HIVNET 023 Sponsored by the US National Institute of Allergy and Infectious Diseases, National Institute of Health through the HIV Prevention Trials Network A Phase I/II Study of the Safety and Pharmacokinetics of Nevirapine Given Daily, Twice a Week or Weekly As Prophylaxis in Breastfeeding Given Daily, Twice a Week or Weekly As Prophylaxis in Breastfeeding Infants From Birth to 24 Weeks in Durban, South Africa and Harare, Zimbabwe Infants From Birth to 24 Weeks in Durban, South Africa and Harare, Zimbabwe Hoosen M. Coovadia, University of Natal, Durban, South Africa AvinashK. Shetty, University of Zimbabwe, Harare, ZW Yvonne Maldonado, Stanford University School of Medicine, USA Mary T. Bassett, University of Zimbabwe, Harare, ZW Salim Abdool Karim, University of Natal, South Africa Samuel Adyenyi Jones, NIAID/NIH, Bethesda, MD, USA Lynne Mofenson, NICHD/NIH, Rockville MD, USA Mark Mirochnick, Boston University School of Medicine, USA Tom Fleming, SCHARP, University of Washington, WA, USA For the HIVNET 023 Study Team

STUDY DESIGN AND OBJECTIVE Design Phase I/II open-label randomized trial Phase I/II open-label randomized trial Three infant NVP dosing regimens Three infant NVP dosing regimensObjectives Safety Safety Minimum infant dosing schedule that will maintain the target NVP trough concentration above 100ng/ml Minimum infant dosing schedule that will maintain the target NVP trough concentration above 100ng/ml HIVNET 023 Target NVP concentration = 100ng/ml (10 times the in vitro IC 50 of NVP against wild type HIV)

METHODS HIVNET 023 Terminated before delivery (n=25) Infant's randomized (n=67) Infant's NOT randomized (n=6) Mother's Dosed (n=72) Infant's randomized (n=8) Infant's NOT randomized randomized (n=1) Mother's NOT dosed (n=9) Mother's Known to have delivered (n=81) Mother's Enrolled (n=106)

HIVNET 023 METHODS: INFANT NEVIRAPINE DOSING 4 mg/kg Birth – 14 day Arm 1 [n=26] Once weekly 28 mg/kg 4 mg/kg 15 d – 24 wk 14 mg/kg 2 mg/kg Birth – 14 day Arm 3 [n=24] Daily 16 mg/kg 8 mg/kg 15 d – 24 wk 8 mg/kg 4 mg/kg Birth – 14 day Arm 2 [n=25] Twice weekly 8 mg/kg 15 d – 24 wk Total Weekly Dose DoseAge Study Arm

HIVNET 023 METHODS Clinical and Laboratory evaluation Infants were evaluated weekly for NVP toxicity  Infants were evaluated weekly for NVP toxicity  Serum bilirubin, AST, ALT, and creatinine monitored  at birth, 2, 4, 8, 12, 16, 20, 24, and 32 weeks  CBC at birth, 2, 8, 16, 20, 24 and 32 weeks NVP Pharmacokinetic samples  Pre-dose (trough) concentrations at 2, 8, 16, 20, & 24 weeks

HIVNET 023 FOLLOW-UP 63 of 75 infants completed full 32 weeks of follow-up 63 of 75 infants completed full 32 weeks of follow-up 12 infants were inactivated, including: 12 infants were inactivated, including:  4 parents unable to adhere to visit schedule  2 parents refused to continue  2 lost to follow-up  2 infants died  2 for other reasons (maternal death, treatment discontinued)

Most common adverse experiences were infections Most common adverse experiences were infections  Respiratory, Diarrhea, Oral thrush No severe Cutaneous, Hepatic or Renal toxicity (  grade 3) No severe Cutaneous, Hepatic or Renal toxicity (  grade 3) Three infant deaths (one after the final 32 week visit) Three infant deaths (one after the final 32 week visit) 1. Neonatal SepsisHIV- (died day 3 after 1 dose) 2. PneumoniaHIV+ 3. PneumoniaHIV+ RESULTS: CLINICAL OUTCOMES HIVNET 023

Neutropenia (  grade 3) in 13 infants Neutropenia (  grade 3) in 13 infants Once weekly: n=5 Twice weekly: n=6 Daily: n=2 Reported at both sites Reported at both sites RESULTS: LABORATORY ABNORMALITIES HIVNET 023

 Ten of 13 cases asymptomatic  Faulty machine calibration at one lab may have contributed to some abnormal values  Neutropenia being investigated  Associated with clinical events in 3 infants two with viral syndrome, one with sepsis RESULTS: LABORATORY ABNORMALITIES HIVNET 023

Neutropenia resolved in all 13 infants Neutropenia resolved in all 13 infants  For 11 infants, the neutropenia transient and dosing continued through 24 weeks  For 2 infants, neutropenia resolved after NVP discontinued RESULTS: LABORATORY ABNORMALITIES HIVNET 023

RESULTS: NVP CONCENTRATION DATA HIVNET 023 Number of Infants with Trough NVP Levels Below Target Target NVP concentration = 100ng/ml (10 times the in vitro IC50 of NVP against wild type HIV)

 NVP appeared safe and well tolerated by infants  The relationship between neutropenia and NVP is unclear CONCLUSIONS HIVNET 023

 NVP concentration maintained above the target of 100ng/ml most often in daily and twice weekly dosing arms  Simplified Daily dosing regimen selected for use in HPTN046 phase III trial of extended NVP dosing to prevent HIV transmission through breast milk CONCLUSIONS HIVNET 023

 Harare Jennifer Wells Patrick Mateta Lynda Stranix Nhamo Gonah  Durban Arthi Ramkissoon Atom Dilraj Selvan Pather  FHI Kathy George  SCHARP Anthony Mwatha Lynda Emel Rita Lai  HPTN Central Lab Estelle Piwowar Fayez M. Hamzeh ACKNOWLEDGEMENTS HIVNET 023