A raltegravir-based regimen is among the preferred for pregnant women living with HIV [1,2], making raltegravir a widely used antiretroviral drug in new mothers in high-income countries. European  and US  guidelines recommend against breastfeeding because of the potential risk of mother-to-child transmission (MTCT). Nevertheless, an increasing number of HIV-infected mothers is breastfeeding their newborns , and it is an ongoing debate if the cultural, psychological and social importance of breastfeeding outweighs the MTCT risk in some circumstances [4–8]. Adequate antiretroviral therapy is of particular importance in these women to prevent transmission, but it is widely unknown, which antiretroviral drugs (ARVs) are preferable for these women . Here, we present the first case of raltegravir in a breastfeeding mother.
A 36-year-old HIV-1-infected woman received raltegravir 800 mg once daily (decreased dose because of low body weight) and emtricitabine/tenofovir disoproxil 200/245 mg once daily. Her plasma HIV-RNA has remained <20 copies/ml for more than 6 years. At 41 + 3 weeks of gestation, she delivered a healthy boy (3580 g, 55 cm, APGAR score 9 at 5 min), who received neonatal prophylaxis with oral zidovudine for 14 days . Breastfeeding was chosen, with exclusive breastfeeding until 4 months of age followed by mixed feeding until the age of 9 months. A mild elevation of total bilirubin levels with normal liver function tests was observed at 14, 32, 48, and 90 days of age (6.71 [conjugated 0.61], 4.58, 5.99, and 1.42 mg/dl, respectively). Infant HIV-DNA PCR results were consistently negative up to the age of 8 months.
Maternal blood (at 4 months) and breastmilk samples (4 and 8 months postpartum) were obtained for pharmacokinetic analyses after observed maternal raltegravir intake with food to assess the breastmilk transfer and estimate infant exposure to raltegravir. A single infant blood sample was taken at 4 h after maternal dosing (assumed Tmax) to assess the infant's exposure. The plasma samples were analyzed using a validated ultra-performance liquid chromatography tandem mass spectrometry assay [lower limit of quantification (LLOQ) 0.01 mg/l] . The method was adapted for analysis of breastmilk samples, which were determined relative to a breastmilk linear calibration curve (0.01–10 mg/l) resulting in circa results of the breastmilk concentration.
An AUC0–12h milk-to-plasma (M:P) ratio of 0.46 was calculated from the paired data of 4 months postpartum (noncompartmental analysis using Phoenix 63), indicating low raltegravir transfer into the breastmilk and little accumulation. A similar M:P ratio (range 0.37–0.71) was observed during the sampling interval (Fig. 1a). A similar breastmilk exposure and M : P ratio (0.55) was observed at 8 months postpartum (Fig. 1b). The unexpected delayed Tmax (12 h) at 4 months postpartum could be attributed to a migraine attack the woman suffered from during blood collection and/or the erratic absorption of raltegravir [11,12].
At 4 and 8 months postpartum, the infant's raltegravir plasma concentrations (∼45 min after last breastfeeding) were below the LLOQ (Fig. 1). At 4 months postpartum, the estimated infant dosage of the exclusively breastfed infant was 0.099 mg/kg/day, based on an average infant daily milk intake of 150 ml/kg, weight of 6.7 kg, and an average raltegravir breastmilk concentration of 0.66 mg/l (derived from AUC0–12h) . This estimated daily infant dosage corresponded to 0.8% of the approved daily raltegravir dose of 12 mg/kg/day .
We showed for the first time that raltegravir can penetrate into breastmilk. The clinical relevance of infant exposure to different ARVs via breastmilk is discussed critically. Therapeutic antiretroviral infant exposure may protect against HIV transmission, whereas low level antiretroviral exposure can result in the development of resistance and false-negative HIV-tests in case of infection [15,16]. The relative raltegravir dose ingested by the tested infant is unlikely to be of therapeutic clinical significance as it seems to be less than 1% of the approved treatment dose and the infant exposure is beneath the protein-adjusted IC95 of 0.016 mg/l .
Raltegravir and bilirubin are both metabolized by UGT1A1 and compete for albumin binding sites . In this case, the UGT1A1 activity of the infant was probably matured at the time of sampling, whereas low UGT1A1 activity in neonates may result in higher raltegravir concentrations [18,19]. The observed hyperbilirubinemia could, therefore, be not only attributed to the raltegravir exposure via breastmilk but also to intrauterine raltegravir exposure as reported in nonbreastfed infants after intrauterine integrase inhibitor exposure [20–22]. More longitudinal data, especially in the neonatal period, are needed to establish the applicability of raltegravir in breastfeeding HIV-infected mothers.
The study was approved by the local ethics committee (Charité-Universitätsmedizin Berlin), the mother gave written informed consent.
The authors wish to thank the patient and her family for participating in the study.
The PANNA network is supported by the European AIDS Treatment Network/European Commission/DG Research, Sixth Framework program (contract LSHP-CT-2006-037570), Gilead B.V., Bristol Myers Squibb, ViiV Healthcare, Merck Sharp & Dohme Corp, and Janssen Pharmaceutica.
Conflicts of interest
There are no conflicts of interest.
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