6 months
F/U FBS, HbA1C q 3
months if
• HbA1C > 9 or
• FBS > 200 mg/dl
Start Insulin SC
Management of Metabolic Complications in
HIV-Infected Children and Adolescents
• Step 1
• Lifestyle modification with diet and exercise
• Weight control
• Change PI to NNRTI or ATV/r or DRV/r, may consider
unboosted ATV or low dose LPV/r
• Step 2
• Metformin (for >10 yo) if impair OGTT, or Insulin
injection if meet criteria for DM
• Fibrate if TG>400 mg/dl
• Lowest dose statin (pravastatin or atorvastatin) if TC >
200 mg/dl (approve in > 8 yo)
Need to work with the family and psychological support
Therapeutic Goals
Glycemic recommendations
HbA1c <7%
FBG: 70-130 mg/dL
Fed glucose <180 mg/dl
Weight/diet
BMI < 25 kg/m2
Exercise > 150 min/week
Diet <7% saturated fat
Adapted from ADA and EASD consensus 2009
Therapeutic Goals
Dyslipidemia
• LDL-C < 100 mg/dl
• HDL-C > 35 mg/dl
• TG < 150 mg/dl
Blood pressure
• Established HT in children: BP <
95th % for age, sex and height
Adapted from ADA and EASD consensus 2009, Libman IM. 2007
How to treat LD?
• Stop using d4T (do not use d4T for > 6 months) >>
Phasing out d4T
• Avoid PI (may not be possible, or use ATV/r or DRV/r
• Medical: None is really effective and practical
• Liposuction for severe buffalo hump
• Filling therapy for facial lipoatrophy: may consider in
adults
Before
After
Prevention of Metabolic Complications
in HIV-Infected Children & Adolescents
 Healthy life style
 weight control
 regular exercise
 low saturated fat diet, eat fish and veggies
 No smoking
 Avoid PI (25% of Asian children are
receiving PI)
 Serious with adherence to first line NNRTI
regimens, NVP has the least long-term problem
 Screening and early intervention in
borderline dyslipidemia
Cardiac
dysfunction
Cardiomyopathy
associated with severe
HIV diseases and
improved with HAART.
However, long term ART
may associated with
increased cIMT.
3 year- old girl with pneumonia and
cardiomyopathy
• Echocardiogram before ART
(14/6/2010)
– Severe MR
– LV dilatation with hypokinesia LV
wall, LVEF 16%
– Minimal pericardial effusion
– Imp: Dilated cardiomyopathy with
severe MR
• CD4= 1,346 (14%), VL 1.5x106
• Treatment
– ATB, Lasix, aldactone, dobutamine
– Start AZT/3TC/NVP
• At 10 yo still have abnormal LVEF
How can we prevent early CHD in
HIV-infected children receiving
ART?
A. Start ART early
B. Strengthen adherence to NNRTI
regimen
C. Diet and excercise
Structural and Functional Vasculature
Changes in HIV-Infected Children
• Carotid intima-media
thickness (IMT):
• Increased in HIV-infected
vs control uninfected
children (p<0.001).
• In infected children, PI
treatment associated
with increased carotid
IMT.
•
HIV+
control
* p=0.04
**p=0.01
• Suggests both HIV &
antiretroviral drugs
play role.
Charakida M et al. Circulation 2005;112:103-9
Untreated
Non-PI treated
PI treated
The cIMT in association with on PI > 6
months in HIV-infected Thai adolescents
cIMT (mm)
Receiving PI > 6
Receiving PI < 6
months (n=53)
months or
P value
never(n=47)
Proximal CCA
0.393 (0.284-0.478)
0.369 (0.289-0.448)
0.019
Distal CCA
0.40 (0.273-0.475)
0.381 (0.311-0.441)
0.022
ICA
0.353 (0.283-0.514)
0.345 (0.26-0.431)
0.179
Overall cIMT
0.379 (0.284-0.451)
0.372 (0.287-0.423)
0.02
The values were presented in median (range)
Low bone mass,
Osteopenia and
Vitamin D
deficiency
A 15 years old Thai boy with growth failure
Age
Regimen
CD4
VL
7y
AZT+3TC+EFV
45
>75,0000
8y
“
461
26,400
11 y
AZT+3TC+TDF+LPV/r
12 y
“
638
163
13 y
“
784
< 40
• At 1 year-old, he had recurrent severe pneumonia,
delayed development, and growth failure.
• At 5 year-old, he had pulmonary TB
• He always be very small despite successful antiretroviral
therapy
DXA scan of lumbar spine (L2-L4)
Bone densitometry
(Dual-energy x-ray
absorptiometry; DXA)
performed at 15 year-old
BMD
Z-score
Adjust to height age
(12 y)
0.721
-0.9
Adjust to Thai
reference (15 y)
0.721
-2.1
Both HIV and ARV Associated with
Osteopenia: A meta-analysis
Brown TT. AIDS 2010;20:2165-74.
Bone Mass Accumulate From
Childhood and Loss in Adulthood
Greatest bone mass gain at spine and hip is at:
- Girls: 11-14 yo. Tanner 2-4
- Boys: 13-17 yo. Tanner 4
Therefore, prevention of osteoporosis
and fracture must be started in
childhood
Theintz G. J Clin Endocrinol Metab 1992;75:1060-5.
Rizzoli R. Osteoporos Int 1999;9 (suppl 2):S17-23.
Bone mineral content is lower in
prepubertal HIV-infected children
Healthy
HIV+
Age versus total body bone mineral content (TBBMC) adjusted for sex,
race, height, and weight in HIV-infected (squares) and healthy (diamonds)
prepubertal children.
Arpadi SM. JAIDS 2002;29:450-4.
Prevalence of low BMD measured by spine BMD
(L2-L4) in Thai HIV-infected adolescents: The
first study in Asia
Adjusted for
Thai reference
%
N=98
Z-score percentage
%
%
%
BMD
Puthanakit P. J Acquir Immune Defic Syndr. 2012 Aug 22
Pathogenesis of osteoporosis in HIV-infected patients
Protease inhibitors
HIV
(gp120)
Other cells
CD4 T cells
TDF associated PRTD
HIV (Tat)
RANKL
M-CSF
Osteoclast
differentiation
RANKL, OPG
Receptor activator
of nuclear factor
kappa-B ligand
Osteoprotegerin
ligand
Osteoclast activity
Bone resorption
- Low calcium intake
- Vit D deficiency
Osteopenia
Osteoporosis
Increased
bone
turnover
Vitamin D and clinical disease progression
in HIV infection: EuroSIDA study
Kaplan–Meier estimation of progression. Kaplan–Meier estimation of
progression to (a) AIDS-defining events, (b) all-cause mortality, and
(c) non-AIDS-defining events according to 25(OH)D concentration
tertile at baseline.
Viard JP. AIDS 2011:25:1305-15.
Association of Vitamin D Insufficiency
with Carotid Intima-Media Thickness
in HIV-Infected Persons
Adjusted Mean Carotid IntimaMedia Thickness by Vitamin D
Category*After adjustment for
traditional cardiovascular risk
factors and HIV-related factors,
a graded relationship between
vitamin D levels and carotid IMT
was observed, P 5 .021).
*Carotid intima-media thickness
predicted by the multivariable
linear regression model after
adjustment for age, sex, race,
coronary heart disease,
hypertension, dyslipidemia,
pack-years of smoking, NRTI
duration, HIV duration, season,
total cholesterol, LDL, waist to
hip ratio, and calcium
supplementation, corrected
calcium, alkaline phosphatase,
parathyroid hormone, and 1,25OH vitamin D level. Error bars
represent 95% confidence
intervals.
Choi AI. CID 2011;0:1-4.
Association between initiation of antiretroviral
therapy with efavirenz and decreases in
25-hydroxyvitamin D
• EFV induces CYP3A4 and CYP24,
reducing CYP2R1, the enzyme involving
in Vit D metabolism
Brown TT. Antiviral Therapy 2010;15:425-9.
Prevalence of vitamin D deficiency in Thai HIV-infected
adolescents: As High as Healthy Thai Children
In healthy children 19% were <20 ng/ml, and 60% were 20-30 ng/ml
Reesukumal K. Clinical Chemistry 2012;58(10) Supplement:A153.
% Vitamin D category
In HIV-infected adolescents
46%
29%
25%
Deficiency
Insufficiency
Chokephaibulkit K. PIDJ 2013
Kidney
Dysfunction
Screening is
important because
early renal diseases
are asymptomatic
Incidence of Persistent Renal Dysfunction in
HIV-Infected Children in PACTG 219/219c
Incidence of new renal lab abnormalities was 3.7
events/100 child-years,
with rates increasing between 1993-2005
Andiman W et al. Pediatr Infect Dis J 2009;28:619-25
Estimated chronic
kidney disease and
antiretroviral drug
use in HIV-positive
patients
CKD defined as confirmed
(persisting for 3 months)
decrease in eGFR to 60
ml/min per 1.73m2 or less
if eGFR at baseline above
60 ml/min per 1.73m2 or
confirmed 25% decrease in
eGFR if baseline eGFR 60
ml/min per 1.73m2 or
less).
Mocroft A. AIDS 2010;24:1667-78.
No chance for HIV-infected
children with renal failure
13 year-old girl died from CRF
An episode of HSV stomatitis
• At 5 yo, presented with nephrotic
syndrome responded well to
HAART and steroid
• She has been virologic suppressed
with normalized CD4 for more
than 6 years
• At 12 yo, presented with renal
failure required renal
replacement with CAPD
• Experienced several peritonitis
events and failed CAPD
• She was refused for hemodialysis
and renal transplantation
Neuro-psychiatric
issues
Impact of HAART on HIV encephalopathy among
perinatally infected children and adolescents.
Incidence of HIV encephalopathy and percentage of
Patel
AIDS 2009;23:1893-1901.
children on HAART from 1994
to K.
2006.
Mental Health Disorders in
HIV-Infected Children and Adolescents
• Review of 8
studies including
328
HIV-infected
children age 4-21
years; prevalence
compare with
overall population
percent
35
29%
30
25
25 %
24%
20
15
10
5
0
ADHD
Increased risk ratio
6x
Anxiety Dis
3.8x
Depression
7.1x
Scharko AM. AIDS Care 2006;18:441-5
Impact of HIV Severity on Cognitive and Adaptive
Functioning During Childhood and Adolescence
% impairment
Exposed uninfected
Infected w/o stage C
Infected w stage C
Smith R. PIDJ 2012;31:592-8.
A 13 Year-old Girl who suddenly became
furious and angry with everything
Date
Age
Regimen
CD4
VL
no
%
11/3/2003
8 yrs. 11 mo.
Start
AZT+3TC+EFV
25
0.9
40,400
10/2/2004
9 yrs. 10 mo.
“
596
19
<400
8/1/2008
13 yrs. 9 mo.
“
1,052
42
<40
Remark
Wt. 35 kg. on EFV 400mg/d
EFV Level=13,945 ng/ml
EFV reduced to 200 mg/
day
EFV Level=5,002 ng/ml
Symptoms improved after
dose reduction
16/6/2009
15 yrs. 2 mo.
“
912
35
<40
5/1/2010
16 yrs. 9 mo.
“
1,171
44
<40
High levels of NVP and EFV may be
found in 10% of Thai children
Nevirapine plasma exposure and CYP2B6 516 G>T
polymorphisms after administration of GPO-VIR Z30 in
HIV-infected Thai children
Rate 45%
45%
10%
Chokephaibulkit K. Antivir Ther 2011;16:1287-95
Without good screening and early
intervention, it may end up with
premature age-related
comorbidities
Premature Age-Related Comorbidities Among
HIV-Infected Persons Compared With General
Population
Comparative risk of hypertension, diabetes mellitus, renal failure,
cardiovascular disease, and fracture, by age, among patients versus
control subjects.
Guaraldi G. CID 2011;53:1120-6.
Prevention of long term
treatment complications
• Start ARV early, prefer NNRTI for 1st regimen
• Support adherence to the 1st line NNRTI regimens as
long as possible>> delayed PI use
• Avoid long-term d4T
• Use TDF only when no other alternative NRTI
• Healthy life style
• Regular exercise, control weight
• Get enough sun light or vit D supplement
• Eat healthy, low saturated fat diet, eat fish and veggies
• Get enough calcium
• No addiction to drugs, games, tobacco, alcohol, etc
• Screen and early treat for metabolic complications,
kidney (esp. TDF), liver, neuropsychiatric, and bone
health (esp. TDF)
Most children and adolescents do
not get enough calcium!
Greer FR. Pediatrics 2011;117:578-85.
Which children should be
monitored BMD?
• May be before or during treatment regimens
with TDF or PI, especially with risks:
- Lean, small, or growth failure
- Have history of fracture with minimal trauma
But make sure to know how to interpret. Best is to use ethnic
specific reference. The different machine do not give same results,
may need conversion
GE-Lunar = 1.195 x Hologic – 0.023
(Fan B, et al. Osteoporos Int (2010) 21:1227–1236.)
Thank
you
for your
attention.