1. Paediatric HIV: update EACS Advanced HIV course Montpellier, 3-5 th Sept 2008 Carlo Giaquinto Department of Paediatrics, Padova, Italy

2. Presentation overview Children & HIV in developed countries Women pregnancy & HIV PMTCT / MTCT in developing countries Children & HIV in developing countries

3. Two Pediatric Epidemics High-resource countries New perinatal infections are rare Effective treatment available Aging cohort of infected children Concerns long-term complications of treatment Low-resource countries 1,000 infants are newly infected each day Diagnosis of infection in infants problematic Problems with drug access Treatment when available is started late.

4. Pediatric HIV Infection in the West: A success story 1.Lee GM et al. Pediatrics 2006;117:273-83 2.219 study summary July 23 2007 With effective prevention of most new perinatal HIV infection, it is estimated that <250 newly infected infants are born annually in the U.S and about 500 in Europe. Effective therapies for HIV in children have prolonged life and quality of life 1. The median age of over 3,500 HIV-infected children followed at US pediatric clinical trials sites is 14.8 years 2.

5. In the USA, the Majority of HIV-Infected Children Are Receiving ART Pediatric Spectrum of Disease Project, 1994-2001 McConnell M et al. JAIDS 2005;38:488-94 – PSD includes over 2,000 children from 6 areas US In 2001, 78% of HIV-infected children were on ARV and 66% were receiving 3-drug HAART 0 20 40 60 80 100 Percentage of children 1994 n=2196 1995 n=2235 1996 n=2235 1997 n=2210 1998 n=2218 1999 n=2218 2000 n=2155 2001 n=2040 Monotherapy No Therapy Unclassified Triple Therapy Dual Therapy HAART era

6. Decrease in AIDS, Death, and Hospital Admissions in HIV+ Children in the HAART Era, United Kingdom Judd A et al. Clin Infect Dis 2007;45:918-24 Same as US rate in 2006

7. Mean age at death 2006: 18.2 years Age at Death (1994-2006) in HIV-Infected Children Enrolled in PACTG 219 Long-Term Follow-Up Study Mean age at death 1994: 8.9 years 3,553 children Median f/u 5.3 yrs 298 deaths HAART Era Courtesy Mike Brady, Paige Williams 0 2 4 6 8 10 12 14 16 18 20 22 Age at Death by Year of Death for Infected Children 1994199619982000200220042006 Year Median Age at Death (IQR)

8. Primary Causes of Death (1994-2006) in HIV-Infected Children Enrolled in PACTG 219 N = 3,553 childrenMedian f/u 5.3 yrs298 deaths Courtesy Mike Brady, Paige Williams AIDS OI Cardiomyopathy Stroke End Stage AIDS CNS disease Hepatitis Pheumonia Malignancy Accident / other Sepsis Renal failure 0% 10% 20% 30% 40% 1994–19961997–20002001–2006 Increase 1994–2006:End stage Aids Sepsis Renal Failure

9. Encephalopathy in Pediatric HIV Infection Van Rie A et al. Eur J Pediatr Neurol 2007;11:1-9 Prior to ART, 13-25% of children with HIV infection and 35-50% with AIDS were diagnosed with encephalopathy. Highest incidence 1 st 2 years of life: incidence rate 9.9% in 1 st year, 4.2% in 2 nd year, and <1% thereafter. Reported risk factors for neuroAIDS include: –Maternal advanced disease –Low CD4 count in child –Elevated plasma and CSF viral load –Perinatal route of transmission –Lack of ARV treatment

10. Decline in Progressive and Static Encephalopathy Children with Perinatal Infection in HAART Era Shabhag MC et al. Arch Pediatr Adolesc Med 2008;159:651-6 P=0.049P=0.02 146 children with perinatal infection followed between 1990 and 2003 at Childrens Hospital Philadelphia

11. Encephalopathy in Pediatric HIV Infection However, ART does not eliminate HIV-related CNS disease. Differential penetration of antiretroviral drugs into CNS (Mitchell C. Mental Retard Develop Disabil 2006;12:216-22; Caparelli E. AIDS 2005;19:949-52; Antinori A. CID 2005;41:1787-93)). –AZT>d4T>ABC>3TC>ddI –NVP>EFV –IDV>LPV>SQV=NFV=RTV=APV (very low)

12. In the HAART era there was a 10-fold decrease in the incidence of HIV encephalopathy Patel et al WAIDS 2008 Incidence rate % on HAART

13. Decline in mortality with HAART sustained over 10 years, but there has not been further decrease since about 2000. Mortality in HIV-infected children is still >30 fold higher than similarly aged children (0.49 per 100 infected children vs 0.02 per 100 children aged 5-14 years in US, p<0.001). As in adults, there has been evolution in causes of death over time, with decrease in AIDS OI and increase in end stage AIDS multi- organ failure, sepsis and renal disease. Comments on Mortality of HIV in Children Today

14. Challenges in the Treatment of Pediatric HIV Infection in High Resource Settings Drug resistance: primary, acquired Pharmacokinetics Lack salvage drugs for children Complications of therapy Adherence Mental health Adolescence - transition to adult care. Effective Therapy is Prolonging Life Spectrum of Disease Changed

15. Prevalence of Transmitted Primary ARV Drug Resistance in New perinatal HIV Infection Type of Resistance NY* 98-99 1 (N=91) NY* 01-02 2 (N=42) US 02-05 3 (N=21) Any resistance 12.1%19.1%23.8% NRTI 7.7%7.1%14.3% NNRTI 3.3%11.9%19.0% PI 3.3%2.4%0% >2 classes 2.2%2.4%9.5% 1 Parker MM, et al. JAIDS 2003;32:292-7. 2 Karchava M, et al. JAIDS 2006;42:614-9. 3 Persaud D, et al. J Infect Dis 2007;195:1402–10. 58% increase * Non-subtype B virus found in 4.4% of infants born 1998-9 &16.7% of infants born 2001-02.

16. Acquired Drug Resistance Leads to the development of multi-drug resistant virus However Newer drugs used for salvage in adults often not available in children Lag in development of pediatric formulations Many older children had sequential mono & dual therapy prior to starting HAART & may have had periods of inadequate adherence Necessitates more complex regimens Limits choices for effective therapy

17. Acquired drug resistance After first line failure 88% of ART treated children have at least 1 significant resistance mutation (RM) -88% NRTI RM -52% NNRTI RM - 8% PI RM Sunpath H et al CROI 2008 Abs 587 After first line NNRTI failure 52% of children have at least 1 significant resistance mutation (RM) -52% NRTI RM -43% NNRTI RM Sungaknuparph S et al CROI 2008 Abs 588

18. Antiretroviral Drugs Approved in Adults N(t)RTINNRTIPIs Entry/Fusion Inhibitors Integrase Inhibitors ABCEFVATVEnfurvirtideRAL ddINVPDRVMVC FTCEtravirineFosAMP 3TCIDV d4TLPV/r TDFNFV Ritonavir SQV TPV but Not Yet Approved in Children

19. LPV/r exposure is initially low in infants < 6 weeks of age but increases dramatically during the first year of life Week 21 yearP value LPV Dose (mg/m2)267 (246-296)331 (305-331)0.047 Cpre (mcg/mL)1.81 (1.54-2.67)8.19 (4.79-10.8)0.031 Cmax (mcg/mL)4.76 (3.30-7.06)14.2 (10.6-15.6)0.031 AUC (mcg*h/mL)36.6 (28.6-62.0)134 (87.9-13.6)0.016 CL/F (L/h/m²)5.64 (4.30-9.98)2.44 (2.44-3.47)0.016 Despite the low initial LPV exposure, viral suppression was achieved by most infants at 48 weeks LPV/r pharmacokinetics in HIV-infected infants < 6 weeks Capparelli, E Poster 573, CROI 2008

20. Recommended dose of LPV/r is sub-optimal in PI-experienced children 47 paediatric patients on 52 weeks of study follow up. 51% achieved VL<400 copies/mL LPV trough <5.7 mg/L (p=0.05) and baseline LPV resistance (p=0.005) were independently and significantly associated with failure to achieve VL<400 copies/mL Pharmacokinetic modelling and simulation Data from 33 patients was used to create a model, and this model was used to simulate 1000 children to determine the % with trough LPV concentration <5.7mg/L after standard dosing. Data from this model showed that in children given standard LPV dose (230 mg/m 2 ), 49.3% would fail to reach the target trough. In PI pre-treated children, LPV plasma levels should be optimized in order to achieve maximal virologic suppression Rahkmanina, N, Poster 574, CROI 2008

21. DELPHI: Darunavir Evaluation in Paediatric HIV-1- Infected Treatment-Experienced Patients Spinosa-Guzman S, Oral Abstract 78LB, CROI 2008 Target treatment-experienced adult DRV exposures were achieved in children across weight bands and age groups Trough concentrations (C 0h ) were well above the protein-binding corrected EC 50 value of 550 ng/mL in all children Pharmacokinetics of DRV, median (range) * DELPHI (paediatric patients) N = 80 Pooled POWER 1 and 2 (adult patients) N = 119 AUC 24hr, nghr/mL 127,340 (67,054 – 230,720) 123,336 (67,714 – 212,980) C 0h, ng/mL 3888 (1836 – 7821) 3539 (1255 – 7368) * Estimated using populations pharmacokinetic analysis; For wild-type virus Primary 24-week analysis of integrated data from POWER 1 and 2 trials, Sekar V, et al., 13 th CROI 2006 Abs J-121 In treatment-experienced HIV-1-infected children and adolescents at week 24, DRV/r showed: good virologic response rates positive clinical outcomes favourable safety and tolerability comparable exposure to adults and confirmed appropriate dose-selection in this paediatric population

22. Long-term Complications of HIV Infection & of ART in Children Metabolic complications Abnormal fat accumulation & wasting Abnormal lipid profiles Insulin resistance Osteopenia/ bone disease Mitochondrial toxicity Liver disease Renal disease Adolescent obesity

23. Metabolic Complications of ART in Children Metabolic disorders reported in HIV-infected children on ART Lipodystrophy 6 - 47% Hyperlipidaemia 13 - 67% Insulin resistance 0 - 13% hyper-insulinaemia 60% Tassiopoulos K et al. JAIDS. 2008; in press Vigano A et al. Antivir Ther. 2007;12:297-302 Ene L et al. Eur J Pediatr. 2007;166:13-21 Ergun-Longmire B et al. Endocr Prac. 2006;12:514-21 Dzwonek AB et al. JAIDS. 2006;43:121-3 Carter RJ et al. JAIDS. 2006;41:453-60 Farley J et al. JAIDS. 2005;38:480-7 Beregszaszi M et al. JAIDS. 2005;40:161-8 European Paediatric Lipdystrophy Group. AIDS. 2004;18:1443-1451 McComsey G et al. Pediatrics. 2003;111:e275-81 Puberty is the time when children are most likely to develop metabolic complications.

24. Cholesterol >220: Entry: 13% of 2123 children Follow-up: additional 13% (median f/u 50.4 mos) Incidence 3.4/100 pt-yr Development of hypercholesterolaemia is more frequent in children on pi-based HAART tassiopoulos K et al. JAIDS 2008 in press 0.7 0.8 0.9 1.0 Prop. hyperchol free 06121824303642485460 Months to consecutive CHOL 220+ or censoring Median – – – – Total 82 378 250 1413 Count 4 42 13 219 Censor 78 336 237 1194 Baseline ART use no ART ART, no HAART HAART, no PI HAART + PI NO ART Incidence 1.3/100 pt/yr HAART, no PI Incidence 1.4/100 pt/yr ART but not HAART Incidence 2.8/100 pt-yr HAART including PI Incidence 4.1/100 pt-yr

25. Probability of Developing Lipodystrophy in HIV- Infected Children Increases with Tanner Stage Taylor P et al. Pediatrics 2004;114:e235-42 012345 Tanner Stage 0 10 20 30 40 50 60 70 80 90 100 Percent without lipodystrophy

26. Impaired glucose homeostasis Impaired glucose tolerance was present in 20% of adolescents and young adults infected perinatally on ART from a mean of 13 years, suggesting an increased risk of Type 2 diabetes and cardiovascular diseases Hadigan C CROI 2008 Abs 591 Puberty is the primary determinant of reduced insulin sensitivity in ART experienced children and adolescents Vigano et al CROI 2008 Abs 592

27. Mental Health in HIV-Infected Children and Youth Scharko AM. AIDS Care 2006;18:441-5 Review of 8 studies including 328 HIV-infected children age 4-21 years; data were compared to prevalence in overall population. Mental health disorder Prevalence (%) Increased Risk-Ratio Attention deficit disorder24%6 - fold Anxiety disorder29%3.8 - fold Depression25%7.1 - fold

28. HIV-Infected Children Have Higher Rates of Psychotropic or Behavioral Treatments Compared to Uninfected Similarly Socioeconomic Controls: P1055 Data provided by Sharon Nachman MD 45% HIV-uninfected HIV-infected Treatment, by HIV Status 40% 35% 30% 25% 20% 15% 10% 5% 0% Med or Behav Tx Behav Tx Med Tx StimulantSSRINeuro- leptic Anti- Hypert Other

29. Challenges in Adolescent HIV Care Knowledge of HIV infection. Linking to (and retaining in) health care. Accepting (and adhering to) therapy. Mental health issues. Complexities of transition to adult care. High risk population for HIV transmission. Rice E et al. Prospect Sex Repro Health 2006;38:162-7 Murphy DA et al. J Adol Health 2001;29S:57-63 Sturdevant MS et al. J Adol Health 2001;29S:64-71 Kadivar H et al. AIDS Care 2006;18:544-9 Rotheram-Borus M et al. J Adoles 2001;24:791-802 Lightfoot M et al. Am J Health Behav 2005;29:162-71. 40-60% of HIV-infected adolescents continue to engage in unprotected sex. High rate substance use, smoking

30. Short-cycle therapy in adolescents following continuous therapy with established viral suppression: The effect on viral load suppression 32 subjects with viral suppression aged 12-24 switched from continuous HAART to short-cycle therapy (SCT) with a schedule of 4 days on (mon-thurs) and 3 days off (fri-sun) HAART. Viral suppression was maintained in 62.5% of participants. Significantly more subjects infected before age 9 discontinued SCT (p=0.0155). No significant losses of CD4+ T cells were noted in those with or without VL breakthrough. Adherence by self report was high for both groups,with no difference in those with viral rebound. Of 12 patients with viral load rebound, 9 re-suppressed after re-initiating continuous HAART. Rudy, B Poster 580, CROI 2008 Total< 9 years> 9 yearsp-value Discontinued SCT: n (%)18 (56.3)12 (80.0)6 (35.3)0.0155 Viral load rebound: n (%)12 (37.5)7 (46.7)5 (29.4)0.4670

31. Cumulative Incidence of First Pregnancy in 174 Perinatally HIV- Infected Sexually Active Girls Age >13 Years, PACTG 219C Brogly SB et al. Am J Public Health 2007;97:1047–1052 By age 19 years, 24.2% of sexually active girls had been pregnant at least once (6 had 2 nd pregnancy, 1 had 3 rd ) 0 5 10 15 20 25 30 35 40 45 Cumulative Incidence of First Pregnancy (%) 05101520253035404550556065707580859095100105110115120125130135 Months Since 13 th Birthday

32. #1 Challenge in Low Resource Countries: Continued HIV Transmission to Women & Poor Implementation of PMTCT Challenges in Management of Pediatric HIV Infection in Low Resource Countries

33. Caribbean 5 % of Female HIV-Infected Adults By Geographic Location, 1990-2007 Source: UNAIDS/WHO Dec 2007

34. Incidence of pregnancy and desire for children Months after ART Initiation Baseline 36 9 12 15 18 21 24 2 0 4 6 8 10 12 0 10 20 30 40 50 60 70 80 90 100 27 p < 0.04 % Women Incidence of pregnancy per 100 WY p < 0.001 Wants more children Partner wants more children Sexually active Weidle, P Oral Abstract 74, CROI 2008

35. Effectiveness of NNRTI-containing ART in women previously exposed to a single dose of nevirapine: A multi-country cohort study Success (%) Time since NVP exposure (months) * P < 0.001 vs unexposed * 91 76 87 92 0 25 50 75 100 Unexposed1 to 67 to 12> 12 Weidle, P Oral Abstract 48, CROI 2008 A high proportion of women in this cohort responded to NNRTI-based HAART at 24 weeks whether previously exposed to SD-NVP or not. Increased risk of failure among women with exposure to SD-NVP within 6 months and perhaps 12 months before initiation on NNRTI-based HAART. Women exposed to SD-NVP more than 12 months prior to initiation of NNRTI-based HAART did as well as women who were not exposed to SD- NVP.

36. Despite Effective Regimens to Prevent MTCT, Globally Only 11% of Women Receive ARV Prophylaxis Interagency Task Team on PMTCT Report Card Feb 2007 UNICEF/WHO/UNAIDS 8% 12% 28% 16% 3% 14% 15% 37% 95% 2% 29% 77% 0 25 50 75 100 IndiaWest & Central Africa East & South Africa Eastern Asia & Pacific Central & South America Central & Eastern Europe %HIV+ women identified 2005%HIV+ women given ARV 2005 Percentage (%) Regions with 95% of all MTCT

37. Very low risk of MTCT in women on HAART who achieve viral suppression: the UK and Ireland, 2000 to 2006 MTCT rate95% CIn infectedtotal Overall1.2(0.9 – 1.5)615151 2000 – 20021.6(1.0 – 2.4)231456 2003 – 20061.0(0.7 – 1.4)383695 At least 14 days of ART0.8(0.6 – 1.1)404864 ART and mode of delivery HAART + elective CS0.7(0.4 – 1.2)172337 HAART + planned vaginal0.7(0.2 – 1.8)4565 HAART + emergency CS1.7(1.0 – 2.8)15877 AZT mono + elective CS0.0(0.0 – 0.8)0467 HAART1.0(0.7 – 1.3)404120 HAART from conception0.1(0.0 – 0.6)1928 HAART + VL<50 copies/ml0.1(0.0 – 0.4)32117 There was no difference in MTCT rates according to BHIVA guidelines: HAART with elective CS, HAART with planned vaginal delivery and AZT with elective CS Townsent, C Poster 653, CROI 2008

38. Prevention of postnatal infection Extended infant post exposure prophylaxis significantly reduces postnatal HIV transmission NVP or NVP/ZDV for 14 weeks in infants (7.2%vs 13% MTCT at 9 mo) Taha T et al CROI 2008 Abs 42LB NVP for 6 weeks in infants (8.0 vs 11% MTCT at 6 mo) Sastry J et al CROI 2008 Abs 43 HAART in women for 6 mo (uncontrolled) (5.9% MTCT at 12 mo) Thomas T et al CROI 2008 Abs 45aLB HAART in women for 12 mo (uncontrolled) (2.9% MTCT at 12 mo) Marazzi M et al CROI 2008 Abs 239 Emergence of HIV drug resistance among breastfeeding infants born to HIV infected mother taking ART Zeh C et al CROI 2008 Abs 84LB

39. The Challenge of Pediatric HIV Infection in Resource-Poor Countries While high rates of HIV infection in women, few women know they are infected and there is poor access to ARV to prevent MTCT. Children often present to health system with advanced disease. Rapid progression and high mortality due to HIV in children, yet few receive treatment. Early treatment would prevent many deaths but infant diagnosis not available.

40. Data from African perinatal prevention trials from breastfeeding HIV transmission study meta-analysis: mortality in infected children was 53% at 2 years of age Newell et al. Lancet 2004;364:1236–43 0 0.1 0.2 0.3 0.4 0.5 0.6 0100200300400500600700800900 Age at last visit or at death (days) Cumulative probability of death Infected Overall Unknown HIV status Not infected Mean survival 1.6 years By age 2.5 years, 60% mortality

41. Estimated Number of HIV-Infected Children Needing and Number Receiving Antiretroviral Treatment By Region as of December 2006 Source: World Health Organization, April 2007 ARV Coverage 13% 67% 21% 20% <1% 0 200,000 400,000 600,000 800,000 Sub-Saharan Africa Latin America/ Caribbean E/S/SE AsiaEurope/ Central Asia N Africa/ Middle East # Needing ART# Receiving ART

42. Virologic Suppression in Children on HAART from 17 Studies in Sub- Saharan Africa Sutdiffe CG et al. Lancet Infect Dis 2008;8:447-89 %<50 copies/mL%<250 or <400 copies/mL or unk%<1,000 copies/mL Median viral load decrease approximately 2.0 log within 1 year of starting ART.

43. Viral Suppression After 1 Year Was 49-81% 17 Studies in Sub- Saharan Africa Sutdiffe CG et al. Lancet Infect Dis 2008;8:447-89 %<50 copies/mL%<250 or <400 copies/mL or unk%<1,000 copies/mL

44. CD4% Increase in Children on HAART from 14 Studies in Sub-Saharan Africa Sutdiffe CG et al. Lancet Infect Dis 2008;8:447-89 CD4% increased in 1 st year of treatment, seeming to plateau after 12-18 months

45. However, Normalization of CD4 Percentage to >25% with HAART was Uncommon

46. However, children in low-resource countries who receive ART are starting at older ages than high resource countries Baseline Median Age % RNA undetectable on HAART Janssens/Cambodia 2007 N=2126.0 yrs74% <400 (17 mos) George/Haiti 2007 N=1006.3 yrs56% <50 (12 mos) Wamawala/Kenya 2007 N=674.4 yrs67% <400 (6 mos) Reddi/S Africa 2007 N=1515.7 yrs80% <50 (12 mos) Puthanakit/Thailand 2007 N=1077.7 yrs70% <50 (3.7 yrs) Kamya/Uganda 2007 N=2509.2 yrs74% <400 (12 mos) Kekitiinwa/Uganda 2008 Abs 584 N=8767.6 yr70% <400 (6 mos)

47. Children in low-resource countries who receive ART are starting treatment when already severely immune deficient Baseline Median Age Baseline Median CD4 % RNA undetectable on HAART Janssens/Cambodia 2007 N=212 6.0 yrs6%74% <400 (17 mos) George/Haiti 2007 N=100 6.3 yrs12%56% <50 (12 mos) Wamawala/Kenya 2007 N=67 4.4 yrs6%67% <400 (6 mos) Reddi/S Africa 2007 N=151 5.7 yrs8%80% <50 (12 mos) Puthanakit/Thailand 2007 N=107 7.7 yrs5%70% <50 (3.7 yrs) Kamya/Uganda 2007 N=250 9.2 yrs8.6%74% <400 (12 mos) Kekitiinwa/Uganda 2008 Abs 584 N=876 7.6 yr8%70% <400 (6 mos)

48. 0 0 Years since HAART initiation 5 10 15 20 25 30 35 40 Mean CD4 % 123456 Recovery of immune status with HAART is dependent on CD4% at time HAART is initiated Patel K et al. Clin infect dis 2008; 46: 507-515 1,236 children enrolled in PACTG 219 not on HAART at study initiation CD4 <15% CD4 15–24% CD4 >25% Not immune deficient Immune deficient

49. Immune reconstitution syndrome in HIV-infected children started on HAART Most commonly reported from low resource countries, likely because they are starting treatment at lower CD4 levels than in US. 19% of 153 children started on HAART had IRIS, median onset 4 weeks; 10% died. Thailand (Puthanakit T et al. PIDJ 2006;25:53-8) 17% of 148 children started on HAART had IRIS, median onset 2 weeks; most common BCG-related IRIS disease. South Africa (Smith K et al. CROI 2008 Abs 75)

50. Implications for when to start antiretroviral therapy in children Children <1 year are at high risk of death; aggressive treatment seems warranted. However: Need to build capacity for early diagnosis Viral suppression with ART less in infants Limited pediatric formulations Minimal data on dosing in children Limited data on efficacy of early treatment

51. Clinical and Immunological Characteristics of HIV-Infected Infants <60 Days Old in South Africa: Evidence from CHER Few clinical characteristics are associated with severe immune suppression Certain clinical characteristics are highly specific for HIV infection in infants <60 days of age - may be useful for early presumptive diagnosis Many HIV-infected infants will be missed – therefore access to PCR in resource limited settings is essential. ROC of HIV infection in exposed infants (area under ROC curve = 0.6624) Any of the following: Oral thrush any LAD Hepatomegaly Splenomegaly clinical GERD Weight below 10th centile # presentSensitivitySpecificity 149.6%78.4% 225%97.6% 310.2%100% 45.6%100% Jaspan, H Oral Abstract 76, CROI 2008

52. Studies early HAART at age <3-12 months show viral suppression in 18%-73% Study N Age Start HAART (MONTHS) Viral response Belgium Van der Linden PIDJ 2007 17 <2.5 <50 71% at 4.7 yrs PACTG 356 Luzuriaga NEJM 2004 25 <3 (median 2) <400 60% at 4 yrs PENTA 7 PENTA AIDS 2004 20 <5 (median 2.5) <400 44% at 1.5 yrs Italian Register Chiappini AIDS 2006 30 <6 (median 3.6) Undetectable 73% at 4 yrs PACTG 1030 Chadwick AIDS 2008 21 <6 (median 3.7) <400 53% at 6 mos French Perinatal Faye PIDJ 2002 31 <12 (median 3.7) <500 18% at 2 yrs

53. Early HAART at age <3-12 months is associated with no AIDS progression and maintenance of immune reconstitution Study N Age Start HAART (MONTHS) Viral response Other Belgium Van der Linden PIDJ 2007 17 <2.5 <50 71% at 4.7 yrs No AIDS 82% CD4 >25% PACTG 356 Luzuriaga NEJM 2004 25 <3 (median 2) <400 60% at 4 yrs No AIDS, 4 yr PENTA 7 PENTA AIDS 2004 20 <5 (median 2.5) <400 44% at 1.5 yrs No AIDS, 1.5 yr 90% CD4 >25% Italian Register Chiappini AIDS 2006 30 <6 (median 3.6) Undetectable 73% at 4 yrs No AIDS, 4 yr 97% CD4 >25% PACTG 1030 Chadwick AIDS 2008 21 <6 (median 3.7) <400 53% at 6 mos French Perinatal Faye PIDJ 2002 31 <12 (median 3.7) <500 18% at 2 yrs No AIDS, 2 yr 88% CD4 >25%

54. CHER: 76% reduction in the risk of death with immediate (arms 2 & 3) compared to deferred (arm 1) HAART CROI 2008 Abs 76, Abs 600 0 0.20 0.40 0.60 0.80 1 Failure probability Deferred Immediate p = 0.0002 036912 Time to death (months) 125 252 104 213 72 145 44 99 22 52 Patients at risk Arm 1 Arm 2 & Arm 3 4% 16% Most deaths occurred within first 6 months (ie. before age 10 months)

55. WHO 2008 Revised Guidelines: When to Start Antiretroviral Therapy in HIV-Infected Children < 12 months Confirmed HIV < 12 months Presumptive Severe HIV* 1- 4 yrs > 5yrs All regardless of CD4/clinical Clinical or immune criteria Clinical or immune criteria <20% or 12-35 mos: <750/uL 36-59 mos: <350/uL <15% or <200/uL *If lack ability for viral test, use WHO presumptive diagnosis of severe HIV (thrush, severe pneumonia or sepsis) in infants with + HIV antibody test and with clinical symptoms of severe HIV – need to confirm infection status as soon as possible.

56. What to start with Implications of resistance following Single-dose NVP prophylaxis Given 1 st line recommendation for NNRTI-based therapy In low resource settings

57. Single-dose NVP prophylaxis is associated with NVP resistance acquisition in infants failing prophylaxis Clade: E,B C A E,B C E,B C C A,D C C CRF01, 06 AZT + SD NVP SD NVP SD NVP, no maternal SD NVP AZT + SD NVP, no maternal SD NVP % with resistance

58. Infants who become HIV-infected despite single-dose NVP prophylaxis may be more likely to have viral failure with later nvp-based HAART Lockman S, et al. Nejm 2007;356:135–47 Analysis after 6 months of HAART: 10/13 in SD NVP group and 1/12 placebo group had HIV RNA >400 copies/mL Median age at start HAART 8.5 months 0 20 40 60 80 061218243036 Months since the Start of ART % with RNA >400 c/mL Single dose of NVP Placebo

59. Optimal initial ART trials for infants with SD NVP exposure StudyAge start HAARTStrategyEndpoint OPH612 Kenya (N=186) 6-12 mos NVP Resistance Screening If sensitive, randomise to NVP vs non-NVP HAART % viral suppression after 24 mos NEVEREST S Africa (N=100) <24 mos Suppress then switch Start with LPV/r, if in 1 st year suppress to 3 mos: Randomize switch to NVP or stay on LPV % RNA <50 at 6 mos post randomisation Strategy obs study S Africa (N=63) Immediate, <2 mos Deferred, median 5 mos 4-drug strategy AZT/3TC/NVP/NFV immediate vs deferred, all exposed to single-dose NVP % suppressed at 1 year P1060 Multicountry (N=576) 6-36 mos Direct Comparison NVP vs PI Infants with/without NVP exp Randomize LPV/r vs NVP HAART % RNA<50 at 6 mos post randomisation

60. What to start (WHO Paediatric HIV/ART working group, Geneva April 2008) For HIV infected infants with no exposure to NNRTIs, or with unknown exposure to maternal or infant ARVs, standard NVP- containing triple therapy should be started Strong recommendation For HIV infected infants with a history of exposure to single dose nevirapine or NNRTI containing maternal ART or preventive antiretroviral regimens, a protease inhibitor based triple ART regimen should be started. Where protease inhibitors are not available, nevirapine based therapy should be used Strong recommendation

61. Challenges in Treatment of HIV-Infected Children in Low Resource Settings Pediatric formulations Fewer ARV approved in children More costly than adult preparations FDC just becoming available Dosing weight/size based, change as child grows, problems for busy health clinic. Liquid drugs transport/storage problems. Complexity of therapy in context multiple co-moribidities (TB, malaria, malnutrition…)

62. Improved therapeutic exposure of NVP using WHO pediatric weight band dosing WHO weight band dosing of NVP: results in therapeutic concentrations in 80% of subjects without incurring a high freq of excessive NVP exposure. achieves target exposure in a greater proportion of subjects than the FDA dose of 4-7mg/kg. The 50-mg tablet strength maximises the therapeutic index. WHO weight band dosing should be used in resource-limited settings. Capparelli, E Poster 576, CROI 2008 Projected Subject NVP doses and exposure WHO Weight Band Dosing Median / IQR FDA Dosing (4 or 7 mg/kg) Median / IQR Dose (mg/m²) every 12h174 (162-187)153 (112-172) Cmin (mcg/mL)5.7 (3.80-8.0)4.6 (3.0-6.9) AUC (mcg*h/mL)77.7 (55.8-107.2)62.2 (45.1-90.8)

63. Thank you for your attention … Courtesy Peter Havens MD