Downloaded from http://journals.lww.com/pidj by BhDMf5ePHKbH4TTImqenVHwXmMsAVI5g3ImrOchK92QhzayE/VSlPhmC8LyvnF1bocbM4KiaVTQ= on 01/17/2019 Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 152 | www.pidj.com The Pediatric Infectious Disease Journal • Volume 38, Number 2, February 2019 Background: Triple-drug infant antiretroviral prophylaxis containing nevi- rapine (NVP) is increasingly used to prevent HIV transmission among neo- nates at high risk of HIV infection. Our aim was to describe NVP concentra- tion from birth through the first month of life. Methods: High-risk HIV-exposed neonates were enrolled in a prospec- tive cohort in Thailand. High-risk neonates defined as maternal HIV RNA >50 copies/mL before delivery or mother received antiretroviral treatment for <12 weeks before delivery. Neonates received zidovudine (4 mg/kg) and lamivudine (2 mg/kg) twice daily, plus NVP (4 mg/kg) once daily (no lead-in) from birth to 6 weeks of life. Infant plasma samples were collected at 1, 2, 14 or 2, 7, 28 days of life. NVP trough concentrations (C 24 ) were estimated using a population pharmacokinetic model and target C 24 was ≥0.1 mg/L. “Washout” efavirenz (EFV) concentrations were assessed in infants whose mother received EFV-based antiretroviral treatment. Results: A total of 48 infants were included: 25 (52%) were male and 12 (25%) were preterm (gestational age 34–37 weeks). Median (interquartile range) predicted NVP C 24 were 1.34 mg/L (1.13–1.84), 2.24 (2.00–2.59), 2.78 (2.61–3.12), 2.20 (1.86–2.44) and 0.81 (0.58–0.98) on days 1, 2, 7, 14 and 28 of life, respectively. NVP C 24 was not significantly different between term and preterm infants. All infants maintained NVP C 24 ≥0.1 mg/L. EFV via placental transfer remained detectable in infants up to 7 days of life. Conclusions: NVP 4 mg/kg daily from birth provided adequate prophylactic concentrations during the first month of life in high-risk HIV-exposed neonates. Key Words: nevirapine, prophylaxis, pharmacokinetics, HIV-exposed infants (Pediatr Infect Dis J 2019;38:152–156) C ombination antiretroviral prophylaxis regimens are recom- mended to prevent HIV mother-to-child transmission for high- risk HIV-exposed infants in many countries, including Thailand. 1–3 Thailand has been very effective at implementing strategies to pre- vent mother-to-child transmission of HIV and was the first country in Asia to be validated from the World Health Organization (WHO) for eliminating mother-to-child transmission of HIV in 2016. 3 As in other settings with a strong prevent mother-to-child transmission program, the remaining transmissions occur in “high-risk” infants whose mother had no or short antenatal care, incident HIV infec- tion during pregnancy or poor antiretroviral therapy (ART) adher- ence before delivery. 4 The definition of “high-risk” infants var- ies between international guidelines but primarily includes those infants whose mother received no or only a short course of ART (eg, less than 12 weeks) before delivery, or have detectable mater- nal HIV-1 RNA viral load near delivery. 1–3,5,6 Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used worldwide as part of combination antiretrovi- ral prophylaxis and therapy in neonates and infants. 7 The pro- posed plasma target trough NVP concentration for prophylaxis is 0.1 mg/L which is approximately 10 times the in vitro IC 50 of NVP. 8,9 In early studies, a single maternal intrapartum dose of NVP plus a single 2 mg/kg oral dose to the infants at 48–72 hours after birth maintained infants serum concentrations above this threshold throughout the first 7 days of life. 10 But there are differences in the recommended NVP dosage and duration as part of multiple dose combination antiretroviral prophylaxis for infants at high risk of HIV acquisition. 1–3,5 For HIV treatment, NVP is usually initiated with a lower “lead-in” dose because of autoinduction of its own metabolism during the first 2–4 weeks of treatment 11 but it remains unclear if this is also optimal for NVP prophylaxis. Thai guidelines recommend 6-week prophylaxis course of zidovudine, lamivudine plus NVP initiated at 4 mg/kg once daily (ie, without a NVP dose- lead period), but limited data on this approach are available. Efavirenz (EFV)-based ART is recommended for HIV- infected pregnant women. Maternal EFV can transfer across the placenta to their infants. 12 Since EFV and NVP are metabolized by the cytochrome P450 2B6 (CYP2B6) isoenzyme, 13,14 it is pos- sible that tranplacental EFV could affect NVP concentrations in the neonate. The objective of this study was to assess NVP plasma con- centrations during the first month of life in neonates at high risk of HIV acquisition receiving the recommended prophylaxis regimen in Thailand. MATERIALS AND METHODS Study Design Neonates with high risk of HIV transmission were enrolled in a prospective cohort in Thailand assessing the safety and Accepted for publication August 23, 2018. From the *Department of Pediatrics, and †Center of Excellence for Pediatric Infec- tious Diseases and Vaccines, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; ‡Program for HIV Prevention and Treatment, Depart- ment of Medical Technology, Faculty of Associated Medical Sciences (PHPT/ IRD), Chiang Mai University, Chiang Mai, Thailand; §Harvard T.H. Chan School of Public Health, Boston, Massachusetts; ¶Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, United King- dom; ║Department of Pediatrics, Faculty of Medicine, Queen Sirikit National Institute of Child Health, Bangkok, Thailand;**Department of Pediatrics, Chi- ang Rai Prachanukroh Hospital, Chiang Rai, Thailand; ††Department of Pedi- atrics, Khon Kaen Hospital, Khon Kaen, Thailand; ‡‡The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), the Thai Red Cross AIDS Research Centre, Bangkok, Thailand; and §§Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. Members of the CIPHER_AEPEP Study Team are given in the Acknowledgments. The study was funded by a CIPHER grant from the International AIDS Soci- ety and the 100th Anniversary Chulalongkorn University Fund for Doctoral Scholarship. The authors have no conflicts of interest to disclose. Address for correspondence: Suvaporn Anugulruengkitt, MD, Division of Infectious Diseases, Department of Pediatrics, Faculty of Medicine, Chu- lalongkorn University, Rama IV Road, Bangkok 10330, Thailand. E-mail: suvaporn.a@chula.ac.th. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. HIV REPORTS ISSN: 0891-3668/19/3802-0152 DOI: 10.1097/INF.0000000000002195 Nevirapine Concentrations During the First Month of Life and Maternal Efavirenz Washout in High-Risk HIV-Exposed Infants Receiving Triple Antiretroviral Prophylaxis Suvaporn Anugulruengkitt, MD,*† Tim R. Cressey, PhD,‡§¶ Piyarat Suntarattiwong, MD,║ Pradthana Ounchanum, MD,** Ussanee Srirompotong, MD,†† Watsamon Jantarabenjakul, MD,*† Jiratchaya Sophonphan, MSc,‡‡ Yardpiroon Tawon, BSc,‡ Sunti Punnahitanon, MD,* Chitsanu Pancharoen, MD,*† Kulkanya Chokephaibulkit, MD,§§ and Thanyawee Puthanakit, MD,*† on Behalf of CIPHER_AEPEP Study Team