Initiating antiretroviral therapy (ART) late in pregnancy (>28 weeks’ gestation) for women with HIV is linked to mother-to-child transmission (MTCT) and increased infant mortality. In an analysis published in Clinical Infectious Diseases, infants born to women diagnosed with HIV in late pregnancy and treated with dolutegravir (DTG) acquired several days of HIV prophylaxis once the maternal treatment was discontinued 3 to 15 days postpartum.
Investigators used data from mothers and infants enrolled in the Dolutegravir in Pregnant HIV Mothers and Their Neonates (DolPHIN)-1 trial (ClinicalTrials.gov Identifier: NCT02245022) to develop a population pharmacokinetic model of DTG. The DolPHIN-1 trial included pregnant women diagnosed with HIV during late pregnancy who had not taken ART within the last 6 months and had never received integrase inhibitors.
Investigators randomized patients 1:1 to DTG-based (50 mg daily) or efavirenz-based ART. Intensive DTG pharmacokinetic sampling was performed in the third trimester for maternal plasma, and within 2 weeks of delivery for umbilical cord, infant plasma, and breast milk.
For the population pharmacokinetic model, DTG pharmacokinetic profiles were simulated for all samples over 24, 48, 72, and 96 hours following the final postpartum dose in samples of maternal plasma, cord, breast milk, and infant plasma from 28 women and 22 infants. Infant DTG was exhibited by a 1-compartment model in which the initial DTG dose was via transplacental transfer followed by input from breast milk over time.
The simulated median infant half-life of dolutegravir was 37.9 hours (range, 22.1-63.5, n=21) 24 hours to 3 days after the final dose of maternal DTG. The median time to infant DTG in vitro protein adjusted (PA)-IC90 of 0.064 mg/L was 108.9 hours (range, 18.6-129.6), or 4.5 days (range, 0.8-5.4), after the final maternal dose within 2 to 18 days postpartum. The amount of DTG in infant plasma waned over time, with the proportion of infants below the PA-IC90 increasing from 18% at week 1 postpartum, to 81% at week 2, and 100% at week 3.
The estimated relative infant dose of DTG from breastfeeding was 0.27% that of the maternal dose, making it a negligible exposure and unlikely to prevent adequate MTCT prophylaxis. The breast milk to maternal plasma DTG ratio was 0.033 (0.021-0.050).
No covariate effects were observed in the DTG model.
The authors noted that although other studies observed higher bioavailability of DTG in female participants, in this analysis “sufficient virological response was achieved and no transmissions occurred, suggesting that 50 mg once daily is adequate in late pregnancy.”
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Dickinson L, Walimbwa S, Singh Y, et al. Infant exposure to dolutegravir through placental and breastmilk transfer: a population pharmacokinetic analysis of DolPHIN-1. Clin Infect Dis. Published online December 21, 2020. doi:10.1093/cid/ciaa1861