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ARV therapy in children - Clinical & Pharmacological Effects: How much do we know and how much do we need to know?

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. How much do we know? A great deal

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ARV therapy in children - Clinical & Pharmacological Effects: How much do we know and how much do we need to know?

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

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

  6. AIDS 2009; 23: 101-106

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

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

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

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

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

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

  13. Baseline characteristics

  14. 1.00 0.80 0.60 0.40 0.20 0.00 0 3 6 9 12 Early ART associated with reduced mortality P = 0.0002 Failure Probability Time to Death (months) Arm 1 Arm 2 & 3 Patients at risk

  15. Most frequent infections per 100 pt years Early ART Deferred

  16. 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

  17. 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

  18. 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

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

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

  21. 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

  22. 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

  23. 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

  24. ARV toxicity in 1st year of lifeCHER study Early Deferred

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

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

  27. 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

  28. 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

  29. 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

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

  31. 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

  32. 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

  33. 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

  34. WHO - 2008

  35. 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)

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

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