Theodore D Ruel1, Edmund V Capparelli2, Camlin Tierney3, Bryan S Nelson3, Anne Coletti4, Yvonne Bryson5, Mark F Cotton6, Stephen A Spector2, Mark Mirochnick7, Rebecca LeBlanc8, Christina Reding8, Bonnie Zimmer8, Deborah Persaud9, Mutsa Bwakura-Dangarembizi10, Kimesh L Naidoo11, Rohan Hazra12, Patrick Jean-Philippe13, Ellen G Chadwick14. 1. University of California San Francisco, San Francisco, CA, USA. Electronic address: theodore.ruel@ucsf.edu. 2. University of California San Diego, La Jolla, CA, USA. 3. Harvard TH Chan School of Public Health, Boston, MA, USA. 4. FHI 360, Durham, NC, USA. 5. University of Los Angeles, Los Angeles, CA, USA. 6. Stellenbosch University, Tygerberg, South Africa. 7. Boston University School of Medicine, Boston, MA, USA. 8. Frontier Science and Technology Research Foundation, Amherst, NY, USA. 9. Johns Hopkins University School of Medicine, Baltimore, MD, USA. 10. University of Zimbabwe College of Health Sciences, Harare, Zimbabwe. 11. Nelson R Mandela School of Medicine, Durban, South Africa. 12. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. 13. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. 14. Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Abstract
BACKGROUND: With increasing intention to treat HIV as early as possible, evidence to confirm the safety and therapeutic drug concentrations of a nevirapine-based antiretroviral regimen in the early neonatal period is needed. This study aims to establish dosing of nevirapine for very early treatment of HIV-exposed neonates at high risk of HIV acquisition. METHODS: IMPAACT P1115 is a multinational phase 1/2 proof-of-concept study in which presumptive treatment for in-utero HIV infection is initiated within 48 h of birth in HIV-exposed neonates at high risk of HIV acquisition. Participants were neonates who were at least 34 weeks gestational age at birth and enrolled within 48 h of birth, born to women with presumed or confirmed HIV infection who had not received antiretrovirals during this pregnancy. The regimen consisted of two nucleoside reverse transcriptase inhibitors plus nevirapine dosed at 6 mg/kg twice daily for term neonates (≥37 weeks gestational age) or 4 mg/kg twice daily for 1 week and 6 mg/kg twice daily thereafter for preterm neonates (34 to <37 weeks gestational age). Here, we report the secondary outcomes of the study: nevirapine exposures in study weeks 1 and 2 and treatment-associated grade 3 or 4 adverse events at least possibly related to study treatment up to study week 4. A population pharmacokinetic model to assess nevirapine exposure was developed from dried blood spot and plasma nevirapine concentrations at study weeks 1 and 2. Nevirapine exposure was assessed in all patients with available blood samples and safety was assessed in all participants. This trial is registered at ClinicalTrials.gov (NCT02140255). FINDINGS: Between Jan 23, 2015, and Sept 4, 2017, 438 neonates were enrolled and included in analyses; 36 had in-utero HIV infection and 389 (89%) were born at term. Neonates without confirmed in-utero HIV infection received nevirapine for a median of 13 days (IQR 7-14). Measured dried blood spot nevirapine concentrations were higher than the minimum HIV treatment target (3 μg/mL) in 314 (90%, 95% CI 86-93) of 349 neonates at week 1 and 174 (87%, 81-91) of 201 at week 2. In Monte-Carlo simulations, week 1 nevirapine concentrations exceeded 3 μg/mL in 80% of term neonates and 82% of preterm neonates. DAIDS grade 3 or 4 adverse events at least possibly related to antiretrovirals occurred in 30 (7%, 95% CI 5-10) of 438 infants but did not lead to nevirapine cessation in any neonates; neutropenia (25 [6%] neonates) and anaemia (six [1%]) were most common. INTERPRETATION: Nevirapine at the dose studied was confirmed to be safe and provides therapeutic exposure concentrations. These data support nevirapine as a component of presumptive HIV treatment in high-risk neonates. FUNDING: National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.
BACKGROUND: With increasing intention to treat HIV as early as possible, evidence to confirm the safety and therapeutic drug concentrations of a nevirapine-based antiretroviral regimen in the early neonatal period is needed. This study aims to establish dosing of nevirapine for very early treatment of HIV-exposed neonates at high risk of HIV acquisition. METHODS: IMPAACT P1115 is a multinational phase 1/2 proof-of-concept study in which presumptive treatment for in-utero HIV infection is initiated within 48 h of birth in HIV-exposed neonates at high risk of HIV acquisition. Participants were neonates who were at least 34 weeks gestational age at birth and enrolled within 48 h of birth, born to women with presumed or confirmed HIV infection who had not received antiretrovirals during this pregnancy. The regimen consisted of two nucleoside reverse transcriptase inhibitors plus nevirapine dosed at 6 mg/kg twice daily for term neonates (≥37 weeks gestational age) or 4 mg/kg twice daily for 1 week and 6 mg/kg twice daily thereafter for preterm neonates (34 to <37 weeks gestational age). Here, we report the secondary outcomes of the study: nevirapine exposures in study weeks 1 and 2 and treatment-associated grade 3 or 4 adverse events at least possibly related to study treatment up to study week 4. A population pharmacokinetic model to assess nevirapine exposure was developed from dried blood spot and plasma nevirapine concentrations at study weeks 1 and 2. Nevirapine exposure was assessed in all patients with available blood samples and safety was assessed in all participants. This trial is registered at ClinicalTrials.gov (NCT02140255). FINDINGS: Between Jan 23, 2015, and Sept 4, 2017, 438 neonates were enrolled and included in analyses; 36 had in-utero HIV infection and 389 (89%) were born at term. Neonates without confirmed in-utero HIV infection received nevirapine for a median of 13 days (IQR 7-14). Measured dried blood spot nevirapine concentrations were higher than the minimum HIV treatment target (3 μg/mL) in 314 (90%, 95% CI 86-93) of 349 neonates at week 1 and 174 (87%, 81-91) of 201 at week 2. In Monte-Carlo simulations, week 1 nevirapine concentrations exceeded 3 μg/mL in 80% of term neonates and 82% of preterm neonates. DAIDS grade 3 or 4 adverse events at least possibly related to antiretrovirals occurred in 30 (7%, 95% CI 5-10) of 438 infants but did not lead to nevirapine cessation in any neonates; neutropenia (25 [6%] neonates) and anaemia (six [1%]) were most common. INTERPRETATION: Nevirapine at the dose studied was confirmed to be safe and provides therapeutic exposure concentrations. These data support nevirapine as a component of presumptive HIV treatment in high-risk neonates. FUNDING: National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.
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