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

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 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 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.

Conclusion

In this short-term study of daily directly observed oral PrEP in HIV-uninfected breastfeeding women, the estimated infant doses from breast milk and resultant infant plasma concentrations for tenofovir and emtricitabine were 12,500 and >200-fold lower than the respective proposed infant therapeutic doses, and tenofovir was not detected in 94% of infant plasma samples. These data suggest that PrEP can be safely used during breastfeeding with minimal infant drug exposure.

Trial Registration

ClinicalTrials.gov, Identifier: NCT02776748

Abstract

In a prospective study, Kenneth Mugwanya and colleagues study the transmission of drugs used for HIV pre-exposure prophylaxis from breastfeeding mothers to their babies.

Author Summary

Why Was This Study Done?

• Pregnancy and breastfeeding represent a period of heightened HIV risk for women and for their infant if acute HIV infection occurs. Preventing HIV acquisition in women is a priority.

• Daily oral PrEP is a potent prevention option to reduce the risk of sexual HIV acquisition for women who are pregnant or breastfeeding, with the advantage relative to other prevention methods that it can be used discreetly and independent of sexual partners.

• As HIV PrEP becomes more common worldwide, large numbers of women of child-bearing age will be using these medications during pregnancy and breastfeeding.

• In order to appropriately evaluate the risk–benefit ratio of administering medications to breastfeeding women, evidence regarding infant drug exposure through breast milk is critical and very often completely lacking.

What Did the Researchers Do and Find?

• We conducted an open-label, short-term, pharmacokinetic study among 50 HIV-uninfected breastfeeding women and infants.

• Women were administered directly observed PrEP, and blood and breast milk were collected to measure the concentrations of PrEP medications (i.e., tenofovir and emtricitabine); no drug was administered directly to infants.

• A single blood sample was obtained from the infant to determine the extent to which infants breastfed by women using PrEP absorb these medications via breast milk.

• We found that the concentrations of PrEP medications in infant blood were very low, and tenofovir was undetectable in 94% of the infant samples.

• The estimated doses of tenofovir and emtricitabine a breastfeeding infant would ingest each day were <0.01% and 0.5%, respectively, compared to the proposed pediatric doses for treatment of infant HIV infection and for prevention of infant postnatal HIV infection. No significant safety concerns were noted in mothers or infants.

What Do These Findings Mean?

• The findings of this study provide important empirical evidence to anticipate safety for the breastfeeding infant after administering PrEP to breastfeeding HIV-uninfected women.

• These findings suggest that PrEP can be safely used during breastfeeding with minimal infant exposure and will guide practice and policy decision-making for PrEP implementation programs in heterosexual populations.

• After the pharmacokinetic demonstration of minimal drug exposure in infants breastfed by women using PrEP, the next incremental step is to explore in implementation science studies the acceptability, adherence, and infant safety in women who choose to continue PrEP throughout their pregnancy or breastfeeding and investigate long-term effects of this low-concentration exposure.