A Child With Metabolic Syndrome and
Diabetes: Management Strategy
By
Kulkanya Chokephaibukit, MD
7th IAS 2013, KL, Malaysia, 30 June-3 July 2013.
Session TUWS05: Optimizing pediatric treatment strategies:
Case study for the clinicians
Professor of Pediatrics
Faculty of Medicine Siriraj Hospital
Mahidol University, Bangkok, Thailand
Disclosure
No conflict of
interest
Scope of discussion
• Clinical picture of metabolic complications
in HIV-infected children and adolescents
receiving ART
• How to make diagnosis of insulin
resistance, diabetes, and metabolic
syndrome
• How to manage metabolic complications
of children/adolescents with HIV infection
receiving ART
Metabolic Complications of
HIV Infection and Its Therapy
• HIV/HAART-associated lipodystrophy
syndrome
• Insulin resistance and glucose homeostasis
abnormalities
• Dyslipidemia
• Metabolic syndrome
Let’s start when he was 9
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 count
VL
ART
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
hump
Hyperpigmentation
of the neck and
armpits,
dorsocervical hump
What is your diagnosis of
his skin
hyperpigmentation?
• A. genetic plus poor hygeine
• B. Acanthosis nigricans
What is the common condition
associated with this skin
hyperpigmentation?
• A. Insulin resistance and diabetes
• B. Dyslipidemia
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–
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
Lipohypertrophy or
combine 2.5%%
Lipoatrophy
23%
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 impair FBS (FBS=159)?
Need to diagnose and treat
impair FBS and DM
What would you do?
A. Perform OGTT
B. 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 lot of treatment and complication of
DM to follow, interrupt normal life
• DM increased risk of ART associated
CVD
• 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
factors
• Obesity (abdominal)
• Physical inactivity
• Genetic
– Family history
– Race
• Older age
• Dyslipidemia
HIV-associated risk factors
• Peripheral lipoatrophy
• Increased liver or muscle fat
• Inflammatory cytokines
• 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
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,
lifestyle-modification 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%
Incidence of DM in lifestyle gr.: 39% lower than metformin gr.
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
BS
58
134
181
165
188
Insulin
88.7
842.3
>1000
>1000
>1000
0
30
60
90
120
BS
58
95
116
99
99
Insulin
13.19
130.9
249.4
139.3
161.1
OGTT 12/1/07
6 Months later…He developed
hyperlipidemia
Fasting lipid profile
Date
Chol
LDL-C
HDL-C
TG
7/25/06
174
120
51
140
12/7/07
232
138.4
71
113
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
HIVinfected
N = 100
Healthy
Total = 50
P value
CHOL > 200
mg/dl
25 (25%)
12 (24%)
0.867
LDL > 130 mg/dl
16 (16%)
8 (16%)
0.733
HDL < 35 mg/dl
8 (8%)
0 (0)
0.017
TG > 150 mg/dl
37 (37%)
1 (2%)
<0.001
49%
receiving PI
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
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
1/6/2010
(12 Y)
20.58
572
-
7/9/2010
(12 Y)
-
-
18/3/2011
(13 Y)
22.88
510
Medication
AZT+3TC+ATV/r
TDF+3TC+ATV/r
**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
13.8 %
Dx: DM
Start Insulin SC
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)
FBS > 100
mg/dl
BP>130/
85mmHg
Waist
circumference >
P90
HDL<40
mg/dl
(<50 mg/dl
in female
>16 yo
TG>150
mg/dl
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
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 HIVinfected 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
normal
Hyperinsulinemia
•F/U FBS q 3-6 months
• Start Metformin
• DM education
• Life style modification
•ART modification
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
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?
• 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
Thank you
for your kind attention