EARLY CHILDHOOD OUTCOMES AT THE BOTSWANABAYLOR 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 Botswana - Background Parameter Total or Estimate Population 1,719,996 HIV prevalence in pregnancy 32.4 % (2006) HIV+ pregnant women delivering per yr 14,215 (2006) ± infant infections per yr without PMTCT 4500 ± Current new infant infections per year 900 (2005) ± HIV infected Children <15 yr on ART 6831 Neonatal/Infant/Child mortality rates 33/70/150 per 1000 Deaths Under Five Years of Age Attributable to HIV/AIDS Global 4.0% Botswana 57.7% Zimbabwe 42.2% Swaziland 40.6% Namibia 36.5% Zambia 0% 10% 20% 33.6% 30% 40% 50% 60% Percent of all HIV-positive pregnant women receiving antiretroviral drugs during pregnancy, and changes to drug regimen Botswana National PMTCT Program, 2002-2006 (Denominator=total number of deliveries x HIV prevalence from surveillance data) 100 Long-course AZT + SD NVP Percent receiving drug 90 80 AZT (or HAART) 70 NVP (or HAART) 60 HAART* 50 40 Short-course AZT + SD NVP Short-course AZT only 30 20 10 0 2002 2003 2004 2005 Year *20-25% of pregnant women are eligible for ARV therapy during pregnancy (CD4<200) Source: Situation Analysis (March 2006) 2006 Early Childhood Outcomes Management According to Botswana National ART Guidelines All received AZT/d4T + 3TC + NVP Criteria: all children <12 months with confirmed HIV infection (DNA PCR) or >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 Virologic Suppression By Baseline VL Baseline VL Suppressed by 6 Number months on therapy <750,000 122 112 (92%) >750,000 180 147 (82%) P= 0.02 Published Data Regarding Virologic Suppression in Adults on NVP-based HAART by Baseline VL (from Raffi et al, HIV Clin Trials 2001) Virologic Suppression By Age at Initiation Age at Initiation Number VL Suppressed by 6 months on therapy <6 months 19 13 (68%) 6-12 months 95 77 (81%) >12-36 months 119 101 (85%) Since baseline viral load is predictive of virologic failure, can we predict baseline VL on the basis of age and baseline CD4 count? 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 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 Virologic Suppression Among Children on NNRTI-based 1st line by PMTCT status 112 infants/young children known to have received PMTCT and initiated HAART 187 infants/young children reported to have received no PMTCTand initiated HAART 85 (76%) achieved a VL<400 on 1st line 171 (91%) achieved VL<400 on 1st line P=0.0003 Virologic Suppression Among Children on NNRTI-based 1st 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 nonsuppression 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 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 nonsuppression at or after 6 months on HAART 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 10 (67%) suppressed 34 (81%) suppressed P=0.29 Limitations of Data Retrospective analysis PMTCT status listed as “yes” or “no” and may not necessarily be reflective of sdNVP status Missing data 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 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 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%) Benefits vs. Risks: Adverse Drug Reactions 3 Rash occurred in first three weeks of therapy: 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 16/17 (94%) were mild or moderate 1 had Steven’s-Johnson syndrome requiring inpatient care 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.