1. Complications of HIV and its treatment in perinatally infected adolescents Thanyawee Puthanakit, MD Div. of Infectious Diseases, Dept of Pediatrics, Faculty of Medicine, Chulalongkorn University AND HIVNAT, Thai Red Cross AIDS Research Center

2. Longterm consequences of HIV& ART Brain BoneCardiovascular

3. NEUROLOGIC COMPLICATIONS NEURODEVELOPMENTAL OUTCOMES Delayed development Basal ganglia calcification Intracranial aneurysms (cerebral vasculopathy) Poor neurocognitive function Delayed development Basal ganglia calcification Intracranial aneurysms (cerebral vasculopathy) Poor neurocognitive function

4. Cerebral Vasculopathy Incidence 3.4 per 10,000 person year (219 C study) – Incidence rate ratio to HEU = 2.44 (95% CI, 0.48-44.3) – Median age 10.8 yrs, CD4 = 22 cell/mm3, VL = 4.97 log 10 – 50% had cerebral aneurysms on imaging Acute stroke : 8 children (4.5%) (JHU cohort ) – Infarction: basal ganglion, focal cortical, internal capsule – 6/6 who have MRA show narrowing/dilatation of the circle of Willis, 3 had fusiform, 1 had saccular aneurysm. Schieffelin JS. J of Ped Infect Dis Jsoc 2012;2: 50-6 Izbudak I. J Neuroradiol 2013 epub

5. Mechanisms of ischemic stroke in HIV – Autoantibodies anticardiolipin – Decreased levels or impaired function of protein S – Aneurysmal arteriopathy (fusiform or saccular dilatation of the cerebral arteries) – Accelerated atherosclerosis – Dyslipidemia – Smoking – Hypertension Singer EJ. Ther Adv Chroni Dis 2013;4:61-70.

6. Neurocognitive function Why it matters ? – Mental age vs. actual age e.g disclosure, adherence – School/ Work performance – High risk behaviors HIV-infected children has poorer neurocognitive outcomes compared to HIV-negative peers – Review articles showed 1-2 SD below population mean 1 – Poor function both CD4 15% 3,4 – Infants: better mental development scale if early initiate ART 5 – Children: no improvement after ART 2,3 1 Le Doore K, Pediatrics 2010;130:e1326, 2 Puthanakit T et al, AIDS Pt care STDs 2010;24:141-6. 3 Puthanakit T et al,Pediatric Infect Dis J 2013 Jan 2, 4 Ruel TD, et al. Clin Infect Dis 2012;1001-9 5 Laughton B et al. AIDS 2012;26:1685-90.

7. Neurocognitive function: PHACS N = 200 N= 270 N= 88 Age 7-16 years (mean 12 yr), WISC-IV: Normative score: 100 (SD 15) 12% 9% 24% Proportion with score below Mean – 2 SD; FSIQ < 70 Smith R, et al. Pediatr Infect Dis J 2012;31:592-8. Adjusted mean FSIQ score: 83.3 vs 83.4 vs 77.8

8. Neurocognitive function: PREDICT Puthanakit T et al. Pediatr Infect Dis 2013; 32:501-8 ** ** ** ** * ** ** ** At week 144; age 4-15 years (mean 9 years), WISC-III N=139 N=145 N= 155 N=164

9. BONE HEALTH IN HIV CHILDREN Puthanakit T. Siberry G. J Int AIDS Soc. 2013 Jun 18;16:18575 DEXA scan Dual-energy x-ray absorptiometry Children: Lumbar spine DEXA scan Dual-energy x-ray absorptiometry Children: Lumbar spine Bone mineral density (BMD) in g/cm3 Children: BMD z-score Adult: BMD T-score Bone mineral density (BMD) in g/cm3 Children: BMD z-score Adult: BMD T-score

10. Normal bone development Adolescent – 26% of bone mass accrual in 4-yr period of peak height velocity – 60% of adult peak bone mass is established Young adult – Peak bone mass achieved by age 20-25 yrs NICHD BMD in Childhood Study. Kalkwarf et al. J Clind Endo Metab 2007 Modified from slide collection of Dr. Siberry G Children: BMD Z-scores < -2 considered as very low Children: BMD Z-scores < -2 considered as very low

11. Prevalence of Low BMD in HIV BMD Z-score ≤-2.0 = “Very low bone mineral density” US- PHACS (350 HIV + /160 HEU) median age 12.6 yr – Prevalence = 4% vs 1% in HIV-ve – Risk Factors; high peak VL and CD4%, duration on ART Thai (100 HIV + / 190 HIV-ve) median age 14. 3 years – Prevalence = 24% – Risk factors: HAZ < -1.5, Hx of WHO stage 4 Brazil (74 HIV +) mean age 17. 3 years – Prevalence = 32.4% – Risk factors: weight, BMI, Tenofovir, Protease inhibitors Dimeglio LA et al. AIDS 2013;27:211-20. Puthanakit et al. JAIDS 2012;61:477-83.Schtsherbyna A. Int J Infect Dis 2012;16:e872-8.

12. Prevention strategies Ensure adequate nutrition: Calcium 1300 mg & Vit D 600 IU/d Behavior: avoid smoking-alcohol, weight bearing exercise Clinical trial – Vitamin D + Calcium supplement Cholecalciferol 100,000 IU q 2 mo + calcium 1g/d for 2 years ( N= 59) S ignificant increase in 25(OH)D in treatment group but no significant difference in bone accrual between arms IMPAACT P1076: alendronate (bisphophonate) Eligibility: LS DXA Z-sore <-1.5 or Fragility Fx (N= 51) Intervention: 2 yrs ALEN vs ALEN +Plac vs Plac + ALEN PLUS Calcium 600 mg/vitD 400 IU/day Arpadi SM, Am J Clin Nutri 2012;95:678-85 DEXA scan screening: Hx of fractures or having risk factors

13. CARDIOVASCULAR COMPLICATIONS Primary pulmonary hypertension Dilated cardiomyopathy Increase carotid intimal thickness

14. Cardiovascular complications Dilated cardiomyopathy, depressed LV contractility – Pre-HAART: 5-yr cumulative incidence 12% Pulmonary arterial hypertension (PAH) – Incidence 0.5% Premature atherosclerosis – 14 (52%) of has coronary vessel walls irregularity (<25% narrowing of lumen ) by cardiac MRA Lipshultz SE. Expert Rev Anti Infect Ther 2012; 661-74. Lipshultz SE. N Engl J Med 1992; 327: 1260-5. Mikhail IJ. Pediatr Infect Dis J 2011:30:710-2.

15. Effect of HAART to heart HAART has cardioprotective effect P 2 C 2 (no HAART)vs AMP cohort (HAART) vs HEU Rate of cardiomyopathy 44.3 % vs 3.7% vs 1.6% Current VL > 5000 c/ml, nadir CD4 < 15% are predictors for abnormal echocardiograph JAMA Pediatr 2013: 167:521-7.

16. HIV and pulmonary arterial hypertension Prevalence – Primary: 0.5% – Secondary: chronic lung disease Pathology – Intimal medial adventitial proliferation/hypertrophy, plexogenic arteriopathy Clinical course – Increase pulmonary artery & pulmonary vascular resistance, RV failure and premature death – Survival at 1,2,3 yr = 73%, 60%,47% Treatment – HAART, Bosentan, Prostaglandin A 6 yr old girl, CD4 73 cell Receive d4T/3TC/EFV for 6 mo. Orthopnea, PND, O2 sat 93% SEM Grade III/VI at LLSB Echocardiogram: RVH, severe TR (PG 97 mmHg), Mild PR (PG 31 mmHg), A 6 yr old girl, CD4 73 cell Receive d4T/3TC/EFV for 6 mo. Orthopnea, PND, O2 sat 93% SEM Grade III/VI at LLSB Echocardiogram: RVH, severe TR (PG 97 mmHg), Mild PR (PG 31 mmHg), Janda S. HIV Med 2000:11:620-4. Lipshultz SE. J Int AIDS Soc. 2013;16:18597.

17. HIV/ART and atherosclerosis risk PIs increase risk of acute coronary syndrome – Attribute to dyslipidemia, endothelial dysfunction, insulin resistance, hypertension – Abacavir : potentially increase risk Increase carotid intima thickness (cIMT) and impaired flow mediated dilation – Compare between 35 HIV+/37 HIV- control (age 10 yrs) – Internal carotid a. cIMT = 0.90 vs 0.78 mm – Common carotid a. cIMT = 1.00 vs 0.95 mm Ross AC. Pediatr Infect Dis J 2010:29:634-8

18. Conclusions Perinatally HIV-infected children and adolescents are increase risk of long term complications due to HIV itself & ART exposure. Poorer neurocognitive function may effect ability of self-care during adolescent/ young adult. More research is needed to address the real clinical impact of abnormal biomarkers observed (e.g bone mineral density, increase carotid intimal thickness ) and also ways to minimize these complications.

19. Our life “ For my future, I would like to have family, house, rice farm, job and money, which I earn for a living.” “I am on the promising way of hope.” Our life “ For my future, I would like to have family, house, rice farm, job and money, which I earn for a living.” “I am on the promising way of hope.”