1. EARLY CHILDHOOD OUTCOMES AT THE BOTSWANA- BAYLOR CHILDREN’S CLINICAL CENTRE OF EXCELLENCE: A REPORT TO THE WHO TECHNICAL REFERENCE GROUP ON PEDIATRIC CARE AND TREATMENT, APRIL 2008 Gabriel M. Anabwani, Executive Director Elizabeth Lowenthal, Associate Director Michelle Eckerle, Pediatric AIDS Corps Doctor

2. Botswana - Background Parameter Total or Estimate Population1,719,996 HIV prevalence in pregnancy32.4 % (2006) HIV+ pregnant women delivering per yr14,215 (2006) ± infant infections per yr without PMTCT4500 ± Current new infant infections per year900 (2005) ± HIV infected Children <15 yr on ART6831 Neonatal/Infant/Child mortality rates33/70/150 per 1000

3. Deaths Under Five Years of Age Attributable to HIV/AIDS

4. Source: Situation Analysis (March 2006)

6. Early Childhood Outcomes Management According to Botswana National ART Guidelines  All received AZT/d4T + 3TC + NVP  Criteria: all children 12 months with mild/moderate or severe immune suppression or clinical manifestations Children initiated on HAART at <36 months of age  Outcomes analyzed via database and manual chart reviews  N = 377  Of these 56 patients had incomplete data (transferred out, lost to follow-up, insufficient laboratory data)  Preliminary data analyzed for remaining 321

7. Virologic Suppression By Baseline VL Baseline VLNumber Suppressed by 6 months on therapy <750,000122112 (92%) >750,000180147 (82%) P= 0.02

8. Published Data Regarding Virologic Suppression in Adults on NVP-based HAART by Baseline VL (from Raffi et al, HIV Clin Trials 2001)

9. Virologic Suppression By Age at Initiation Age at InitiationNumber VL Suppressed by 6 months on therapy <6 months1913 (68%) 6-12 months9577 (81%) >12-36 months119101 (85%)

10. Since baseline viral load is predictive of virologic failure, can we predict baseline VL on the basis of age and baseline CD4 count?

11. Correlation Matrices on BANA2 Trial Patients Baseline VL >750,000 compared with VL <750,000 with regards to:  Age  CD4%  CD4 absolute count  CDC Immunologic category No statistically significant correlations

12. Role of PMTCT In Early Infant Outcomes Standard program is:  Maternal AZT started as early as 28 weeks (unless mother on HAART)  sd-NVP to mother  sd-NVP to baby at birth  4 weeks of AZT to baby Mothers rarely know whether sd-NVP was received  PMTCT is recorded as:  “yes” - some received  “no” - none known to have been received  Or “unknown”- not recorded  Based on reported excellent uptake of sd-NVP use by national programme, it is assumed that most children received sd-NVP if some PMTCT is reported

13. Virologic Suppression Among Children on NNRTI-based 1 st line by PMTCT status 112 infants/young children known to have received PMTCT and initiated HAART  85 (76%) achieved a VL<400 on 1 st line 187 infants/young children reported to have received no PMTCTand initiated HAART  171 (91%) achieved VL<400 on 1 st line P=0.0003

14. Virologic Suppression Among Children on NNRTI-based 1 st Line by PMTCT Status and Age at Initiation 15 patients initiated HAART at <6 months of age with a follow-up VL confirming virologic suppression (VL <400 copies/ml) or non- suppression at or after 6 months on HAART  10 (67%) suppressed 59 patients initiated HAART between 6 and 12 months of age with a follow-up VL confirming virologic suppression (VL<400 copies/ml) at or after 6 months on HAART  44 (75%) suppressed P=0.53

15. No difference between outcomes among patients who initiated before 6 months and after 12 months 15 patients initiated HAART at <6 months of age with a follow-up VL confirming virologic suppression (VL <400 copies/ml) or non- suppression at or after 6 months on HAART  10 (67%) suppressed 42 patients initiated HAART between 1 and 3 years of age with a follow-up VL confirming virologic suppression (VL<400 copies/ml) at or after 6 months on HAART  34 (81%) suppressed P=0.29

16. Limitations of Data Retrospective analysis PMTCT status listed as “yes” or “no” and may not necessarily be reflective of sd- NVP status Missing data

17. Benefits vs. Risks: Early HAART Initiation A recent chart review of 281 children who initiated HAART >2 years ago at age <3 years at the COE  235 confirmed alive  46 confirmed dead (16%) 93 were CDC category C3 at initiation  66 confirmed alive  27 confirmed dead (29%) Benefit: children are more likely to live if you initiate HAART before they are very sick and immune suppressed Note: Because we have liberal initiation criteria, we do not have a comparison of death rates among untreated children

18. Benefits vs. Risks : Adverse Drug Reactions 1 The charts of the first 110 treatment naïve children who had received HAART at the COE for >52 w were reviewed for ADRs:  Mean age = 70 m; Male: female = 1:1  106 (96%) received ZVD+3TC+NVP  4 with Hb<7.5 g/dl received d4T in lieu of ZVD  Median VL/CD4% were 310,000/15%  44 (40%) were in CDC immune category 3  Median Hb was:  9.4 g/dl in patients < 24 m  10.6 g/dl in those > 24 m

19. Benefits vs. Risks : Adverse Drug Reactions 2 Overall Median Hb increased by 52 w:  9.4 to 10.4 among those aged <24 m  10.6 to 11.2 g/dl in those aged >24 m Median ALT unchanged at 19.0±0.5 u/L over 52 weeks ADR occurred in 23 (21%) patients:  Rash in 17 (74%)  Severe anemia (Hb <3 g/dl) in 3 (13%)  Vomiting in 3 (13%)

20. Benefits vs. Risks : Adverse Drug Reactions 3 Rash occurred in first three weeks of therapy:  16/17 (94%) were mild or moderate  1 had Steven’s-Johnson syndrome requiring inpatient care Severe anemia developed at 3 m in one and at 4 m in 2 patients  All were transfused and switched from ZVD to d4T Vomiting was mild and resolved without therapy Grade 3 lipase toxicity developed in 2 patients  Subsequently normalized without further intervention Conclusion: HAART in naïve African children using a regimen consisting of ZVD or d4T + 3TC + NVP was both generally safe and well tolerated.