Abstract:
Background
As 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 Findings
We 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
PLOS Medicine 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-topeak
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 minimize
venipunctures for the children. However, maternal daily DOT and specimen collection at
drug concentration steady state provided an adequate approach to address the key
research question. Importantly, there was minimal variation in breast milk concentrations of
tenofovir and emtricitabine (respective median trough-to-peak concentration ratio ~1),
demonstrating that infants were exposed to consistent drug dosing via breast milk.