Presenter: Linda Barlow-Mosha MD, MPH, FAAP

1. The Effectiveness of generic Highly Active Antiretroviral Therapy for the treatment of HIV infected Ugandan children Presenter: Linda Barlow-Mosha MD, MPH, FAAP Makerere University- Johns Hopkins University Research Collaboration 3rd IAS Conference July 27, 2005

2. Background • 90% of the 2.1million HIV infected children are in sub-Saharan Africa (UNAIDS, 2004) • Uganda has approximately 143,000 children living with HIV and 20,000 children are infected each year through mother to child transmission (MTCT) (MOH, 2001) • MU-JHU Research Collaboration has taken care of over 3000 HIV infected children since 1988 • Death occurred in 30%,66%, 75% of the children at 1, 3, and 5 years respectively (Marum et al. July 1996)

3. Background • Benefits of HAART have not yet been fully realized in resource limited countries due to: • High cost of drugs • Limited infrastructure to monitor patients • Access has recently been increased for patients in the developing world through: • Global funds • World Bank funds-MAP • PEPFAR (President Bush’s Initiative)

4. HAART in Uganda • Approximately 64,000 individuals on HAART (Ministry of Health,2005) • < 4000 are children under 15 years of age (Ministry of Health,2005) • Majority of the children on HAART are in a few clinics • Children are often left out because of : • Lack of infant HIV diagnostic tests • Limited appropriate drug formulation • Inadequate knowledge on ARV use in children

5. Triomune • Fixed dose combination (d4T+3TC+NVP) - CIPLA • Reduced cost has made HAART more accessible • Clinical experience has documented satisfactory response (Laurent et al, 2004) • In Uganda a study in adults documented a decline in viral load and increase in CD4 count at 12 weeks into therapy (Oyugi et al, Bangkok 2004) • Most of the fixed dose combinations available are in tablet or capsule form and not in formulations appropriate for young children

6. Objectives • Primary Objective • To determine the feasibility and effectiveness of a generic fixed dose combination tablet (Triomune) in HIV infected children • Secondary Objectives • To assess adherence to Triomune among HIV infected children • To document mortality rate of the children on therapy

7. Methods • Screening • HIV infected children from perinatal trials at MU-JHU Research Collaboration and PIDC Mulago Hospital were screened using WHO criteria for antiretroviral therapy in resource limited settings and CD4 count/percent

8. Methods • Data collection • Baseline • CBC, CD4%/CD4 abs,Viral Load • Liver function test and Renal function test • Follow up 2 years • CBC, CD4%/CD4 abs, and viral load – every 12 wks • Adherence assessment by self report and pill counts – at all routine visits • Plasma storage for later NVP resistance testing • Sub-study for NVP pharmacokinetic (n=20) • Preliminary data after 48 weeks on therapy will be presented

9. Results • Total number screened – 164 HIV infected children • 90 enrolled • 81 given Triomune (d4T/3TC/NVP) as 1st line regime • 72 remain on Triomune • 14 are on alternative regimens • 8 due to weight <13kg • 4 due to hypersensitivity to NVP • 1 hepatitis • 1 virologic failure • 4 deaths

10. Results At Enrollment • Median age – 5yrs (1-14yrs) • 48% female • 96% < 3rd percentile expected weight for age • 67% < 5th percentile expected height for age • 60% WHO stage II and 16% WHO stage III • 26% with CD4 percent < 5% • 67% with CD4 percent between 5-15%

11. Results

12. Results

13. Baseline 12wks 24wks 36 wks 48 wks ResultsViral Load vs Baseline, 12, 24,36, & 48 Weeks Baseline VIRAL LOAD 12wks 12wks 24wks 36wks 48wks 12wks

14. Results • 48 weeks after therapy • 96% (22/23) of children have CD4% > 15 • 83% (19/23) of children have undetectable viral load (<400copies/ml) • 42% (8/19) of the children with undetectable viral loads were NVP exposed at birth • Adherence rate – 95% in 90% of the children • Majority of children with poor adherence were on syrups

15. Results- Toxicity and Mortality • Side Effects • skin rash - 4% (4/90) • hepatitis - 1% (1/90) • Mortality rate is 4% (4/90) • 2/4 children had an initial CD4 count less than 1% • 3/4 children were severely immuno-suppressed or WHO stage III • Causes of death include toxoplasmosis, malaria, and pneumonia

16. Results • Treatment Failure • Defined as viral load >400 copies/ml at 48 wks • The 4 children with detectable viral loads • history of poor/fair adherence to syrups • exposure to single-dose Nevirapine at birth • baseline viral loads >750,000 copies/ml • viral rebound effect

17. Results- Treatment Failure • 1/4 children with detectable viral loads has also shown immunologic failure to therapy

18. Conclusions • The use of fixed dose combination in HIV infected children is feasible and effective • Triomune led to a significant increase in CD4 count and a decrease in viral load during the initial 48 weeks of therapy • Adherence is better with a fixed dose combination than syrups • We are still monitoring the effect of single-dose Nevirapine exposure on response to future NVP containing HAART regimens

19. Acknowledgments • Elizabeth Glaser Pediatric AIDS Foundation • International Leadership Award (ILA) • Dr. Phillipa Musoke – Department of Pediatrics, Makerere University Mulago / MU-JHU Research Collaboration, Recipient of ILA • Program Staff – MU-JHU Research Collaboration • P. Ajuna, M. Luttajumwa, B. Musoke, J. Walabyeki, M. Owor, M. Mubiru, M.G. Nalubega, M. Namawejje, E. Babirekere • MU-JHU Research Collaboration • Children and their caretakers

22. Thank You