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HIVNET 023

HIVNET 023. A Phase I/II Study of the Safety and Pharmacokinetics of Nevirapine Given Daily, Twice a Week or Weekly As Prophylaxis in Breastfeeding Infants From Birth to 24 Weeks in Durban, South Africa and Harare, Zimbabwe. Hoosen M. Coovadia, University of Natal, Durban, South Africa

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HIVNET 023

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  1. HIVNET 023 A Phase I/II Study of the Safety and Pharmacokinetics of Nevirapine Given Daily, Twice a Week or Weekly As Prophylaxis in Breastfeeding Infants From Birth to 24 Weeks in Durban, South Africa and Harare, Zimbabwe Hoosen M. Coovadia, University of Natal, Durban, South Africa Avinash K. 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 Sponsored by the US National Institute of Allergy and Infectious Diseases, National Institute of Health through the HIV Prevention Trials Network

  2. Design Phase I/II open-label randomized trial Three infant NVP dosing regimens Objectives Safety Minimum infant dosing schedule that will maintain the target NVP trough concentration above 100ng/ml HIVNET 023 STUDY DESIGN AND OBJECTIVE Target NVP concentration = 100ng/ml (10 times the in vitro IC50 of NVP against wild type HIV)

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

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

  5. HIVNET 023 METHODS • Clinical and Laboratory evaluation • 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

  6. 63 of 75 infants completed full 32 weeks of follow-up 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) HIVNET 023 FOLLOW-UP

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

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

  9. 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 HIVNET 023 RESULTS: LABORATORY ABNORMALITIES

  10. HIVNET 023 RESULTS: LABORATORY ABNORMALITIES • 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

  11. HIVNET 023 RESULTS: NVP CONCENTRATION DATA 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)

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

  13. 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 HIVNET 023 CONCLUSIONS

  14. 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 HIVNET 023 ACKNOWLEDGEMENTS

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