Initiation of ART in the 3rd trimester of pregnancy is associated with adverse outcomes and increased vertical transmission of HIV. DolPHIN-1 (NCT02245022) is a randomised trial of EFV or DTG plus 2NRTIs in pregnant women initiating ART between 28-36w of gestation in Uganda and South Africa. This scheduled interim review was undertaken after the first 16 mothers delivered. The primary endpoint was pharmacokinetics (PK) of DTG; secondary endpoints included VL responses, safety and tolerability of DTG, and placental/breast milk transfer of DTG.
Eligible, consenting mothers were randomised 1:1 to EFV or DTG arms. To comply with national guidelines, EFV-containing ART was initiated on the day of referral. Subjects randomized to DTG were switched from EFV within 7 days. Demographic, serial clinical and laboratory data and birth outcome data were collected. VL responses were collected at baseline, 14d and 28d, as well as post-partum. All infants were exclusively breastfed. Intensive PK sampling (0-24h) was performed at 14d on DTG, and 2w post-partum.
Of the 16 subjects who delivered, 8 each received DTG or EFV. Median baseline VL was log 4.15 (range 2.43-6.07) copies/mL and similar between arms. PK data in 3rd trimester are shown (Table 1). The proportion of VL reported as less than 50 copies or undetectable at 2 weeks and at 4 weeks of therapy was 5/8 and 4/8 in mothers on DTG, and 1/5 and 2/7 in mothers on EFV, respectively. At 2 weeks post-partum 5/6 and 4/7 mothers on DTG, and EFV respectively had VL less than 50 copies. Two mothers in the DTG arm were withdrawn for virological failure; the first had no detectable drug in plasma and was non-adherent, the second had evidence of 3 class drug resistance (RT and protease mutations); no women were withdrawn from the EFV arm. Both regimens were well-tolerated. A total of 4 SAE’s were reported: DTG arm: 1 G3 elevation in liver function tests (possibly drug related, concomitant herbal use recorded) with stillbirth in the same mother (tight cord around the neck, deemed unrelated to study drug); EFV arm: 1 G3 hypertension, 1 baby with polydactyly.
This planned interim assessment suggests DTG appears to be well-tolerated and effective when initiated in late pregnancy. PK findings are consistent with other studies and suggest that dosing of DTG at 50mg once-daily appears appropriate in third trimester. The study continues, with a definitive efficacy study (DolPHIN-2) in development.