Background:
Global guidance supports exclusive breastfeeding for infants up to six months of age, continued breastfeeding with the introduction of complementary foods. World Health Organization (WHO) guidance also supports provision of oral pre-exposure prophylaxis (PrEP) for breastfeeding people at substantial risk of HIV acquisition. In January 2021, WHO recommended the 25 mg dapivirine vaginal ring (DVR) as an HIV prevention choice as part of combination prevention approaches. However, data are limited on DVR safety and pharmacokinetics during breastfeeding, a period of increased risk for HIV acquisition.
Methods:
Microbicide Trials Network (MTN)-043 was a phase 3b, randomized, open-label trial, with 12 weeks of exposure to monthly DVR or daily oral PrEP (200 mg emtricitabine [FTC]/300mg tenofovir disoproxil fumarate [TDF]). From September 2020 to July 2021, healthy, HIV-negative, exclusively breastfeeding, mother-infant pairs were enrolled 6-12 weeks after delivery at sites in Malawi, South Africa, Uganda, and Zimbabwe. Mother-infant pairs were randomized in a 3:1 ratio (DVR: PrEP). Adverse event data were collected for mothers and infants throughout product exposure and at two weeks following end of product use. Drug concentrations were measured in maternal plasma, maternal dried blood spots (DBS), breast milk, infant plasma, and infant DBS.
Results:
We enrolled 197 mother-infant pairs (DVR: 148, PrEP: 49). Median infant age at enrollment was 9 weeks and >95% of visits were completed. No SAEs or ≥Grade 3 events in mothers or infants were deemed related to study product. Drug concentrations are presented in the Table. Results indicate high uptake of study product in both arms with extremely low concentrations of dapivirine (DVR arm) detected in infant plasma samples. In the oral PrEP arm, tenofovir diphosphate concentrations from infant DBS were all below the lower limit of quantitation.
Conclusions:
In this first evaluation of DVR safety and drug detection during breastfeeding, few SAEs or ≥Grade 3 AEs occurred among mothers and infants and all infant AEs were deemed unrelated to study product. While dapivirine appears to concentrate in breastmilk, detection in infant plasma was low. This favorable safety profile, along with data demonstrating low dapivirine transfer to infants, supports updates to WHO and national guidelines to include breastfeeding people when recommending the DVR as an additional HIV prevention choice.
Drug concentrations in maternal plasma, maternal dried blood spots, breast milk, and infant plasma by study arm