Presenter : Dr T. G. Nematadzira on behalf of The IMPAACT PROMISE 1077BF/1077FF Team Efficacy and Safety of Two Strategies to Prevent Perinatal HIV Transmission : results from the Antepartum Component of the PROMISE study 1

IMPAACT PROMISE Sites PROMISE is an ongoing prospective, open label randomized trial being conducted at NIH IMPAACT Clinical Research Sites in resource-limited settings Sites in: India(1) Malawi (2) South Africa (5) Tanzania (1) Uganda (1) Zambia (1) Zimbabwe (3) 2

OBJECTIVES of the antepartum component  To evaluate the comparative efficacy of maternal triple ARV prophylaxis versus antepartum ZDV + sdNVP +TRV tail to reduce antepartum and intrapartum HIV transmission.  To assess and compare the safety and tolerability of triple ARVs compared to other proven regimens among healthy HIV women with higher CD4 counts.  To assess HIV transmission rates at birth by study arm. 3

PROMISE Methods Eligibility based on: –Currently pregnant, gestational age > 14 weeks, documented HIV infection –No receipt of triple ARVs in current pregnancy –Did not meet country guidelines for ART –CD4 > 350 cells/uL or > country-specific threshold for ART if it was above 350 cells/uL –Laboratory: Hematology and ALT screening values < grade 3 Cr Cl > 60 mL/min (Cockroft-Gault equation) –Age of legal majority –No active TB or other serious health conditions –No social circumstances that would prevent follow up 4

PROMISE Methods  Screening and recruitment were done after written informed consent was obtained which included discussion of current country PMTCT guidelines and the woman’s options.  3529 women were enrolled and seen at 2, 4, 8, 12 weeks and then every 4 weeks till delivery.  After delivery, women and infants were seen at week 1(between 6-12 days post delivery under V 2, and 5-14 days in V3)  Laboratory safety testing was done at all these visits. CD4 was done at screening and entry; labor/delivery and 1 week post partum visit; viral load (VL) at entry, wk 4, L/D, and week 1 5

Antepartum Labor/ Postpartum Maternal Health ( 14 wks-term) Delivery (for duration of BF) (after BF cessation) Infant NVP Prophylaxis Triple ARV Prophylaxis RandomizeRandomize Late Presenters Continue Triple ARV Regimen Stop All ARVs Mother RandomizeRandomize infant uninfected at birth ZDV ZDV + sdNVP+ TRV Triple ARV Prophylaxis Triple ARV Prophylaxis RandomizeRandomize Maternal CD4 >350 Today: Focus on Antepartum Component ENROLLED 3,529 WOMEN 6

Antepartum Component Maternal Randomization Pregnant Women (both HBV+ and HBV-) Arm A ZDV +sdNVP+ FTC-TDF tail R Arm B 3TC-ZDV + LPV-RTV Arm C FTC-TDF + LPV-RTV 7

Maternal Baseline Characteristics: Young Pregnant African Women with High CD4 Counts Entry Characteristics (N=3,523)Value Age (median)26 years Race – Black African97% Gestational age (median)26 weeks CD4 cell count (median)530 cells/uL WHO Clinical Stage 197% Hepatitis B Surface Antigen +4% No ARV for prior PMTCT or no prior pregnancy 94% 8

Efficacy and Safety Outcomes Through 14 Days Post-Delivery  Mother to Child HIV Transmission (primary efficacy outcome)  Maternal Adverse Events and Mortality  Adverse Pregnancy Outcomes  Infant Adverse Events and Mortality 9

MTCT Through Age 14 Days Significantly Lower in Triple ARV Arms 1.8% Difference in MTCT Risk (Repeated Confidence Interval): -1.28% (95% CI -2.11%, -0.44%) infections/ 1,326 9 infections/ 1,710

Summary of safety results  In HIV-infected pregnant women with high CD4, all regimens had low MTCT (<2%), but the triple ARVs had significantly lower early MTCT rates than ZDV Arm A regimen: –0.5% (3TC-ZDV+LPV-RTV) and 0.6% (FTC- TDF+LPV/RTV) vs 1.8% (ZDV)  There was an increased risk of maternal AEs with triple ARVs compared to ZDV regimen, driven by increased ALT.  Higher risk of moderate but not severe pregnancy outcomes for triple ARVs compared to ZDV (such as LBW, preterm birth).  There was a significantly lower risk of infant death for LPV-RTV +ZDV/3TC vs TDF/FTC 0.6 % (2/346) vs 4.4 %(15/341), p=0.001 The difference was primarily seen in deaths among infants <34 weeks gestation. 11

Conclusions  These results provide the first clinical trial evidence to support the current 2013 WHO recommendations for use of triple ARV regimens in pregnancy to achieve the lowest risk of transmission.  The safety findings require further study. 12

Acknowledgements 13 The PROMISE Team gratefully acknowledges the dedication and commitment of the more than 3,500 mother-infant pairs without whom this study would not have been possible.