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

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

5. Triomune Fixed dose combination (d4T+3TC+NVP) - CIPLA Fixed dose combination (d4T+3TC+NVP) - CIPLA Reduced cost has made HAART more accessible Reduced cost has made HAART more accessible Clinical experience has documented satisfactory response (Laurent et al, 2004) 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) 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 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 Primary Objective To determine the feasibility and effectiveness of a generic fixed dose combination tablet (Triomune) in HIV infected children To determine the feasibility and effectiveness of a generic fixed dose combination tablet (Triomune) in HIV infected children Secondary Objectives Secondary Objectives To assess adherence to Triomune among HIV infected children To assess adherence to Triomune among HIV infected children To document mortality rate of the children on therapy To document mortality rate of the children on therapy

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

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

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

11. Results Baseline n= 90 12 wks n= 78 24 wks n= 52 36 wks n=25 48 wks n=23 Median CD4% 9%(0.2-22)17%(1-41)p<0.000123%(7-44)p<0.000127%(8-58)p<0.000132%(10-76)p<0.0001 Median Viral Load (copies/mL ) Non-detectable <400copies/ml 284,391(150->750,000)121(0->750,000)p<0.0001141(0-133,469)p<0.0001190(0-140,418)p<0.0001190(0-416,941)p<0.0001

12. Results

13. Baseline 12wks 24wks 36wks 48wks Results Viral Load vs Baseline, 12, 24,36, & 48 Weeks VIRAL LOADVIRAL LOAD 12wks Baseline24 wks36 wks48 wks

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

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

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

17. Results- Treatment Failure 1/4 children with detectable viral loads has also shown immunologic failure to therapy 1/4 children with detectable viral loads has also shown immunologic failure to therapy BaselineCD4%12wkCD4%24wkCD4%36wkCD4%48wkCD4% A11.131.827.432.132.5 B7.114.415.520.531.8 C2.27.812.414.59.9 (4.5 at 60wk) D13.221.130.634.839.2

18. Conclusions The use of fixed dose combination in HIV infected children is feasible and effective 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 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 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 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 Elizabeth Glaser Pediatric AIDS Foundation International Leadership Award (ILA) International Leadership Award (ILA) Dr. Phillipa Musoke – Department of Pediatrics, Makerere University Mulago / MU-JHU Research Collaboration, Recipient of ILA Dr. Phillipa Musoke – Department of Pediatrics, Makerere University Mulago / MU-JHU Research Collaboration, Recipient of ILA Program Staff – MU-JHU Research Collaboration 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 P. Ajuna, M. Luttajumwa, B. Musoke, J. Walabyeki, M. Owor, M. Mubiru, M.G. Nalubega, M. Namawejje, E. Babirekere MU-JHU Research Collaboration MU-JHU Research Collaboration Children and their caretakers Children and their caretakers

22. Thank You