Long Term Complications of

Treatment in Children

By By

Kulkanya Chokephaibukit, MDKulkanya Chokephaibukit, MDProfessor of PediatricsProfessor of Pediatrics

Faculty of Medicine Siriraj HospitalFaculty of Medicine Siriraj Hospital

Mahidol University, Bangkok, Mahidol University, Bangkok, ThailandThailand

Lecture at HIVNAT 25 July 2013Lecture 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

Age %CD4 CD4 count VL ART

18 mo 12.39 256 - AZT+3TC

3 Y 2.03 48 - d4T+ddI+EFV

4.5 Y 2.79 72 504,000M41L, D67N

K101E, V179D

d4T+3TC+EFV

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 for 2 years

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

The 9 year-old boy with dark neck

Hyperpigmentation of the neck and

armpits, dorsocervical hump

What is your diagnosis of his skin hyperpigmentation?

A. genetic B. Acanthosis nigricansC. poor hygeine

What is the common condition associated with this skin hyperpigmentation?

A. Insulin resistance and diabetes

B. Dyslipidemia

C. Malignant melanoma

Acanthosis nigricansAcanthosis nigricansA clue for IRA 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 ListsProblem 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. Likan

onsakul 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

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

Lipodystrophy from d4T

Alam NM. J Acquir Immune Defic Syndr. 2012 March 1; 59(3): 314–324

Body fat abnormality in HIV-infected children and adolescents: The difference of regions

Lipoatrophy 23%

Europe (N= 426, LD = 42% Receiving PI 60%, Received d4T 10%

Thailand, N=202, LD = 25%Receiving PI 41%, Received d4T 60%

Lipohypertrophy or combine 2.5%

%

No fat maldistribution 75%

Sawawiboon N. International Journal of STD & AIDS 2012; 23: 497–501

Study Population

Facial Lipoatrophy may improve after stopping d4T

Improvement found in 23%, at mean duration of 45 months after stopping d4T, around early adolescence

Sawawiboon N. International Journal of STD & AIDS 2012; 23: 497–501

Facial lipoatrophyIs it reversible?

Need to stop d4T before reaching

adolescence

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

Provisional DMNormal FBS

Impaired FBS

100 mg/dl 126 mg/dlFBS

Oral Glucose Challenge Test: Must be done in all cases of impair FBS

Provisional DMNormal OGTT

Impaired OGTT

140 mg/dl 200 mg/dl2 hr PG

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

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

Diagnosis of Diabetes MellitusDiagnosis of Diabetes Mellitus

Oral Glucose Tolerance Test

0 30 60 90 120

BS 58 134 181 165 188

Insulin 88.7 842.3 >1000 >1000 >1000

Normal fasting lipid profile

Chol LDL-C HDL-C TG

174 120 51 140

Diagnosis: Impaired OGTT with hyperinsulinemia>>Pre-diabetes

9 yo. boy with acanthosis nigricans9 yo. boy with acanthosis nigricans

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

Insulin Resistance and Type 2 Diabetes in HIV-Infected Children

1.Vigouroux C. Diabetes & Metabolism 19992. Bitnun A. J Clin Endocrinol Metab 2005

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

Insulin Resistance and HIV

How can we prevent DM in this patient?

A. Diet and exercise

B. Diet and exercise and metformin

C. Control other factor:

dyslipidemia

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

Diabetes Prevention Program. N Engl J Med 2002:346:393-403

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.

Exercise and Metformin can prevent 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

Drugs that may delay or prevent the development of Type2 DM

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)

OGTT 12/1/07

0 30 60 90 120

BS 58 95 116 99 99

Insulin 13.19 130.9 249.4 139.3 161.1

0 30 60 90 120

BS 58 134 181 165 188

Insulin 88.7 842.3 >1000 >1000 >1000

OGTT 8/11/06

After 4 months of Metformin Rx and exercise: Improved hyperinsulinemia and BS

Fasting lipid profileDate Chol LDL-C HDL-C TG

7/25/06 174 120 51 140

12/7/07 232 138.4 71 113

6 Months later…He developed hyperlipidemia

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

Prevalence of Dyslipidemia in a European cohort of HIV-infected children and adolescents (N=426), 60% receiving PI4

Fasting Hypertriglyceridemia66%

Hyper-cholesterolemia49%

Glucose intolerance5%

4%

21%

28%

1%

45%

Dyslipidemia found 40%-80% in children, associated with receiving PI and lipodystrophy1-3

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 adolescentsSiriraj, Bangkok, 2013

HIV-infected N = 100

HealthyTotal = 50

P value

CHOL > 200 mg/dl 25 (25%) 12 (24%) 0.867

LDL > 130 mg/dl 16 (16%) 8 (16%) 0.733HDL < 35 mg/dl 8 (8%) 0 (0) 0.017

TG > 150 mg/dl 37 (37%) 1 (2%) <0.001

V. Poomlek. 7th IAS 2013, KL, MOPE047

49% receiving PI

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

• 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

• 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

Intervention in this patient:• Educate for life style modification: Low fat diet and exercise• Change LPV/r to ATV/r

Treatment of dyslipidemia in children

Lipid Changes at Week 48 with Baseline in PI Studies

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 <40 TDF+3TC+ATV/r

He started to be uneasy to take ARV

**Once daily regimen

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

He becomes an uneasy adolescent and start to have poor compliance to metformin and diet and weight control

- He continue to gain more weightBP: 130/90 mmHgTG = 202 mg/dl, HDL 52 mg/dl, Cholesterol 224 mg/dL

He becomes an uneasy adolescent and start to have poor compliance to metformin and diet and weight control

- He continue to gain more weightBP: 130/90 mmHgTG = 202 mg/dl, HDL 52 mg/dl, Cholesterol 224 mg/dL

Follow-up • FBS 400 mg/dl• HbA1C 13.8 %

Follow-up • FBS 400 mg/dl• HbA1C 13.8 %

Does he meet the criteria for metabolic syndrome? …..Yes or No

Does he meet the criteria for metabolic syndrome? …..Yes or No

Dx: DMStart Insulin SC

5 Years after starting treatmentAnd became a teenager

Metabolic Syndrome

A Cluster of Abdominal obesity Increased triglyceride levels Decreased HDL-cholesterol levels Hyperglycemia HypertensionA 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

Zimmet P et al on Behalf of the International Diabetes Federation Task Force on Epidemiology and Prevention of Diabetes. Lancet 2007:369:2059-2061

Central obesity plus any two of other criteria

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

BW > P97 Triglyceride > 150 mg/dl FBS > 100 mg/dl BP 120/80-128/80 mmHg HDL 45-50 mg/dl

Jerico C. Diabetes Care. 2005 Jan;28(1):132-7.

Incidence 5.1% in <30 yo., 27% in 50-59 yo.

Metabolic syndrome among HIV-infected patients: related factors

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 dysfunctionlactic acidosis adipocyte death

Anuurad E. Curr Opin Endocrinol Diabetes Obes. 2010 Oct;17(5):478-85.

11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1; FFA, free

fatty acids; ROS, reactive

oxygen species;

Development of HIV and PI associated lipodystrophy/ IR

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

Rotger M. CID 2013 Jul;57(1):112-21.

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).

Impaired FBS

Oral Glucose Tolerance Test (OGTT) • Glucose 1.75g/kg/dose (Max 75g)• Blood for Blood sugar and insulin • (at 0, 60, 120 min)

Impaired OGTT normal

Hyperinsulinemia

F/U FBS, HbA1C q 3 months if• HbA1C > 9 or • FBS > 200 mg/dlStart Insulin SC

•F/U FBS q 3-6 months

• Start Metformin• DM education• Life style modification• ART modification

Physical exam/wt/ht/wcCheck FBS, Lipid q 6 mo.

Dyslipidemia

• Life style modification• ART modification • Lipid lowering agent if not response

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 supportNeed to work with the family and psychological support

Therapeutic Goals

Glycemic recommendationsHbA1c <7%FBG: 70-130 mg/dLFed glucose <180 mg/dl

Weight/dietBMI < 25 kg/m2

Exercise > 150 min/weekDiet <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 Complicationsin 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.

• Suggests both HIV & antiretroviral drugs play role.

* p=0.04

**p=0.01

• HIV+

control

PI treatedNon-PI treatedUntreatedCharakida M et al. Circulation 2005;112:103-9

cIMT (mm) Receiving PI > 6

months (n=53)

Receiving PI < 6

months or

never(n=47)

P value

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)

The cIMT in association with on PI > 6 months in HIV-infected Thai adolescents

Low bone mass, Osteopenia and

Vitamin D deficiency

A 15 years old Thai boy with growth failure

• 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

Age Regimen CD4 VL

7 y AZT+3TC+EFV 45 >75,0000

8 y “ 461 26,400

11 y AZT+3TC+TDF+LPV/r

12 y “ 638 163

13 y “ 784 < 40

BMD Z-score

Adjust to height age (12 y)

0.721 -0.9

Adjust to Thai reference (15 y)

0.721 -2.1

DXA scan of lumbar spine (L2-L4)DXA scan of lumbar spine (L2-L4)

Bone densitometry (Dual-energy x-ray

absorptiometry; DXA) performed at 15 year-old

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

Theintz G. J Clin Endocrinol Metab 1992;75:1060-5.

Rizzoli R. Osteoporos Int 1999;9 (suppl 2):S17-23.

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

Bone mineral content is lower in prepubertal HIV-infected children

Arpadi SM. JAIDS 2002;29:450-4.

Age versus total body bone mineral content (TBBMC) adjusted for sex, race, height, and weight in HIV-infected (squares) and healthy (diamonds) prepubertal children.

Healthy

HIV+

Prevalence of low BMD measured by spine BMD (L2-L4) in Thai HIV-infected adolescents: The first study in Asia

Adjusted for Thai reference

Z-s

core

perc

en

tag

e

Puthanakit P. J Acquir Immune Defic Syndr. 2012 Aug 22

N=98%

%

%

%

BMD

HIV(gp120)

HIV (Tat)RANKLM-CSF

Osteoclastdifferentiation

CD4 T cells

Protease inhibitors

Other cells

RANKL, OPG

Osteoclast activity

Bone resorption

OsteopeniaOsteoporosis

- Low calcium intake- Vit D deficiency

Pathogenesis of osteoporosis in HIV-infected patients

TDF associated PRTD

Increased bone

turnover

Receptor activator of nuclear factor kappa-B ligand

Osteoprotegerin ligand

Vitamin D and clinical disease progression in HIV infection: EuroSIDA study

Viard JP. AIDS 2011:25:1305-15.

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.

Association of Vitamin D Insufficiency - with Carotid Intima Media Thickness

- in HIV Infected Persons

Choi AI. CID 2011;0:1-4.

- AdjustedMean Carotid Intima Media Thickness by Vitamin D Category* A

f ter adj ustment for tradi ti onal cardi ovascul ar ri sk factors and

- HIV related factors, a gradedrelatio nship between vitamin D levels and

carotid IMT was observed, P5 .0 - 2 1 ). * Carotid intima media thick

ness predicted by the multivariable l inear regression model after adjust ment for age, sex, race, coronary he

artdisease,hypertensi on, dyslipidemia, pac- k years of smoking, NRTI duration, H

IVduration,season,totalcholesterol,LDL,waisttohi prati o,andcal ci umsup plementation,correctedcal ci um,al kal i ne phosphatase,

-parathyroidhormone, and 1 ,2 5 OHvitamin D level. Error bars repres

ent95%confidencei nterval s.

Association between initiation of antiretroviral therapy with efavirenz and decreases in 25-hydroxyvitamin D

Brown TT. Antiviral Therapy 2010;15:425-9.

• EFV induces CYP3A4 and CYP24, reducing CYP2R1, the enzyme involving in Vit D metabolism

Chokephaibulkit K. PIDJ 2013

In healthy children 19% were <20 ng/ml, and 60% were 20-30 ng/ml

Prevalence of vitamin D deficiency in Thai HIV-infected

adolescents: As High as Healthy Thai Children

25%

46%

29%

Deficiency Insufficiency

% Vitamin D category In HIV-infected adolescents

Reesukumal K. Clinical Chemistry 2012;58(10) Supplement:A153.

Kidney Dysfunction

Screening is important because

early renal diseases are asymptomatic

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

Incidence of Persistent Renal Dysfunction in Incidence of Persistent Renal Dysfunction in

HIV-Infected Children in PACTG 219/219cHIV-Infected Children in PACTG 219/219c

Incidence of Persistent Renal Dysfunction in Incidence of Persistent Renal Dysfunction in

HIV-Infected Children in PACTG 219/219cHIV-Infected Children in PACTG 219/219c

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).

Estimated chronic kidney disease and antiretroviral drug use in HIV-positive

patients

Estimated chronic kidney disease and antiretroviral drug use in HIV-positive

patients

Mocroft A. AIDS 2010;24:1667-78.

13 year-old girl died from CRF

• 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 transplantationAn episode of HSV stomatitis

No chance for HIV-infected children with renal failure

Neuro-psychiatric issues

Impact of HAART on HIV encephalopathy among perinatally infected children and adolescents.

Patel K. AIDS 2009;23:1893-1901.Incidence of HIV encephalopathy and percentage of

children on HAART from 1994 to 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

Scharko AM. AIDS Care 2006;18:441-5

24

29

25

0

5

10

15

20

25

30

35

ADHD Anxiety Dis Depression

Increased risk ratio 6x 3.8x 7.1xIncreased risk ratio 6x 3.8x 7.1x

percent

%

%%

Impact of HIV Severity on Cognitive and Adaptive Functi oning During Childhood and Adolescence

Smith R. PIDJ 2012;31:592-8.

Exposed uninfected

Infected w/o stage C

Infected w stage C

% impairment

A 13 Year-old Girl who suddenly became furious and angry with everything

Date Age Regimen CD4 VL Remark

no %

11/3/2003 8 yrs. 11 mo. StartAZT+3TC+EF

V

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 Wt. 35 kg. on EFV 400mg/dEFV Level=13,945 ng/ml

EFV reduced to 200 mg/ dayEFV Level=5,002 ng/mlSymptoms 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 inHIV-infected Thai children

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            

45% 45% 10%

Chokephaibulkit K. Antivir Ther 2011;16:1287-95

Rate

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

Guaraldi G. CID 2011;53:1120-6.

Comparative risk of hypertension, diabetes mellitus, renal failure, cardiovascular disease, and fracture, by age, among patients versus control subjects.

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.)

GE-Lunar = 1.195 x Hologic – 0.023 (Fan B, et al. Osteoporos Int (2010) 21:1227–1236.)

Thank you

for your attention.