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Paediatric HIV: update EACS Advanced HIV course Montpellier, 3-5 th Sept 2008 Carlo Giaquinto

Paediatric HIV: update EACS Advanced HIV course Montpellier, 3-5 th Sept 2008 Carlo Giaquinto Department of Paediatrics, Padova, Italy. Presentation overview. Children & HIV in developed countries Women pregnancy & HIV PMTCT / MTCT in developing countries

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Paediatric HIV: update EACS Advanced HIV course Montpellier, 3-5 th Sept 2008 Carlo Giaquinto

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  1. Paediatric HIV: update EACS Advanced HIV course Montpellier, 3-5th 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 • 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 life1. • The median age of over 3,500 HIV-infected children followed at US pediatric clinical trials sites is 14.8 years2 . • Lee GM et al. Pediatrics 2006;117:273-83 • 219 study summary July 23 2007

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

  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. Age at Death (1994-2006) in HIV-Infected Children Enrolled in PACTG 219 Long-Term Follow-Up Study Age at Death by Year of Deathfor Infected Children 3,553 children Median f/u 5.3 yrs 298 deaths 22 20 18 16 14 12 Median Age at Death (IQR) 10 8 6 4 Mean age at death 1994: 8.9 years Mean age at death 2006: 18.2 years 2 0 1994 1996 1998 2000 2002 2004 2006 Year HAART Era Courtesy Mike Brady, Paige Williams

  8. Primary Causes of Death (1994-2006) in HIV-Infected Children Enrolled in PACTG 219 AIDS OI End Stage AIDS Pheumonia Sepsis Cardiomyopathy CNS disease Malignancy Renal failure Stroke Hepatitis Accident / other 40% Increase 1994–2006: End stage AidsSepsisRenal Failure 30% 20% 10% 0% 1994–1996 1997–2000 2001–2006 N = 3,553 children Median f/u 5.3 yrs 298 deaths Courtesy Mike Brady, Paige Williams

  9. Encephalopathy in Pediatric HIV InfectionVan 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 1st 2 years of life: incidence rate 9.9% in 1st year, 4.2% in 2nd 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 EraShabhag MC et al. Arch Pediatr Adolesc Med 2008;159:651-6 P=0.049 P=0.02 146 children with perinatal infection followed between 1990 and 2003 at Children’s 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 encephalopathyPatel et al WAIDS 2008 % on HAART Incidence rate

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

  15. Prevalence of Transmitted Primary ARVDrug Resistance in New perinatal HIV Infection 58% increase * Non-subtype B virus found in 4.4% of infants born 1998-9 &16.7% of infants born 2001-02. 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.

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

  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 but Not Yet Approved in Children

  19. LPV/r pharmacokinetics in HIV-infected infants < 6 weeks • LPV/r exposure is initially low in infants < 6 weeks of age but increases dramatically during the first year of life Despite the low initial LPV exposure, viral suppression was achieved by most infants at 48 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/m2), 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 • Target treatment-experienced adult DRV exposures were achieved in children across weight bands and age groups • Trough concentrations (C0h) were well above the protein-binding corrected EC50 value of 550 ng/mL† in all children * 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., 13th 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 Spinosa-Guzman S, Oral Abstract 78LB, CROI 2008

  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 ChildrenMetabolic disorders reported in HIV-infected children on ART • Lipodystrophy 6 - 47% • Hyperlipidaemia 13 - 67% • Insulin resistance 0 - 13% • hyper-insulinaemia 60% Puberty is the time when children are most likely to develop metabolic complications. 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 PaediatricLipdystrophy Group. AIDS. 2004;18:1443-1451 McComsey G et al. Pediatrics. 2003;111:e275-81

  24. 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 Baseline ART useno ARTART, no HAARTHAART, no PIHAART + PI Censor783362371194 Count44213219 Total823782501413 Median–––– Development of hypercholesterolaemia is more frequent in children on pi-based HAART tassiopoulos K et al. JAIDS 2008 in press 1.0 Cholesterol >220: Entry: 13% of 2123 children Follow-up: additional 13% (median f/u 50.4 mos) Incidence 3.4/100 pt-yr 0.9 0.8 Prop. hyperchol free 0.7 0 6 12 18 24 30 36 42 48 54 60 Months to consecutive CHOL 220+ or censoring

  25. Probability of Developing Lipodystrophy in HIV-Infected Children Increases with Tanner Stage Taylor P et al. Pediatrics 2004;114:e235-42 100 90 80 70 60 Percent without lipodystrophy 50 40 30 20 10 0 0 1 2 3 4 5 Tanner Stage

  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 YouthScharko 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.

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

  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. 40-60% of HIV-infected adolescents continue to engage in unprotected sex. High rate substance use, smoking 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. 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

  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

  31. Cumulative Incidence of First Pregnancy in 174 Perinatally HIV-Infected Sexually Active Girls Age >13 Years, PACTG 219CBrogly SB et al. Am J Public Health 2007;97:1047–1052 45 40 35 30 25 Cumulative Incidence of First Pregnancy (%) 20 By age 19 years, 24.2% of sexually active girls had been pregnant at least once (6 had 2nd pregnancy, 1 had 3rd) 15 10 5 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110 115 120 125 130 135 Months Since 13th Birthday

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

  33. % of Female HIV-Infected Adults By Geographic Location, 1990-2007 70 60 Sub-Saharan Africa 50 GLOBAL Caribbean 40 Percent female (%) Asia 30 E Europe & C Asia Latin America 20 10 0 1990 ‘91 ‘92 ‘93 ‘94 ‘95 ‘96 ‘97 ‘98 ‘99 ‘00 ‘01 ‘02 ‘03 ‘04 ‘05 ‘06 2007 Year Source: UNAIDS/WHO Dec 2007 5

  34. Incidence of pregnancy and desire for children 12 100 90 10 80 p < 0.001 70 8 60 % Women Incidence of pregnancy per 100 WY 6 50 40 4 p < 0.04 30 20 2 10 0 0 Baseline 24 21 15 27 3 6 12 18 9 Months after ART Initiation 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 100 92 91 87 76 75 50 25 0 Unexposed 1 to 6 7 to 12 > 12 • 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. * *P < 0.001 vs unexposed Success (%) Time since NVP exposure (months) Weidle, P Oral Abstract 48, CROI 2008

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

  37. Very low risk of MTCT in women on HAART who achieve viral suppression: the UK and Ireland, 2000 to 2006 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 ageNewell et al. Lancet 2004;364:1236–43 0.6 Mean survival 1.6 years 0.5 By age 2.5 years, 60% mortality Infected Overall 0.4 Unknown HIV status Not infected Cumulative probability of death 0.3 0.2 0.1 0 0 100 200 300 400 500 600 700 800 900 Age at last visit or at death (days)

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

  42. Virologic Suppression in Children on HAART from 17 Studies in Sub-Saharan AfricaSutdiffe 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 AfricaSutdiffe 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 AfricaSutdiffe CG et al. Lancet Infect Dis 2008;8:447-89 CD4% increased in 1st year of treatment, seeming to plateau after 12-18 months

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

  46. However, children in low-resource countries who receive ART are starting at older ages than high resource countries

  47. Children in low-resource countries who receive ART are starting treatment when already severely immune deficient

  48. Recovery of immune status with HAART is dependent on CD4% at time HAART is initiatedPatel K et al. Clin infect dis 2008; 46: 507-515 40 35 Notimmunedeficient 30 25 20 Immunedeficient Mean CD4 % 15 10 CD4 <15% CD4 15–24% 5 CD4 >25% 0 0 1 2 3 4 5 6 Years since HAART initiation 1,236 children enrolled in PACTG 219 not on HAART at study initiation

  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

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