1. 1 ARV therapy in children - Clinical & Pharmacological Effects: How much do we know and how much do we need to know? Mark Cotton KID-CRU, Tygerberg Children’s Hospital Avy Violari PHRU, University Witwatersrand South Africa ILF Forum, CROI 2009, Montréal

2. 2 How much do we know?  A great deal How much do we need to know?  A great deal more How can we better implement what we already know?  A lot better?

3. 3 Research Questions When to start What to start Can you interrupt

4. 4 Evolving MTCT issues Single dose Nevirapine Protecting the tail (for the mother) –Truvada –ZDV + LMV Urgent need for more ARV choices for children - where enhanced PMTCT fails –ARVs to breast-feeding mothers –ARVs to breast-fed infants

5. 5 Cumulative mortality of HIV- infected African infants Newell ML et al Lancet 2004; 364: 1236-43

6. 6 AIDS 2009; 23: 101-106

7. 7 Annual post-neonatal deaths (X), Age 1- 11 months, & antenatal HIV prevalence (%) (--), South Africa, 1990-2002

8. 8 Observed and fitted likely HIV/AIDS-related deaths, Age 1-11 months, South Africa, 1997-2002

9. 9 Non-HIV/AIDS-related deaths, Age 1-11 months, South Africa, 1997- 2002

10. 10 N Engl J Med 2008; 359: 2233-44

11. 11 CHER Trial - Hypothesis  Early limited ART until 1 st or 2 nd birthday will:  Have long-term benefit by delaying disease progression  And delaying the need for long-term continuous ART

12. 12

13. 13 Number of Participants prescreened: 5985 Number of Participants HIV+: 405 (6.8% of prescreened) Total Number of HIV+ Participants: 560 Number of referred HIV+ participants: 155 Number of Participants screened: 532 Participants enrolled CHER: 377 Participants with CD4<25%: 104 (19.5%) Not enrolled for Other reasons: 51 Screening & Enrolment

14. 14 Baseline characteristics VariableArm 2 & 3Arm 1 Number of participants enrolled252125 Sex: Female (%)147(58.3 %)74(59 %) Age (weeks, median (IQR)7.4(6.6 - 8.9)7.1(6.4 - 8.9) Mother receiving ART for PMTCT No Therapy26(10.3 %)15(12 %) NVP (%)162(64.3 %)72(58 %) AZT (%)8(3.2 %)5(4 %) AZT + NVP (%)51(20.2 %)26(21 %) HAART (%)2(0.8 %)5(4 %) Weight (Median IQR (kg)4.4(4.0 - 4.9)4.5(4.0 - 5.0) CDC Classification Class N & A (%)237(94.0 %)121(96.8 %) Class B (%)11(4.4 %)3(2.4 %) CD4 % (median (IQR)35.1(29.1 - 40.8)35.6(29 -43.8) CD4 Count (cells/mm 3 ) median (IQR)2035(1519-2754)2044(1585-2960)

15. 15 0.00 0.20 0.40 0.60 0.80 1.00 036912 Time to Death (months) Failure Probability Arm 1Arm 2 & 3 Early ART associated with reduced mortality Patients at risk Month 0 Month 3Month 6Month 9Month 12 Arm 1125 104724422 Arm 2 & Arm 3252 2131459952 P = 0.0002

16. 16 Most frequent infections per 100 pt years Early ARTDeferred

17. 17 Programmatic issues - ART <12 m of age Single policy easy to implement Majority infants need HAART in 1st year of life Easier to manage if low transmission rates Can implement without waiting for CD4 results ARV education should start antenatally & must be “fast-tracked” when +ve PCR –Continues after ART started

18. 18 Mothers have many issues May not be psychologically prepared Own health –Often underestimated Disclosure –Complex –Visits to grandparents –Lack of privacy Infant feeding TB exposure Socio-economic

19. 19 Current diagnostic strategy for infants in lower income countries WHO –4-6 weeks of age RSA - rigidly interpreted as 6w (immunization visit) –If unknown, establish exposure status at 1st contact with healthcare services

20. 20 Can we do earlier PCR’s Do we know enough about pK in first 3 months of life?

21. 21 CD4% & death HPMCS Dunn et al Lancet 2003; 362: 1605-11 Number of Deaths

22. 22 1st and 2nd line Regimens could be better 1st line 3rd drug –Most African Countries NVP –RSA LPVR NRTI component –RSA 1st line D4T + 3TC 2nd line ZDV + ddI Abacavir reserved for lipoatrophy, lactic acidosis

23. 23 What is the best ARV strategy for children over a year of age? Ongoing morbidity at all ages and levels of CD4 USA - 1 to 5 y –CD4 <25% WHO - June 2008

24. 24 ARV toxicity 127 uninfected infants born to HIV-infected mothers –HAART –Post natal ZDV 61 had elevated lactate 3 had minor self-limited developmental delay Pediatrics 2004; 114; e598

25. 25 ARV toxicity in 1st year of life CHER study Early Deferred

26. 26 MTCT - Paradigm shifts for ARV resistance Single dose Nevirapine –Sd NVP + ZDV HAART –Antenatal –Protection of breast-fed infants ARVs to breast-feeding infants

27. 27 Long-term toxicity PENTA 11 www.pentatrials.org www.pentatrials Cross-sectional survey 477 children Median age - 10y Median ARV exposure - 4.5y Central lipohypertrophy +/- peripheral lipo- atrophy - 25% Dyslipidaemia - 33%

28. 28 Strategies When to start - Older children –PREDICT - Thailand Interruption studies –PENTA 11 - pilot exploratory study - CD4 strategy –BANA-2 - Botswana - CD4 guided approach –CHER trial - RSA –Ithemba - KZN, RSA

29. 29 ARV strategies Neverest II - RSA –Can you switch from LPV/r to NVP once stable Arrow - Zim, Uganda –Induction with 4 drugs and maintenance with 3 –Clinical versus Laboratory monitoring PENPACT 1 –PI vs NNRTI –At what viral load to switch P1060 - African Sites –PI vs NNRTI in NVP-exposed and non-exposed infants >6m LPV/r monotherapy pilot trial - Thailand

30. 30 Rifampicin co-treatment IMPAACT: EFV study for <3 years of age with and without TB Double Dose LPV/r - CROI 2009 –Helen McIlleron & Colleagues, UCT

31. 31 pK studies for new and re-formulated drugs Industry and Networks (IMPAACT) –Raltegravir –Vicirviroc –TMC 125 –Paediatric Alluvia® –etc

32. 32

33. 33 Key points Key requirements - minimal –Administration frequency –Impact on lifestyle –Minimum, non-toxic excipients Convenient easy administration –Palatable –Requires minimal manipulation by HCWs –Ability for reliable division unit dose Transportable, low bulk Easily produced and stable in variety climates Affordable Commercially viable

34. 34 Flexible solid dosage forms Mini-tablets / granules –Oro-dispersible –Or used for preparation of liquids –Can be dissolved in breast milk Easy to manufacture Cheaper than existing liquid formulations

35. 35 Research Needs What particle size can be safely and comfortably ingested by infants & children at different developmental stages? Optimize acceptability of dosage forms –Granularity –Texture Standards for palatability testing

36. 36 WHO - 2008

37. 37 Vileness of taste directly proportional to importance LPV/r - 1st line for NVP- exposed infants RTV-boosted LPV/r needed for co-treatment with Rifampicin Ren et al, J Acquir Immune Defic Syndr, 2008 Jan 11 Ritonavir (RTV) (80mg/ml) Lopinavir/ritonavir (LPV/r) (80/2omg/ml)

38. 38 Acknowledgements Elaine Abrams, Andy Wiznia, Tammy Meyers, Quianna Douglas –IMPAACT Primary Therapy Committee –Seminar December 8, 2008