Pre-exposure Prophylaxis Use by Breastfeeding HIV-Uninfected Women: A Prospective Short-Term Study of Antiretroviral Excretion in Breast Milk and Infant Absorption

Abstract

BackgroundAs pre-exposure prophylaxis (PrEP) becomes more widely used in heterosexual populations, an important consideration is its safety in infants who are breastfed by women taking PrEP. We investigated whether tenofovir and emtricitabine are excreted into breast milk and then absorbed by the breastfeeding infant in clinically significant concentrations when used as PrEP by lactating women.Methods and FindingsWe conducted a prospective short-term, open-label study of daily oral emtricitabine–tenofovir disoproxil fumarate PrEP among 50 HIV-uninfected breastfeeding African mother–infant pairs between 1–24 wk postpartum (ClinicalTrials.gov Identifier: NCT02776748). The primary goal was to quantify the steady-state concentrations of tenofovir and emtricitabine in infant plasma ingested via breastfeeding. PrEP was administered to women through daily directly observed therapy (DOT) for ten consecutive days and then discontinued thereafter. Non-fasting peak and trough samples of maternal plasma and breast milk were obtained at drug concentration steady states on days 7 and 10, and a single infant plasma sample was obtained on day 7. Peak blood and breast milk samples were obtained 1–2 h after the maternal DOT PrEP dose, while maternal trough samples were obtained at the end of the PrEP dosing interval (i.e., 23 to 24 h) after maternal DOT PrEP dose. Tenofovir and emtricitabine concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays.Of the 50 mother–infant pairs enrolled, 48% were ≤12 wk and 52% were 13–24 wk postpartum, and median maternal age was 25 y (interquartile range [IQR] 22–28). During study follow-up, the median (IQR) daily reported frequency of infant breastfeeding was 15 times (12 to 18) overall, 16 (14 to 19) for the ≤12 weeks, and 14 (12 to 17) for the 13–24 wk infant age groups. Overall, median (IQR) time-averaged peak concentrations in breast milk were 3.2 ng/mL (2.3 to 4.7) for tenofovir and 212.5 ng/mL (140.0 to 405.0) for emtricitabine. Similarly, median (IQR) time-averaged trough concentrations in breast milk were 3.3 ng/mL (2.3 to 4.4) for tenofovir and 183.0 ng/mL (113.0 to 250.0) for emtricitabine, reflecting trough-to-peak breast milk concentration ratios of 1.0 for tenofovir and 0.8 for emtricitabine, respectively. In infant plasma, tenofovir was unquantifiable in 46/49 samples (94%), but emtricitabine was detectable in 47/49 (96%) (median [IQR] concentration: 13.2 ng/mL [9.3 to 16.7]). The estimated equivalent doses an infant would ingest daily from breastfeeding were 0.47 μg/kg (IQR 0.35 to 0.71) for tenofovir and 31.9 μg/kg (IQR 21.0 to 60.8) for emtricitabine, translating into a <0.01% and 0.5% relative dose when compared to the 6 mg/kg dose that is proposed for therapeutic treatment of infant HIV infection and for prevention of infant postnatal HIV infection; a dose that has not shown safety concerns. No serious adverse effects were recorded during study follow-up.The key study limitation was that only a single infant sample was collected to ...

Pre-exposure prophylaxis for HIV prevention in women: current perspectives

“…A pharmacokinetic study suggests that women can safely breastfeed their infants while using PrEP 34. In this study, investigators measured infant exposure to tenofovir or FTC during breast feeding by women who were using PrEP.…”

Delivering preexposure prophylaxis to pregnant and breastfeeding women in Sub-Saharan Africa

“…However, PrEP trials excluded pregnant women from enrolment, and those who fell pregnant during these studies were discontinued from PrEP [11, 14]. A recent systematic review demonstrated that PrEP was not associated with increased pregnancy-related adverse events, and no studies have found adverse effects among infants exposed to tenofovir disoproxil fumarate (TDF) as part of treatment for HIV-infected women during pregnancy [15, 19–21] or breastfeeding [16, 22, 23]. In addition, our studies in South Africa demonstrated that the use of tenofovir during pregnancy was not associated with adverse events among infants [20, 21].…”

The Current Status of PrEP in Key Populations

“…Among a study with 50 mother-infant pairs enrolled, median peak concentration of tenofovir and emtricitabine were 3.2 ng/mL and 212.5 ng/mL, respectively (( [36]). In infant plasma, tenofovir was not detectable, and the median concentration of emtricitabine was 13.2 ng/mL.…”