Dolutegravir in breast milk and maternal and infant plasma during breastfeeding

The integrase inhibitor dolutegravir (DTG) is a new effective first-line antiretroviral agent for treatment-naive HIV-positive individuals with a variety of baseline characteristics [1–5]. Because of its effectiveness, good tolerability, limited drug–drug interactions, and high-resistance barrier, DTG is also suggested as possible treatment option in the resource-limited setting [6], where WHO recommends exclusive breastfeeding for infants of HIV-positive mothers, as formula feeding is associated with high infant mortality [7]. However, to date, no pharmacokinetic and safety data of DTG from lactating women and their breastfed infants are available. Here, we present the first case of DTG transfer into breast milk and the breastfed infant. Total DTG levels in breast milk and plasma of a 35-years-old HIV-1-positive mother (CRF01_AE, CDC A1, CD4+ nadir 432/μl) and her breastfed infant were determined over a period of 10 months. The mother had been treated with darunavir/ritonavir and tenofovir disoproxil fumarate/emtricitabine during pregnancy and switched to designated single-tablet DTG/ABC/3TC (Triumeq, containing 50 mg DTG) after delivery while she continued breastfeeding against all medical expert advice. Measurements in plasma obtained during routine blood sampling were conducted with the understanding and consent of the parents. The responsible ethical committee confirmed that the study was conducted according to local law. DTG plasma concentrations were determined using a validated ultra-performance liquid chromatography tandem mass spectrometry method developed by the laboratory of the Department of Pharmacy of the Radboud University Medical Center, Nijmegen, The Netherlands, and adapted for the bioanalysis of breast milk. With 4.48 mg/l, the DTG plasma concentration of the mother 11 h after dosing was high compared with available adult pharmacokinetic data [8,9]. Corresponding DTG concentrations in breast milk were around 0.10 mg/l (during the 10 months of breastfeeding). This translates into a milk-to-plasma ratio of about 0.02. This is somewhat higher than expected based on a DTG plasma protein binding of more than 99% and possibly related to active DTG excretion into breast milk by drug transporters (e.g., breast cancer resistance protein) [10–13]. Based on average infant daily milk intake (150 ml/kg) and infant weight (4 kg), we estimate a daily infant DTG dose of about 0.015 mg/kg [14] resulting in infant DTG plasma concentrations during exclusive breastfeeding of 0.10 mg/l and declined during supplementary formula feeding (Fig. 1). Achieving these notable steady-state concentrations may be in part facilitated by an immature metabolizing system in newborns resulting in limited DTG clearance. [15]Fig. 1: Dolutegravir concentrations during the observation period.Dolutegravir concentrations in serum and breast milk measured by ultra-performance liquid chromatography tandem mass spectrometry in the different matrices and time points after birth, as described in the present case report.During our observation period, HIV-1 RNA in plasma was always below the detection limit in the mother and undetectable in the infant until more than 3 months after discontinuation of breastfeeding. No obvious side-effects were identified during the 14-month follow-up period. Our main finding is the significant DTG transfer by maternal breast milk to the infant. Daily maternal 50 mg DTG during the period of exclusive breastfeeding resulted in infant plasma levels comparable with proposed target trough concentration in treatment-naive patients. As such infant DTG levels may be seen as protective against HIV acquisition, a therapeutic range for prophylaxis has not been established but, similarly, it cannot be excluded that they may cause adverse events. Food and Drug Administration and the European Medicines Agency have not approved DTG for children younger than 12 years of age. However, because of increasing DTG prescribing in women of child-bearing age, fetuses and infants will be exposed to DTG through placental passage and breastfeeding [16–18]. A recent review on studies of antiretroviral drug (ARV) transfer during breastfeeding concludes that for some nucleoside/nucleotide reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors transfer via breast milk to untreated infants appears to be quantitatively important [19]. Infants who acquire HIV infections via breast milk, despite maternal ARV use, were reported to have limited treatment options and lower life expectancy because of high drug resistance rates [20,21]. Although DTG demonstrated a high barrier to the emergence of HIV-1 resistance mutations, occasionally mutations leading to cross-resistance to integrase inhibitors can develop, especially during monotherapy [22]. Therefore, low DTG infant plasma concentrations because of exposure through breast milk during continuous HIV-1 exposure by breastfeeding warrant a caution. Also, early infant diagnosis may be further complicated because of delayed HIV-1 detection among infants exposed to maternal ARV transferred via breastfeeding [23]. As reported for other ARVs, DTG might sufficiently suppress HIV-1 replication in infants leading to false-negative diagnosis during the period of continued breastfeeding. In summary, although in this single case analysis, blood sampling was limited because of ethical reasons, we demonstrated significant DTG transfer from breast milk to infant plasma. As DTG is a promising ARV for future treatment strategies, more pharmacokinetic, resistance, and safety data during pregnancy, breastfeeding, and infancy must be systematically collected in the years to come. Acknowledgements Conflicts of interest There are no conflicts of interest.