Transfer of antiretroviral drugs into breastmilk: a prospective study from the Swiss Mother and Child HIV Cohort Study

Karoline Aebi-Popp, Christian R Kahlert, Pierre-Alex Crisinel, Laurent Decosterd, Susana Alves Saldanha, Irene Hoesli, Begona Martinez De Tejada, Andrea Duppenthaler, Andri Rauch, Catia Marzolini, Swiss Mother and Child HIV Cohort Study (SHCS), A I Abela, K Aebi-Popp, A Anagnostopoulos, M Battegay, E Bernasconi, D L Braun, H C Bucher, A Calmy, M Cavassini, A Ciuffi, G Dollenmaier, M Egger, L Elzi, J Fehr, J Fellay, H Furrer, C A Fux, H F Günthard, A Hachfeld, D Haerry, B Hasse, H H Hirsch, M Hoffmann, I Hösli, M Huber, C R Kahlert, L Kaiser, O Keiser, T Klimkait, R D Kouyos, H Kovari, K Kusejko, G Martinetti, B Martinez de Tejada, C Marzolini, K J Metzner, N Müller, J Nemeth, D Nicca, P Paioni, G Pantaleo, M Perreau, A Rauch, P Schmid, R Speck, M Stöckle, P Tarr, A Trkola, G Wandeler, S Yerly, Karoline Aebi-Popp, Christian R Kahlert, Pierre-Alex Crisinel, Laurent Decosterd, Susana Alves Saldanha, Irene Hoesli, Begona Martinez De Tejada, Andrea Duppenthaler, Andri Rauch, Catia Marzolini, Swiss Mother and Child HIV Cohort Study (SHCS), A I Abela, K Aebi-Popp, A Anagnostopoulos, M Battegay, E Bernasconi, D L Braun, H C Bucher, A Calmy, M Cavassini, A Ciuffi, G Dollenmaier, M Egger, L Elzi, J Fehr, J Fellay, H Furrer, C A Fux, H F Günthard, A Hachfeld, D Haerry, B Hasse, H H Hirsch, M Hoffmann, I Hösli, M Huber, C R Kahlert, L Kaiser, O Keiser, T Klimkait, R D Kouyos, H Kovari, K Kusejko, G Martinetti, B Martinez de Tejada, C Marzolini, K J Metzner, N Müller, J Nemeth, D Nicca, P Paioni, G Pantaleo, M Perreau, A Rauch, P Schmid, R Speck, M Stöckle, P Tarr, A Trkola, G Wandeler, S Yerly

Abstract

Introduction: In 2018, Switzerland changed its guidelines to support women living with HIV wishing to breastfeed. The exposure of antiretroviral drugs (ARVs) in breastmilk and the ingested daily dose by the breastfed infant are understudied, notably for newer ARVs. This study aimed to quantify ARV concentrations in maternal plasma and breastmilk to determine the milk/plasma ratio, to estimate daily infant ARV dose from breastfeeding and to measure ARV concentrations in infants.

Methods: All women wishing to breastfeed were included, regardless of their ARV treatment. Breastmilk and maternal plasma samples were mostly collected at mid-dosing interval.

Results: Twenty-one mother/child pairs were enrolled; of those several were on newer ARVs including 10 raltegravir, 1 bictegravir, 2 rilpivirine, 2 darunavir/ritonavir and 3 tenofovir alafenamide. No vertical HIV transmission was detected (one infant still breastfed). The median milk/plasma ratios were 0.96/0.39 for raltegravir once/twice daily, 0.01 for bictegravir, 1.08 for rilpivirine, 0.12 for darunavir/ritonavir and 4.09 for tenofovir alafenamide. The median estimated infant daily dose (mg/kg) from breastfeeding was 0.02/0.25 for raltegravir once/twice daily, 0.01 for bictegravir, 0.02 for rilpivirine, 0.05 for darunavir/ritonavir and 0.007 for tenofovir alafenamide, resulting in relative infant dose <10% exposure index for all ARVs.

Conclusions: ARVs were transferred to a variable extent in breastmilk. Nevertheless, the estimated daily ARV dose from breastfeeding remained low. Differential ARV exposure was observed in breastfed infants with some ARVs being below/above their effective concentrations raising the concern of resistance development if HIV infection occurs. More data on this potential risk are warranted to better support breastfeeding.

© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.

References

    1. Flynn PM, Taha TE, Cababasay Met al. . Association of maternal viral load and CD4 count with perinatal HIV-1 transmission risk during breastfeeding in the PROMISE postpartum component. J Acquir Immune Defic Syndr 2021; 88: 206–13. 10.1097/QAI.0000000000002744
    1. Waitt C, Low N, Van de Perre Pet al. . Does U = U for breastfeeding mothers and infants? Breastfeeding by mothers on effective treatment for HIV infection in high-income settings. Lancet HIV 2018; 5: e531–6. 10.1016/S2352-3018(18)30098-5
    1. Kahlert C, Aebi-Popp K, Bernasconi Eet al. . Is breastfeeding an equipoise option in effectively treated HIV-infected mothers in a high-income setting? Swiss Med Wkly 2018; 148: w14648. 10.4414/smw.2018.14648
    1. Waitt CJ, Garner P, Bonnett LJet al. . Is infant exposure to antiretroviral drugs during breastfeeding quantitatively important? A systematic review and meta-analysis of pharmacokinetic studies. J Antimicrob Chemother 2015; 70: 1928–41. 10.1093/jac/dkv080
    1. Courlet P, Alves Saldanha S, Cavassini Met al. . Development and validation of a multiplex UHPLC-MS/MS assay with stable isotopic internal standards for the monitoring of the plasma concentrations of the antiretroviral drugs bictegravir, cabotegravir, doravirine, and rilpivirine in people living with HIV. J Mass Spectrom 2020; 55: e4506. 10.1002/jms.4506
    1. Courlet P, Spaggiari D, Cavassini Met al. . Determination of nucleosidic/tidic reverse transcriptase inhibitors in plasma and cerebrospinal fluid by ultra-high-pressure liquid chromatography coupled with tandem mass spectrometry. Clin Mass Spectrom 2018: 8–20. 10.1016/j.clinms.2018.04.001
    1. Aouri M, Calmy A, Hirschel Bet al. . A validated assay by liquid chromatography-tandem mass spectrometry for the simultaneous quantification of elvitegravir and rilpivirine in HIV positive patients. J Mass Spectrom 2013; 48: 616–25. 10.1002/jms.3200
    1. Fayet A, Béguin A, Zanolari Bet al. . A LC-tandem MS assay for the simultaneous measurement of new antiretroviral agents: raltegravir, maraviroc, darunavir, and etravirine. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877: 1057–69. 10.1016/j.jchromb.2009.02.057
    1. Aebi-Popp K, Bernaconi E, Kahlert CRet al. . Recommendations of the Swiss federal commission for sexual health (FCSH) for medical care of HIV-infected women and their offspring. Dec 2018. .
    1. Kwara A, Tashima KT, Dumond JBet al. . Modest but variable effect of rifampicin on steady-state plasma pharmacokinetics of efavirenz in healthy African-American and Caucasian volunteers. Antimicrob Agents Chemother 2011; 55: 3527–33. 10.1128/AAC.00980-10
    1. Cooper CL, van Heeswijk RPG. Once daily nevirapine dosing: a pharmacokinetics, efficacy and safety review. HIV Med 2007; 8: 1–7. 10.1111/j.1468-1293.2007.00426.x
    1. Ford SL, Gould E, Chen Set al. . Lack of pharmacokinetic interaction between rilpivirine and integrase inhibitors dolutegravir and GSK1265744. Antimicrob Agents Chemother 2013; 57: 5472–7. 10.1128/AAC.01235-13
    1. Wenning LA, Hanley WD, Brainard DMet al. . Effect of rifampicin, a potent inducer of drug-metabolizing enzymes, on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother 2009; 53: 2852–6. 10.1128/AAC.01468-08
    1. Krishna R, East L, Larson Pet al. . Effect of metal-cation antacids on the pharmacokinetics of 1200 mg raltegravir. J Pharm Pharmacol 2016; 68: 1359–65. 10.1111/jphp.12632
    1. Molto J, Valle M, Ferrer Eet al. . Reduced darunavir dose is as effective in maintaining HIV suppression as the standard dose in virologically suppressed HIV-infected patients: a randomized clinical trial. J Antimicrob Chemother 2014; 70: 1139–45. 10.1093/jac/dku516
    1. Singh RP, Adkinson K, Wolstenholme Aet al. . Pharmacokinetics, safety, and tolerability of a single oral dose of abacavir/dolutegravir/lamivudine combination tablets in healthy Japanese study participants. Clin Pharmacol Drug Dev 2021; 10: 985–93. 10.1002/cpdd.996
    1. Crauwels HM, Baugh B, van Landuyt Eet al. . Bioequivalence of the once-daily single-tablet regimen darunavir, cobicistat, emtricitabine, and tenofovir alafenamide compared to combined intake of the separate agents and the effect of food on bioavailability. Clin Pharmacol Drug Dev 2019; 8: 480–91. 10.1002/cpdd.628
    1. Custodio JM, Chuck SK, Chu Het al. . Lack of clinically important PK interaction between coformulated ledipasvir/sofosbuvir and rilpivirine/emtricitabine/tenofovir alafenamide. Pharmacol Res Perspect 2017; 5: e00353. 10.1002/prp2.353
    1. Droste JAH, Verweij-van Wissen CPWGM, Kearney BPet al. . Pharmacokinetic study of tenofovir disoproxil fumarate combined with rifampin in healthy volunteers. Antimicrob Agents Chemother 2005; 49: 680–4. 10.1128/AAC.49.2.680-684.2005
    1. Ito S. Drug therapy for breast-feeding women. N Engl J Med 2000; 343: 118–26. 10.1056/NEJM200007133430208
    1. Hodel EM, Marzolini C, Waitt Cet al. . Pharmacokinetics, placental and breast milk transfer of antiretroviral drugs in pregnant and lactating women living with HIV. Curr Pharm Des 2019; 25: 556–76. 10.2174/1381612825666190320162507
    1. Jonker JW, Merino G, Musters Set al. . The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk. Nat Med 2005; 11: 127–9. 10.1038/nm1186
    1. Marzolini C, Gray GE. Maternal antiretroviral prophylaxis and breastfeeding. Antivir Ther 2012; 17: 1503–6. 10.3851/IMP2314
    1. Olagunju A, Bolaji O, Amara Aet al. . Breast milk pharmacokinetics of efavirenz and breastfed infants’ exposure in genetically defined subgroups of mother-infant pairs: an observational study. Clin Infect Dis 2015; 61: 453–63. 10.1093/cid/civ317
    1. Mugwanya KK, Hendrix CW, Mugo NRet al. . Pre-exposure prophylaxis use by breastfeeding HIV-uninfected women: a prospective short-term study of antiretroviral excretion in breast milk and infant absorption. PLoS Med 2016; 13: e1002132. 10.1371/journal.pmed.1002132
    1. Yang N, Zhou G, Cheng Xet al. . Distribution evaluation of tenofovir in the breast milk of mothers with HBeAg-positive chronic HBV infection after treatment with tenofovir alafenamide and tenofovir disoproxil fumarate by a sensitive UPLC-MS/MS method. Front Pharmacol 2021; 12: 734760. 10.3389/fphar.2021.734760
    1. Begley R, Das M, Zhong Let al. . Pharmacokinetics of tenofovir alafenamide when coadministered with other HIV antiretrovirals. J Acquir Immun Defic Syndr 2018; 78: 465–72. 10.1097/QAI.0000000000001699
    1. Marzolini C, Mueller R, Li-Blatter Xet al. . The brain entry of HIV-1 protease inhibitors is facilitated when used in combination. Mol Pharm 2013; 10: 2340–9. 10.1021/mp300712a
    1. Feiterna-Sperling C, Bukkems VE, Teulen MJet al. . Low raltegravir transfer into the breastmilk of a woman living with HIV. AIDS 2020; 34: 1863–7. 10.1097/QAD.0000000000002624
    1. Waitt C, Orrell C, Walimbwa Set al. . Safety and pharmacokinetics of dolutegravir in pregnant mothers with HIV infection and their neonates: a randomised trial (DolPHIN-1 study). PLoS Med 2019; 16: e1002895. 10.1371/journal.pmed.1002895
    1. Dickinson L, Walimbwa S, Singh Yet al. . Infant exposure to dolutegravir through placental and breast milk transfer: a population pharmacokinetic analysis of DolPHIN-1. Clin Infect Dis 2021; 73: e1200–7. 10.1093/cid/ciaa1861
    1. Fogel JM, Mwatha A, Richardson Pet al. . Impact of maternal and infant antiretroviral drug regimens on drug resistance in HIV-infected breastfeeding infants. Pediatr Infect Dis J 2013; 32: e164–9. 10.1097/INF.0b013e31827f44ee
    1. Zeh C, Weidle PJ, Nafisa Let al. . HIV-1 drug resistance emergence among breastfeeding infants born to HIV-infected mothers during a single-arm trial of triple-antiretroviral prophylaxis for prevention of mother-to-child transmission: a secondary analysis. PLoS Med 2011; 8: e1000430. 10.1371/journal.pmed.1000430

Source: PubMed

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