Pharmacokinetics and safety of early nevirapine-based antiretroviral therapy for neonates at high risk for perinatal HIV infection: a phase 1/2 proof of concept study

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.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Participant Flow Chart

^ Dried blood spots for pharmacokinetic testing were obtained from 349 infants at Week 1 and 201 infants at Week 2; *Initial HIV testing of mother was positive, but subsequent confirmatory testing negative. ~Safety follow-up data were included from all participants up to 37 days of age or at the time of study exit prior; data censored at time of initiating LPV/r prior for those with in utero HIV.

Figure 2. Nevirapine Concentrations at Weeks 1 and 2 Visits

Dried Blood Spot (DBS) nevirapine concentrations, excluding those deemed non-adherent with concentrations below the assay quantitative limit. Dashed lines represent target exposure range. The centred line is the line is the median, the box is the interquartile range, and the whiskers are the 5th and 95th percentiles.

Figure 3. Infant Time to Grade 3/4 Safety Event (at least Possibly Related)

Age at first Grade 3 or 4 safety event (at least possibly related to one or more study ARV drugs) for infants with and without in utero HIV infection. Each blue line presents the estimated probability of remaining Grade 3/4 event free, where event time is censored (at tick marks) at the earlier of study follow-up discontinuation and 37 days of age. For infants with in utero HIV infection the Grade 3/4 event time is additionally censored at LPV/r initiation. The blue shaded band presents the 95% CI for the Grade 3/4 event free probabilities. The black dashed line presents the estimated probability of not yet initiating LPV/r among infants with in utero HIV infection. The dotted black line presents the estimated probability of not yet reducing/discontinuing NVP among infants without in utero HIV infection.

Figure 4. Infant Absolute Neutrophil Count and Haemoglobin at Weeks 0 and 2 Visits

Infants’ absolute neutrophil count (ANC) and Hemoglobin values at scheduled study visits entry and week 2 (triangles). The red line is a loess smooth.