Infants born to HIV-infected women with no or a short duration of antiretroviral treatment during pregnancy are at high-risk of perinatal transmission. Nevirapine (NVP) is a key component of antiretroviral (ARV) prophylaxis for infants at high risk of intrapartum HIV infection. We developed a population pharmacokinetic (PK) model to describe NVP concentrations in infants from birth through the first 2 weeks of life.
Infants were enrolled in an adaptive single-arm, multicenter trial in Thailand assessing ‘Perinatal Antiretroviral Intensification’ to prevent mother-to-child transmission of HIV in pregnant women with <8 weeks of triple ARV treatment prior to delivery (ClinicalTrials.gov NCT01511237). Intensification consisted of maternal single-dose NVP (sd-NVP) during labor and an infant 2 week course of AZT+3TC+ NVP, followed by AZT+3TC for 2 weeks. NVP dosing was 2 mg/kg for 7 days, then 4 mg/kg for 7 days. Infant blood samples were draw from the umbilical cord, on the first day of life and at 2 weeks. NVP population PK parameters were estimated using non-linear mixed-effects regression models. Monte Carlo simulations were performed to estimate the probability of achieving target NVP trough concentrations (C24) for prophylaxis (>0.10 mg/L) and for therapeutic efficacy (>3.0 mg/L).
Sixty two infants (56% male) were included. At birth, median (range) gestational age was 38.6 (35.7-41.7) weeks and weight was 2.9 (2.3-3.7) kg. NVP concentrations were best described by a one compartment PK model. Body weight influenced oral clearance (CL/F) and volume of distribution (Vd/F). Population estimates of NVP CL/F and Vd/F were 3.67 L/h and 0.144 L, respectively. Based on simulations for a 3 kg infant, without maternal sd-NVP, >88% would have a NVP C24 >0.1 mg/L after 24 hours through 2 weeks. Predictions using the WHO recommended 15 mg once daily dose, >92% of infants have a NVP C24 >0.1 mg/L after 24 hours. For NVP-based therapy, assuming linear kinetics, a 6 mg/kg twice daily dose produced a C24 >3.0 mg/L in 72% of infants at 48 hours and 76% at 2 weeks. With 8 mg/kg twice daily the C24 was predicted to be >3.0 mg/L in 81% of infants at 48 hours and 86% at 2 weeks.
The escalating NVP dose in PHPT-5 and the WHO single dose approach rapidly achieve and maintain target prophylactic concentrations over the first 2 weeks of life. Therapeutic NVP doses of 6 to 8 mg/kg twice daily should be studied in infants initiating treatment within the first few days of life.