Safety and pharmacokinetics of dolutegravir in pregnant mothers with HIV infection and their neonates: A randomised trial (DolPHIN-1 study)

Abstract

Background: The global transition to use of dolutegravir (DTG) in WHO-preferred regimens for HIV treatment is limited by lack of knowledge on use in pregnancy. Here we assessed the relationship between drug concentrations (pharmacokinetics, PK), including in breastmilk, and impact on viral suppression when initiated in the third trimester (T3).

Methods and findings: In DolPHIN-1, HIV-infected treatment-naïve pregnant women (28-36 weeks of gestation, age 26 (19-42), weight 67kg (45-119), all Black African) in Uganda and South Africa were randomised 1:1 to dolutegravir (DTG) or efavirenz (EFV)-containing ART until 2 weeks post-partum (2wPP), between 9th March 2017 and 16th January 2018, with follow-up until six months postpartum. The primary endpoint was pharmacokinetics of DTG in women and breastfed infants; secondary endpoints included maternal and infant safety and viral suppression. Intensive pharmacokinetic sampling of DTG was undertaken at day 14 and 2wPP following administration of a medium-fat breakfast, with additional paired sampling between maternal plasma and cord blood, breastmilk and infant plasma. No differences in median baseline maternal age, gestation (31 vs 30 weeks), weight, obstetric history, viral load (4.5 log10 copies/mL both arms) and CD4 count (343 vs 466 cells/mm3) were observed between DTG (n = 29) and EFV (n = 31) arms. Although DTG Ctrough was below the target 324ng/mL (clinical EC90) in 9/28 (32%) mothers in the third trimester, transfer across the placenta (121% of plasma concentrations) and into breastmilk (3% of plasma concentrations), coupled with slower elimination, led to significant infant plasma exposures (3-8% of maternal exposures). Both regimens were well-tolerated with no significant differences in frequency of adverse events (two on DTG-ART, one on EFV-ART, all considered unrelated to drug). No congenital abnormalities were observed. DTG resulted in significantly faster viral suppression (P = 0.02) at the 2wPP visit, with median time to <50 copies/mL of 32 vs 72 days. Limitations related to the requirement to initiate EFV-ART prior to randomisation, and to continue DTG for only two weeks postpartum.

Conclusion: Despite low plasma DTG exposures in the third trimester, transfer across the placenta and through breastfeeding was observed in this study, with persistence in infants likely due to slower metabolic clearance. HIV RNA suppression <50 copies/mL was twice as fast with DTG compared to EFV, suggesting DTG has potential to reduce risk of vertical transmission in mothers who are initiated on treatment late in pregnancy.

Trial registration: clinicaltrials.gov NCT02245022.

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: ML declared research grants from ViiV, Janssen and personal fees from Mylan.

Figures

Fig 1. Consort diagram.

Fig 2. Maternal plasma DTG concentrations in 3rd trimester and postpartum (median 10 days [range 7–18]).

Fig 3. Breast milk and infant DTG concentrations at steady state and terminal elimination.

A: Maternal plasma and breast milk DTG concentrations at steady-state B: Maternal plasma and infant plasma DTG concentrations at steady-state C: Maternal plasma and breast milk DTG concentrations at 24–96 hours after final maternal dose D: Maternal plasma and infant plasma DTG concentrations at 24–96 hours after final maternal dose.

Fig 4

4A log10 HIV RNA results for each individual over time on ART. The thick line shows the median viral load at each time point (marked at the median day for each visit since screening [median days on any ART]) for each group. The vertical dashed line shows the median day of delivery (59 days) and the horizontal line shows the HIV RNA 50 copies/mL threshold. 4B Proportion of participants with HIV-RNA <50, 50–199, 200–999, and 1000+ copies/mL at each time point by arm (observed results; individuals with missing results at each timepoint were excluded [M = X]).

Fig 5. Kaplan-Meier curve indicating time to HIV viral load