Background: The 25 mg dapivirine (DPV) vaginal ring (VR) can reduce women''s risk of acquiring HIV infection. Most studies of HIV prevention products exclude lactating women, despite global recommendations for breastfeeding and continued risk for HIV acquisition during lactation. MTN-029/IPM 039 was a Phase I, open-label study of pharmacokinetics; safety and tolerability, and adherence associated with DPV VR use.
Methods: Between January 2016 and March 2017, 16 healthy, HIV-uninfected women aged 18 or older were enrolled in Pittsburgh and Birmingham, USA. Eligible women had weaned infants from breastfeeding before enrollment, but were able to pump breast milk. Participants were instructed to wear the VR continuously for 14 days. Milk and blood plasma samples were collected (pre-insertion, Hour 3, Hour 6, Hour 24, Day 7, Day 14 after ring placement, and two days after ring removal) and analyzed for DPV using validated ultra-performance liquid chromatography-tandem mass spectrometry assays, with lower limits of quantification of 10 pg/mL and 20 pg/mL for milk and plasma, respectively. We estimated infant DPV intake assuming 150 mL/kg/day milk ingestion. Adverse events (AEs) were collected at all participant contacts.
Results: All participants had detectable DPV in milk and plasma. Median DPV concentrations in milk and plasma rose gradually to relatively steady concentrations on Day 7 and Day 14, followed by falling concentrations after ring removal to approximately 40% of Day 14 concentrations by Day 16. Median (interquartile range) peak concentration for milk and plasma were 676 pg/mL (443, 924.5) and 327 pg/mL (274.5, 378), respectively. Time-adjusted median milk/plasma ratio was 1.70 (1.38, 1.86). Estimated daily infant exposure was 68.0 ng/kg/day (53.0, 85.1). Estimated terminal concentration half-life after ring removal was 39.0 hours (27.1, 53.4) and 35.2 hours (29.8, 46.4) for milk and plasma, respectively. Six of 16 (38%) participants experienced eight total AEs, most of which were mild.
Conclusions: In this first study of DPV exposure during lactation, DPV VR use was associated with low levels of detectable DPV in milk and plasma, very low estimated levels of infant exposure, and a favorable safety profile. Future DPV VR studies should evaluate longer periods of use among breastfeeding mother-infant pairs.