Pharmacokinetics, Placental and Breast Milk Transfer of Antiretroviral Drugs in Pregnant and Lactating Women Living with HIV

Author(s): E.M. Hodel*, C. Marzolini, C. Waitt, N. Rakhmanina

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 5 , 2019


Become EABM
Become Reviewer
Call for Editor

Abstract:

Background: Remarkable progress has been achieved in the identification of HIV infection in pregnant women and in the prevention of vertical HIV transmission through maternal antiretroviral treatment (ART) and neonatal antiretroviral drug (ARV) prophylaxis in the last two decades. Millions of women globally are receiving combination ART throughout pregnancy and breastfeeding, periods associated with significant biological and physiological changes affecting the pharmacokinetics (PK) and pharmacodynamics (PD) of ARVs. The objective of this review was to summarize currently available knowledge on the PK of ARVs during pregnancy and transport of maternal ARVs through the placenta and into the breast milk. We also summarized main safety considerations for in utero and breast milk ARVs exposures in infants.

Methods: We conducted a review of the pharmacological profiles of ARVs in pregnancy and during breastfeeding obtained from published clinical studies. Selected maternal PK studies used a relatively rich sampling approach at each ante- and postnatal sampling time point. For placental and breast milk transport of ARVs, we selected the studies that provided ratios of maternal to the cord (M:C) plasma and breast milk to maternal plasma (M:P) concentrations, respectively.

Results: We provide an overview of the physiological changes during pregnancy and their effect on the PK parameters of ARVs by drug class in pregnancy, which were gathered from 45 published studies. The PK changes during pregnancy affect the dosing of several protease inhibitors during pregnancy and limit the use of several ARVs, including three single tablet regimens with integrase inhibitors or protease inhibitors co-formulated with cobicistat due to suboptimal exposures. We further analysed the currently available data on the mechanism of the transport of ARVs from maternal plasma across the placenta and into the breast milk and summarized the effect of pregnancy on placental and of breastfeeding on mammal gland drug transporters, as well as physicochemical properties, C:M and M:P ratios of individual ARVs by drug class. Finally, we discussed the major safety issues of fetal and infant exposure to maternal ARVs.

Conclusions: Available pharmacological data provide evidence that physiological changes during pregnancy affect maternal, and consequently, fetal ARV exposure. Limited available data suggest that the expression of drug transporters may vary throughout pregnancy and breastfeeding thereby possibly impacting the amount of ARV crossing the placenta and secreted into the breast milk. The drug transporter’s role in the fetal/child exposure to maternal ARVs needs to be better understood. Our analysis underscores the need for more pharmacological studies with innovative study design, sparse PK sampling, improved study data reporting and PK modelling in pregnant and breastfeeding women living with HIV to optimize their treatment choices and maternal and child health outcomes.

Keywords: HIV, women, antiretroviral drugs, pharmacology, pregnancy, placental transfer, breastfeeding.

[1]
Joint United Nations Programme on HIV and AIDS (UNAIDS). progress towards the 90-90-90 targets. Global AIDS update 2017. 2017. Available from: http://www.unaids.org/sites/ default/files/media_asset/Global_AIDS_update_2017_en.pdf
[2]
World Health Organization (WHO). Global guidance in criteria and process for validation: elimination of mother-to-child transmission of HIV and syphillis 2017.Available from:. http://apps. who.int/iris/bitstream/handle/10665/259517/9789241513272-eng.pdf?sequence=1
[3]
Taylor M, Newman L, Ishikawa N, et al. Elimination of mother-to-child transmission of HIV and Syphilis (EMTCT): Process, progress, and program integration. PLoS Med 2017; 14: e1002329.
[4]
Townsend CL, Byrne L, Cortina-Borja M, et al. Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000-2011. Aids 28: 1049-57.
[5]
Centers for Disease Control and Prevention (CDC). Enhanced perinatal surveillance – 15 areas, 2005-2008. HIV Surveillance Supplemental Report. 2011; Volume 16, Number 2. Available from: https://www.cdc.gov/hiv/library/reports/hiv-surveillance-archive.html#supplemental-archive
[6]
Joint United Nations Programme on HIV and AIDS (UNAIDS). UNAIDS data 2018. Available from:. http://www.unaids.org/sites/ default/files/media_asset/unaids-data-2018_en.pdf
[7]
Knettel BA, Cichowitz C, Ngocho JS, et al. Retention in HIV Care During Pregnancy and the Postpartum Period in the Option B+ Era: Systematic Review and Meta-Analysis of Studies in Africa. J Acquir Immune Defic Syndr 2018; 77: 427-38.
[8]
United Nations Children’s Fund (UNICEF). For Every Child, End AIDS: Seventh Stocktaking Report. 2016.Available from:. https://www.unicef.org/publications/files/Children_and_AIDS_Seventh_Stocktaking_Report_2016_EN.pdf.pdf
[9]
World Health Organization (WHO). Prevention of mother-to-child transmission of HIV: selection and use of nevirapine Technical notes. WHO/HIV_AIDS/2001.03. 2001. Available from: . http:// www.who.int/hiv/pub/mtct/en/who_hiv_aids_2001.03.pdf?ua=1
[10]
World Health Organization (WHO). Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants World Health Organization: Geneva 2010. Available from:. http://apps.who.int/iris/bitstream/handle/10665/75236/9789241599818_eng.pdf?sequence=1
[11]
World Health Organization (WHO). Consolidated guidelines on general HIV care and the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach World Health Organization: Geneva 2013. Available from: http://www.who.int/hiv/pub/guidelines/arv2013/en/
[12]
Joint United Nations Programme on HIV and AIDS (UNAIDS), United Nations Children’s Fund (UNICEF), World Health Organization (WHO). Global AIDS Response Progress Reporting 2016. 2016. Available from: https://aidsreportingtool. unaids.org/static/docs/GARPR_Guidelines_2016_EN.pdf
[13]
Idele P, Hayashi C, Porth T, Mamahit A, Mahy M. Prevention of Mother-to-Child Transmission of HIV and Paediatric HIV Care and Treatment Monitoring: From Measuring Process to Impact and Elimination of Mother-to-Child Transmission of HIV. AIDS Behav 2017; 21: 23-33.
[14]
World Health Organization (WHO). Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: what’s new 2015.Available from: . http://www.who. int/hiv/pub/arv/policy-brief-arv-2015/en/
[15]
World Health Organization (WHO). Consolidated guidelines onthe use of antiretroviral drugs for treating and preventing HIV infection Recommendations for a public health approach. World Health Organization: Geneva 2016. Available from: http://apps. who.int/iris/bitstream/handle/10665/208825/9789241549684_eng.pdf?sequence=1
[16]
European AIDS Clinical Society (EACS). Guidelines Version 9.0, October 2017 Available from: http://www.eacsociety.org/ files/guidelines_9.0-english.pdf
[17]
United States Department of Health and Human Services (DHHS) Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission. Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States 2017.
[18]
World Health Organization (WHO). Update on antiretroviral regimensfor treating and preventing HIV infection and update on early infant diagnosis of HIV World Health Organization: Geneva 2018. Available from: http://apps.who.int/ iris/bitstream/handle/ 10665/273129/WHO-CDS-HIV-18.19-eng.pdf?ua=1
[19]
European AIDS Clinical Society (EACS). Guidelines Version 9.1, October 2018 2018. Available from: http://www.eacsociety. org/files/2018_guidelines-9.1-english.pdf
[20]
Moodley J, Moodley D, Pillay K, et al. Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. J Infect Dis 1998; 178: 1327-33.
[21]
Marzolini C, Decosterd L, Winterfeld U, et al. Free and total plasma concentrations of elvitegravir/cobicistat during pregnancy and postpartum: A case report. Br J Clin Pharmacol 2017; 83: 2835-8.
[22]
Schalkwijk S, Colbers A, Konopnicki D, Greupink R, Russel FG, Burger D. network P. First reported use of elvitegravir and cobicistat during pregnancy. AIDS 2016; 30: 807-8.
[23]
McCormack SA, Best BM. Protecting the fetus against HIV infection: A systematic review of placental transfer of antiretrovirals. Clin Pharmacokinet 2014; 53: 989-1004.
[24]
Else LJ, Taylor S, Back DJ, Khoo SH. Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: the fetal compartment (placenta and amniotic fluid). Antivir Ther 2011; 16: 1139-47.
[25]
Koren G, Pariente G. Pregnancy-associated changes in pharmacokinetics and their clinical implications. Pharm Res 2018; 35: 61.
[26]
Pariente G, Leibson T, Carls A, Adams-Webber T, Ito S, Koren G. Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review. PLoS Med 2016; 13: e1002160.
[27]
Aweeka FT, Hu C, Huang L, et al. Alteration in cytochrome P450 3A4 activity as measured by a urine cortisol assay in HIV-1-infected pregnant women and relationship to antiretroviral pharmacokinetics. HIV Med 2015; 16: 176-83.
[28]
Jeong H, Choi S, Song JW, Chen H, Fischer JH. Regulation of UDP-glucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination. Xenobiotica 2008; 38: 62-75.
[29]
Acosta EP, Gerber JG. Position paper on therapeutic drug monitoring of antiretroviral agents. AIDS Res Hum Retroviruses 2002; 18: 825-34.
[30]
Burger DM. The role of therapeutic drug monitoring in pediatric HIV/AIDS. Ther Drug Monit 2010; 32: 269-72.
[31]
Pretorius E, Klinker H, Rosenkranz B. The role of therapeutic drug monitoring in the management of patients with human immunodeficiency virus infection. Ther Drug Monit 2011; 33: 265-74.
[32]
Punyawudho B, Singkham N, Thammajaruk N, et al. Therapeutic drug monitoring of antiretroviral drugs in HIV-infected patients. Expert Rev Clin Pharmacol 2016; 9: 1583-95.
[33]
Gilbert EM, Darin KM, Scarsi KK, McLaughlin MM. Antiretroviral Pharmacokinetics in Pregnant Women. Pharmacotherapy 2015; 35: 838-55.
[34]
Momper JD, Best B, Wang J, et al. IMPAACT P1026s Protocol Team. Tenofovir alafenamide pharmacokinetics with and without cobicistat in pregnancy [THAB0302]. 2018. 10th IAS Conference on HIV Science (IAS 2018). Available from:. http://programme.aids 2018.org/Abstract/Abstract/5960
[35]
Akanbi MO, Scarsi KK, Taiwo B, Murphy RL. Combination nucleoside/nucleotide reverse transcriptase inhibitors for treatment of HIV infection. Expert Opin Pharmacother 2012; 13: 65-79.
[36]
Stek AM, Best BM, Luo W, et al. Effect of pregnancy on emtricitabine pharmacokinetics. HIV Med 2012; 13: 226-35.
[37]
Colbers AP, Hawkins DA, Gingelmaier A, et al. network P. The pharmacokinetics, safety and efficacy of tenofovir and emtricitabine in HIV-1-infected pregnant women. AIDS 2013; 27: 739-48.
[38]
Best BM, Mirochnick M, Capparelli EV, et al. Impact of pregnancy on abacavir pharmacokinetics. AIDS 2006; 20: 553-60.
[39]
Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): A randomised, double-blind, placebo-controlled, non-inferiority trial. Lancet 2014; 383: 1474-82.
[40]
Boffito M, Lamorde M, Watkins M, Pozniak A. Antiretroviral dose optimization: the future of efavirenz 400 mg dosing. Curr Opin HIV AIDS 2017; 12: 339-42.
[41]
Cressey TR, Stek A, Capparelli E, et al. Efavirenz pharmacokinetics during the third trimester of pregnancy and postpartum. J Acquir Immune Defic Syndr 2012; 59: 245-52.
[42]
Schalkwijk S, Colbers A, Best B, et al. Pharmacokinetics of Efavirenz 600 mg QD during Pregnancy and Postpartum [Abstract 433]. 2016. 2016 Conference on Retroviruses and Opportunistic Infections (CROI). Boston, Massachusetts. Available from: http://www.croiconference.org/sites/default/files/posters-2016/433.pdf
[43]
Dooley KE, Denti P, Martinson N, et al. Pharmacokinetics of efavirenz and treatment of HIV-1 among pregnant women with and without tuberculosis coinfection. J Infect Dis 2015; 211: 197-205.
[44]
Olagunju A, Bolaji O, Amara A, et al. Pharmacogenetics of pregnancy-induced changes in efavirenz pharmacokinetics. Clin Pharmacol Ther 2015; 97: 298-306.
[45]
Lamorde M, Wang X, Neary M, et al. Pharmacokinetics, pharmacodynamics and pharmacogenomics of efavirenz 400mg once-daily during pregnancy and postpartum [TUPDB0203LB]. 2017. 9th IAS Conference on HIV Science (IAS 2017). Available from: http://programme.ias2017.org/Abstract/Abstract/5612
[46]
Schalkwijk S, Ter Heine R, Colbers AC, et al. A Mechanism-Based Population Pharmacokinetic Analysis Assessing the Feasibility of Efavirenz Dose Reduction to 400 mg in Pregnant Women . Clin Pharmacokinet, 2018. Available from:. https://www. ncbi.nlm.nih.gov/pubmed/29520730
[47]
Mulligan N, Schalkwijk S, Best BM, et al. Etravirine Pharmacokinetics in HIV-Infected Pregnant Women. Front Pharmacol 2016; 7: 239.
[48]
Olagunju A, Bolaji O, Neary M, Back D, Khoo S, Owen A. Pregnancy affects nevirapine pharmacokinetics: evidence from a CYP2B6 genotype-guided observational study. Pharmacogenet Genomics 2016; 26: 381-9.
[49]
Tran AH, Best BM, Stek A, et al. Pharmacokinetics of Rilpivirine in HIV-Infected Pregnant Women. J Acquir Immune Defic Syndr 2016; 72: 289-96.
[50]
Osiyemi O, Yasin S, Zorrilla C, et al. Pharmacokinetics, Antiviral Activity, and Safety of Rilpivirine in Pregnant Women with HIV-1 Infection: Results of a Phase 3b, Multicenter, Open-Label Study. Infect Dis Ther 2018; 7: 147-59.
[51]
Schalkwijk S, Colbers A, Konopnicki D, et al. Pharmacokinetics of newly developed antiretroviral agents in H. I. V. infected pregnant women Network. Lowered Rilpivirine Exposure During the Third Trimester of Pregnancy in Human Immunodeficiency Virus Type 1-Infected Women. Clin Infect Dis 2017; 65: 1335-41.
[52]
Ramgopal M, Osiyemi O, Zorrilla C, et al. Pharmacokinetics of Total and Unbound Etravirine in HIV-1-Infected Pregnant Women. J Acquir Immune Defic Syndr 2016; 73: 268-74.
[53]
Capparelli EV, Aweeka F, Hitti J, et al. Chronic administration of nevirapine during pregnancy: impact of pregnancy on pharmacokinetics. HIV Med 2008; 9: 214-20.
[54]
Lamorde M, Byakika-Kibwika P, Okaba-Kayom V, et al. Suboptimal nevirapine steady-state pharmacokinetics during intrapartum compared with postpartum in HIV-1-seropositive Ugandan women. J Acquir Immune Defic Syndr 2010; 55: 345-50.
[55]
Barry M, Gibbons S, Back D, Mulcahy F. Protease inhibitors in patients with HIV disease. Clinically important pharmacokinetic considerations. Clin Pharmacokinet 1997; 32: 194-209.
[56]
Momper JD, Best B, Wang J, et al. Pharmacokinetics of darunavir boosted with cobicistat during pregnancy and postpartum [WEPEB118]. 2018. 10th IAS Conference on HIV Science (IAS 2018). Available from: http://programme.aids2018.org/Abstract/ Abstract/6026
[57]
Molto J, Curran A, Miranda C, et al. Pharmacokinetics of darunavir/cobicistat and etravirine alone and co-administered in HIV-infected patients. J Antimicrob Chemother 2018; 73: 732-7.
[58]
Boffito M, Back DJ, Blaschke TF, et al. Protein binding in antiretroviral therapies. AIDS Res Hum Retroviruses 2003; 19: 825-35.
[59]
Kreitchmann R, Best BM, Wang J, et al. Pharmacokinetics of an increased atazanavir dose with and without tenofovir during the third trimester of pregnancy. J Acquir Immune Defic Syndr 2013; 63: 59-66.
[60]
Mirochnick M, Best BM, Stek AM, et al. Team IsS. Atazanavir pharmacokinetics with and without tenofovir during pregnancy. J Acquir Immune Defic Syndr 2011; 56: 412-9.
[61]
Taburet AM, Piketty C, Chazallon C, et al. Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2004; 48: 2091-6.
[62]
Le MP, Mandelbrot L, Descamps D, et al. Pharmacokinetics, safety and efficacy of ritonavir-boosted atazanavir (300/100 mg once daily) in HIV-1-infected pregnant women. Antivir Ther 2015; 20: 507-13.
[63]
Colbers A, Hawkins D, Hidalgo-Tenorio C, et al. network P. Atazanavir exposure is effective during pregnancy regardless of tenofovir use. Antivir Ther 2015; 20: 57-64.
[64]
Ripamonti D, Cattaneo D, Maggiolo F, et al. Atazanavir plus low-dose ritonavir in pregnancy: pharmacokinetics and placental transfer. AIDS 2007; 21: 2409-15.
[65]
Foca E, Calcagno A, Bonito A, et al. Atazanavir intracellular concentrations remain stable during pregnancy in HIV-infected patients. J Antimicrob Chemother 2017; 72: 3163-6.
[66]
Colbers A, Molto J, Ivanovic J, et al. Pharmacokinetics of total and unbound darunavir in HIV-1-infected pregnant women. J Antimicrob Chemother 2015; 70: 534-42.
[67]
Lambert J, Jackson V, Else L, et al. Darunavir pharmacokinetics throughout pregnancy and postpartum. J Int AIDS Soc 2014; 17: 19485.
[68]
Zorrilla CD, Wright R, Osiyemi OO, et al. Total and unbound darunavir pharmacokinetics in pregnant women infected with HIV-1: results of a study of darunavir/ritonavir 600/100 mg administered twice daily. HIV Med 2014; 15: 50-6.
[69]
Crauwels HM, Kakuda TN, Ryan B, et al. Pharmacokinetics of once-daily darunavir/ritonavir in HIV-1-infected pregnant women. HIV Med 2016; 17: 643-52.
[70]
Stek A, Best BM, Wang J, et al. Pharmacokinetics of Once Versus Twice Daily Darunavir in Pregnant HIV-Infected Women. J Acquir Immune Defic Syndr 2015; 70: 33-41.
[71]
Stek A, Best B, Caparelli E, et al. Pharmacokinetics of Increased Dose Darunavir During Late Pregnancy and Postpartum [Abstract 775]. 2016. 2016 Conference on Retroviruses and Opportunistic Infections (CROI). Boston, Massachusetts. Available from: http: //www.croiconference.org/sites/default/files/posters-2016/775.pdf
[72]
Else LJ, Douglas M, Dickinson L, Back DJ, Khoo SH, Taylor GP. Improved oral bioavailability of lopinavir in melt-extruded tablet formulation reduces impact of third trimester on lopinavir plasma concentrations. Antimicrob Agents Chemother 2012; 56: 816-24.
[73]
Lambert JS, Else LJ, Jackson V, et al. Therapeutic drug monitoring of lopinavir/ritonavir in pregnancy. HIV Med 2011; 12: 166-73.
[74]
Santini-Oliveira M, Estrela Rde C, Veloso VG, et al. Randomized clinical trial comparing the pharmacokinetics of standard- and increased-dosage lopinavir-ritonavir coformulation tablets in HIV-positive pregnant women. Antimicrob Agents Chemother 2014; 58: 2884-93.
[75]
Sha BE, Tierney C, Sun X, et al. Pharmacokinetic Exposure and Virologic Response in Hiv-1 Infected Pregnant Women Treated with Lopinavir/Ritonavir: Aids Clinical Trials Group Protocol A5153s: A Substudy to A5150. Jacobs J AIDS HIV 2015; (1)3
[76]
Stek AM, Mirochnick M, Capparelli E, et al. Reduced lopinavir exposure during pregnancy. AIDS 2006; 20: 1931-9.
[77]
Mirochnick M, Best BM, Stek AM, et al. Team PsS. Lopinavir exposure with an increased dose during pregnancy. J Acquir Immune Defic Syndr 2008; 49: 485-91.
[78]
Best BM, Stek AM, Mirochnick M, et al. Lopinavir tablet pharmacokinetics with an increased dose during pregnancy. J Acquir Immune Defic Syndr 2010; 54: 381-8.
[79]
Fayet-Mello A, Buclin T, Guignard N, et al. Swiss HIVCS, Mother, Child HIVCS. Free and total plasma levels of lopinavir during pregnancy, at delivery and postpartum: implications for dosage adjustments in pregnant women. Antivir Ther 2013; 18: 171-82.
[80]
Patterson KB, Dumond JB, Prince HA, et al. Protein binding of lopinavir and ritonavir during 4 phases of pregnancy: implications for treatment guidelines. J Acquir Immune Defic Syndr 2013; 63: 51-8.
[81]
Mulligan N, Best BM, Wang J, et al. Dolutegravir pharmacokinetics in pregnant and postpartum women living with HIV. AIDS 2018; 32: 729-37.
[82]
Bollen P, Colbers A, Schalkwijk S, Konopnicki D, Weizsäcker K, Hidalgo Tenorio C. A comparison of the pharmacokinetics of dolutegravir during pregnancy and postpartum A comparison of the pharmacokinetics of dolutegravir during pregnancy and postpartum 2017. International Workshop on Clinical Pharmacology of Antiviral Therapy. Available from: . http://www.natap.org/ 2017/Pharm/Pharm_34.htm
[83]
Orrell C, Kintu K, Coombs J, et al. DolPHIN-1 Study Group Dol- PHIN-1: Randomised controlled trial of dolutegravir (DTG)- versus efavirenz (EFV)-based therapy in mothers initiating antiretroviral treatment in late pregnancy [THAB0307LB]. 2018. 10th IAS Conference on HIV Science (IAS 2018). Available from:. http://programme.aids2018.org/Abstract/Abstract/13144
[84]
Blonk MI, Colbers AP, Hidalgo-Tenorio C, et al. Pharmacokinetics of Newly Developed Antiretroviral Agents in HIVIPWPN, Network P. Raltegravir in HIV-1-Infected Pregnant Women: Pharmacokinetics, Safety, and Efficacy. Clin Infect Dis 2015; 61: 809-16.
[85]
Watts DH, Stek A, Best BM, et al. team Iss. Raltegravir pharmacokinetics during pregnancy. J Acquir Immune Defic Syndr 2014; 67: 375-81.
[86]
Colbers A, Schalkwijk S, Konopnicki D, Rockstroh J, Burger D. Elvitegravir pharmacokinetics during Pregnancy and Postpartum. 2018 19th International Workshop on Clinical Pharmacology of Antiviral Therapy 2018.Baltimore, USA.
[87]
Momper JD, Best BM, Wang J, et al. Elvitegravir/cobicistat pharmacokinetics in pregnant and postpartum women with HIV. AIDS 2018; 32: 2507-16.
[88]
Colbers A, Best B, Schalkwijk S, et al. the IST. Maraviroc Pharmacokinetics in HIV-1-Infected Pregnant Women. Clin Infect Dis 2015; 61: 1582-9.
[89]
Schalkwijk S, Colbers A, Konopnicki D, et al. network P. The pharmacokinetics of abacavir 600 mg once daily in HIV-1-positive pregnant women. AIDS 2016; 30: 1239-44.
[90]
Crauwels HM, Osiyemi O, Zorrilla C, Bicer C, Brown K. Pharmacokinetics of Total and Unbound Darunavir in HIV-1–infected Pregnant Women Receiving a Darunavir/Cobicistat-based Regimen [Poster 36]. 2018. 2018 Conference on Retroviruses and Opportunistic Infections (CROI). Boston, Massachusetts. Available from: http://www.natap.org/2018/CROI/HIV&Women2018DRVcPKPregnancyPoster_JUV-63244_FINAL.PDF
[91]
Huppertz B. The anatomy of the normal placenta. J Clin Pathol 2008; 61: 1296-302.
[92]
Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994; 331: 1173-80.
[93]
World Health Organization (WHO). Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants in resource-limited settings: towards universal access Recommendations for a public health approach. World Health Organization: Geneva 2006. Available from:. http://www.who.int/hiv/ pub/mtct/arv_guidelines_mtct.pdf?ua=1
[94]
Marzolini C, Kim RB. Placental transfer of antiretroviral drugs. Clin Pharmacol Ther 2005; 78: 118-22.
[95]
Meyer Zu Schwabedissen HE, Grube M, Heydrich B, et al. Expression, localization, and function of MRP5 (ABCC5), a transporter for cyclic nucleotides, in human placenta and cultured human trophoblasts: effects of gestational age and cellular differentiation. Am J Pathol 2005; 166: 39-48.
[96]
Sato K, Sugawara J, Sato T, et al. Expression of organic anion transporting polypeptide E (OATP-E) in human placenta. Placenta 2003; 24: 144-8.
[97]
Ugele B, St-Pierre MV, Pihusch M, Bahn A, Hantschmann P. Characterization and identification of steroid sulfate transporters of human placenta. Am J Physiol Endocrinol Metab 2003; 284: E390-8.
[98]
Sata R, Ohtani H, Tsujimoto M, et al. Functional analysis of organic cation transporter 3 expressed in human placenta. J Pharmacol Exp Ther 2005; 315: 888-95.
[99]
Govindarajan R, Bakken AH, Hudkins KL, et al. In situ hybridization and immunolocalization of concentrative and equilibrative nucleoside transporters in the human intestine, liver, kidneys, and placenta. Am J Physiol Regul Integr Comp Physiol 2007; 293: R1809-22.
[100]
Staud F, Cerveny L, Ceckova M. Pharmacotherapy in pregnancy; effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure. J Drug Target 2012; 20: 736-63.
[101]
Tetro N, Moushaev S, Rubinchik-Stern M, Eyal S. The Placental Barrier: the Gate and the Fate in Drug Distribution. Pharm Res 2018; 35: 71.
[102]
Lankas GR, Wise LD, Cartwright ME, Pippert T, Umbenhauer DR. Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice. Reprod Toxicol 1998; 12: 457-63.
[103]
Mathias AA, Hitti J, Unadkat JD. P-glycoprotein and breast cancer resistance protein expression in human placentae of various gestational ages. Am J Physiol Regul Integr Comp Physiol 2005; 289: R963-9.
[104]
Marzolini C, Paus E, Buclin T, Kim RB. Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 2004; 75: 13-33.
[105]
Moss MD, Siccardi M, Marzolini C. Mechanisms of drug interactions II: Transport proteins.Drug interactions in Infectious Diseases 2018; 49-85.
[106]
van der Galien R, Ter Heine R, Greupink R, et al. Pharmacokinetics of HIV-Integrase Inhibitors During Pregnancy: Mechanisms, Clinical Implications and Knowledge Gaps. Clin Pharmacokinet 2019; 58: 309-23.
[107]
Marzolini C, Mueller R, Li-Blatter X, Battegay M, Seelig A. The brain entry of HIV-1 protease inhibitors is facilitated when used in combination. Mol Pharm 2013; 10: 2340-9.
[108]
ChemAxon Ltd. Chemicalize. Last accessed: 23/07/2018. Available from: https://chemicalize.com/
[109]
Chappuy H, Treluyer JM, Jullien V, et al. Maternal-fetal transfer and amniotic fluid accumulation of nucleoside analogue reverse transcriptase inhibitors in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother 2004; 48: 4332-6.
[110]
Fauchet F, Treluyer JM, Preta LH, et al. Population pharmacokinetics of abacavir in pregnant women. Antimicrob Agents Chemother 2014; 58: 6287-9.
[111]
Hirt D, Urien S, Rey E, et al. Population pharmacokinetics of emtricitabine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Antimicrob Agents Chemother 2009; 53: 1067-73.
[112]
Flynn PM, Mirochnick M, Shapiro DE, et al. Pharmacokinetics and safety of single-dose tenofovir disoproxil fumarate and emtricitabine in HIV-1-infected pregnant women and their infants. Antimicrob Agents Chemother 2011; 55: 5914-22.
[113]
Rimawi BH, Johnson E, Rajakumar A, et al. Pharmacokinetics and Placental Transfer of Elvitegravir, Dolutegravir, and Other Antiretrovirals during Pregnancy. Antimicrob Agents Chemother 2017; 61: e02213-6.
[114]
Calcagno A, Trentini L, Marinaro L, et al. Transplacental passage of etravirine and maraviroc in a multidrug-experienced HIV-infected woman failing on darunavir-based HAART in late pregnancy. J Antimicrob Chemother 2013; 68: 1938-9.
[115]
Yeh RF, Rezk NL, Kashuba AD, et al. Genital tract, cord blood, and amniotic fluid exposures of seven antiretroviral drugs during and after pregnancy in human immunodeficiency virus type 1-infected women. Antimicrob Agents Chemother 2009; 53: 2367-74.
[116]
Mandelbrot L, Peytavin G, Firtion G, Farinotti R. Maternal-fetal transfer and amniotic fluid accumulation of lamivudine in human immunodeficiency virus-infected pregnant women. Am J Obstet Gynecol 2001; 184: 153-8.
[117]
Benaboud S, Treluyer JM, Urien S, et al. Pregnancy-related effects on lamivudine pharmacokinetics in a population study with 228 women. Antimicrob Agents Chemother 2012; 56: 776-82.
[118]
Mirochnick M, Taha T, Kreitchmann R, et al. Pharmacokinetics and safety of tenofovir in HIV-infected women during labor and their infants during the first week of life. J Acquir Immune Defic Syndr 2014; 65: 33-41.
[119]
Hirt D, Urien S, Ekouevi DK, et al. Anrs. Population pharmacokinetics of tenofovir in HIV-1-infected pregnant women and their neonates (ANRS 12109). Clin Pharmacol Ther 2009; 85: 182-9.
[120]
Mirochnick M, Rodman JH, Robbins BL, et al. Pharmacokinetics of oral zidovudine administered during labour: A preliminary study. HIV Med 2007; 8: 451-6.
[121]
Rodman JH, Flynn PM, Robbins B, et al. Systemic pharmacokinetics and cellular pharmacology of zidovudine in human immunodeficiency virus type 1-infected women and newborn infants. J Infect Dis 1999; 180: 1844-50.
[122]
Watts DH, Brown ZA, Tartaglione T, et al. Pharmacokinetic disposition of zidovudine during pregnancy. J Infect Dis 1991; 163: 226-32.
[123]
Fauchet F, Treluyer JM, Valade E, et al. Maternal and fetal zidovudine pharmacokinetics during pregnancy and labour: too high dose infused at labour? Br J Clin Pharmacol 2014; 78: 1387-96.
[124]
Phuapradit W, Sirinavin S, Taneepanichskul S, et al. Maternal and umbilical cord serum zidovudine levels in human immunodeficiency virus infection. Aust N Z J Obstet Gynaecol 1998; 38: 288-92.
[125]
Izurieta P, Kakuda TN, Feys C, Witek J. Safety and pharmacokinetics of etravirine in pregnant HIV-1-infected women. HIV Med 2011; 12: 257-8.
[126]
Ivanovic J, Nicastri E, Anceschi MM, et al. Pregnancy, Newborn Clinical Outcome Group in HIVI. Transplacental transfer of antiretroviral drugs and newborn birth weight in HIV-infected pregnant women. Curr HIV Res 2009; 7: 620-5.
[127]
Benaboud S, Ekouevi DK, Urien S, et al. Population pharmacokinetics of nevirapine in HIV-1-infected pregnant women and their neonates. Antimicrob Agents Chemother 2011; 55: 331-7.
[128]
Taylor GP, Lyall EG, Back D, Ward C, Tudor-Williams G. Pharmacological implications of lengthened in-utero exposure to nevirapine. Lancet 2000; 355: 2134-5.
[129]
Musoke P, Guay LA, Bagenda D, et al. A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS 1999; 13: 479-86.
[130]
Marzolini C, Rudin C, Decosterd LA, et al. Swiss Mother + Child HIVCS. Transplacental passage of protease inhibitors at delivery. AIDS 2002; 16: 889-93.
[131]
Mirochnick M, Fenton T, Gagnier P, et al. Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Pediatric AIDS Clinical Trials Group Protocol 250 Team. J Infect Dis 1998; 178: 368-74.
[132]
Gingelmaier A, Kurowski M, Kastner R, et al. Placental transfer and pharmacokinetics of lopinavir and other protease inhibitors in combination with nevirapine at delivery. AIDS 2006; 20: 1737-43.
[133]
Conradie F, Zorrilla C, Josipovic D, et al. Safety and exposure of once-daily ritonavir-boosted atazanavir in HIV-infected pregnant women. HIV Med 2011; 12: 570-9.
[134]
Lechelt M, Lyons F, Clarke A, Magaya V, Issa R, de Ruiter A. Human placental transfer of atazanavir: A case report. AIDS 2006; 20: 307.
[135]
Ivanovic J, Bellagamba R, Nicastri E, et al. Use of darunavir/ritonavir once daily in treatment-naive pregnant woman: pharmacokinetics, compartmental exposure, efficacy and safety. AIDS 2010; 24: 1083-4.
[136]
Ripamonti D, Cattaneo D, Cortinovis M, Maggiolo F, Suter F. Transplacental passage of ritonavir-boosted darunavir in two pregnant women. Int J STD AIDS 2009; 20: 215-6.
[137]
Pinnetti C, Tamburrini E, Ragazzoni E, De Luca A, Navarra P. Decreased plasma levels of darunavir/ritonavir in a vertically infected pregnant woman carrying multiclass-resistant HIV type-1. Antivir Ther 2010; 15: 127-9.
[138]
Pinnetti C, Baroncelli S, Villani P, et al. Rapid HIV-RNA decline following addition of raltegravir and tenofovir to ongoing highly active antiretroviral therapy in a woman presenting with high-level HIV viraemia at week 38 of pregnancy. J Antimicrob Chemother 2010; 65: 2050-2.
[139]
Croci L, Trezzi M, Allegri MP, et al. Pharmacokinetic and safety of raltegravir in pregnancy. Eur J Clin Pharmacol 2012; 68: 1231-2.
[140]
Lewis JM, Railton E, Riordan A, Khoo S, Chaponda M. Early experience of dolutegravir pharmacokinetics in pregnancy: high maternal levels and significant foetal exposure with twice-daily dosing. AIDS 2016; 30: 1313-5.
[141]
Shapiro RL, Rossi S, Ogwu A, et al. Therapeutic levels of lopinavir in late pregnancy and abacavir passage into breast milk in the Mma Bana Study, Botswana. Antivir Ther 2013; 18: 585-90.
[142]
Waitt C, Olagunju A, Nakalema S, et al. Plasma and breast milk pharmacokinetics of emtricitabine, tenofovir and lamivudine using dried blood and breast milk spots in nursing African mother-infant pairs. J Antimicrob Chemother 2018; 73: 1013-9.
[143]
Mugwanya KK, Hendrix CW, Mugo NR, et 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.
[144]
Corbett AH, Kayira D, White NR, et al. Antiretroviral pharmacokinetics in mothers and breastfeeding infants from 6 to 24 weeks post-partum: results of the BAN Study. Antivir Ther 2014; 19: 587-95.
[145]
Giuliano M, Guidotti G, Andreotti M, et al. Triple antiretroviral prophylaxis administered during pregnancy and after delivery significantly reduces breast milk viral load: A study within the Drug Resource Enhancement Against AIDS and Malnutrition Program. J Acquir Immune Defic Syndr 2007; 44: 286-91.
[146]
Palombi L, Pirillo MF, Andreotti M, et al. Antiretroviral prophylaxis for breastfeeding transmission in Malawi: drug concentrations, virological efficacy and safety. Antivir Ther 2012; 17: 1511-9.
[147]
Palombi L, Pirillo MF, Marchei E, et al. Concentrations of tenofovir, lamivudine and efavirenz in mothers and children enrolled under the Option B-Plus approach in Malawi. J Antimicrob Chemother 2016; 71: 1027-30.
[148]
Mirochnick M, Thomas T, Capparelli E, et al. Antiretroviral concentrations in breast-feeding infants of mothers receiving highly active antiretroviral therapy. Antimicrob Agents Chemother 2009; 53: 1170-6.
[149]
Shapiro RL, Holland DT, Capparelli E, et al. Antiretroviral concentrations in breast-feeding infants of women in Botswana receiving antiretroviral treatment. J Infect Dis 2005; 192: 720-7.
[150]
Schneider S, Peltier A, Gras A, et al. Efavirenz in human breast milk, mothers’, and newborns’ plasma. J Acquir Immune Defic Syndr 2008; 48: 450-4.
[151]
Spencer LY, Liu S, Wang C, Neely M, Louie S. Intensive Etravirine PK and HIV-1 Viral Load in Breast Milk and Plasma in HIV+ Women Receiving HAART [Abstract 891]. 2014. 2014 Conference on Retroviruses and Opportunistic Infections (CROI). Boston, Massachusetts. Available http://www.croiconference.org/ sites/default/files/posters/891.pdf
[152]
Colebunders R, Hodossy B, Burger D, et al. The effect of highly active antiretroviral treatment on viral load and antiretroviral drug levels in breast milk. AIDS 2005; 19: 1912-5.
[153]
Kobbe R, Schalkwijk S, Dunay G, et al. Dolutegravir in breast milk and maternal and infant plasma during breastfeeding. AIDS 2016; 30: 2731-3.
[154]
Annaert P, Ye ZW, Stieger B, Augustijns P. Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1. Xenobiotica 2010; 40: 163-76.
[155]
Begley R, Das M, Zhong L, Ling J, Kearney BP, Custodio JM. Pharmacokinetics of Tenofovir Alafenamide When Coadministered With Other HIV Antiretrovirals. J Acquir Immune Defic Syndr 2018; 78: 465-72.
[156]
Cano-Soldado P, Lorrayoz IM, Molina-Arcas M, et al. Interaction of nucleoside inhibitors of HIV-1 reverse transcriptase with the concentrative nucleoside transporter-1 (SLC28A1). Antivir Ther 2004; 9: 993-1002.
[157]
Ceckova M, Reznicek J, Ptackova Z, et al. Role of ABC and Solute Carrier Transporters in the Placental Transport of Lamivudine. Antimicrob Agents Chemother 2016; 60: 5563-72.
[158]
Cihlar T, Ho ES, Lin DC, Mulato AS. Human renal organic anion transporter 1 (hOAT1) and its role in the nephrotoxicity of antiviral nucleotide analogs. Nucleosides Nucleotides Nucleic Acids 2001; 20: 641-8.
[159]
Custodio JM, Wang H, Hao J, et al. Pharmacokinetics of cobicistat boosted-elvitegravir administered in combination with rosuvastatin. J Clin Pharmacol 2014; 54: 649-56.
[160]
Hoque MT, Kis O, De Rosa MF, Bendayan R. Raltegravir permeability across blood-tissue barriers and the potential role of drug efflux transporters. Antimicrob Agents Chemother 2015; 59: 2572-82.
[161]
Hyland R, Dickins M, Collins C, Jones H, Jones B. Maraviroc: in vitro assessment of drug-drug interaction potential. Br J Clin Pharmacol 2008; 66: 498-507.
[162]
Kis O, Zastre JA, Ramaswamy M, Bendayan R. pH dependence of organic anion-transporting polypeptide 2B1 in Caco-2 cells: potential role in antiretroviral drug oral bioavailability and drug-drug interactions. J Pharmacol Exp Ther 2010; 334: 1009-22.
[163]
Lepist EI, Zhang X, Hao J, et al. Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat. Kidney Int 2014; 86: 350-7.
[164]
Moss DM, Siccardi M, Murphy M, et al. Divalent metals and pH alter raltegravir disposition in vitro. Antimicrob Agents Chemother 2012; 56: 3020-6.
[165]
Muller F, Konig J, Hoier E, Mandery K, Fromm MF. Role of organic cation transporter OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2-K for transport and drug interactions of the antiviral lamivudine. Biochem Pharmacol 2013; 86: 808-15.
[166]
Reese MJ, Savina PM, Generaux GT, et al. In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase inhibitor. Drug Metab Dispos 2013; 41: 353-61.
[167]
Reznicek J, Ceckova M, Cerveny L, Muller F, Staud F. Emtricitabine is a substrate of MATE1 but not of OCT1, OCT2, P-gp, BCRP or MRP2 transporters. Xenobiotica 2017; 47: 77-85.
[168]
Shaik N, Giri N, Pan G, Elmquist WF. P-glycoprotein-mediated active efflux of the anti-HIV1 nucleoside abacavir limits cellular accumulation and brain distribution. Drug Metab Dispos 2007; 35: 2076-85.
[169]
Takeda M, Khamdang S, Narikawa S, et al. Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J Pharmacol Exp Ther 2002; 300: 918-24.
[170]
Wang X, Furukawa T, Nitanda T, et al. Breast cancer resistance protein (BCRP/ABCG2) induces cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors. Mol Pharmacol 2003; 63: 65-72.
[171]
Weiss J, Rose J, Storch CH, et al. Modulation of human BCRP (ABCG2) activity by anti-HIV drugs. J Antimicrob Chemother 2007; 59: 238-45.
[172]
Weiss J, Theile D, Ketabi-Kiyanvash N, Lindenmaier H, Haefeli WE. Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors. Drug Metab Dispos 2007; 35: 340-4.
[173]
Yao SY, Ng AM, Sundaram M, Cass CE, Baldwin SA, Young JD. Transport of antiviral 3′-deoxy-nucleoside drugs by recombinant human and rat equilibrative, nitrobenzylthioinosine (NBMPR)-insensitive (ENT2) nucleoside transporter proteins produced in Xenopus oocytes. Mol Membr Biol 2001; 18: 161-7.
[174]
Ye ZW, Camus S, Augustijns P, Annaert P. Interaction of eight HIV protease inhibitors with the canalicular efflux transporter ABCC2 (MRP2) in sandwich-cultured rat and human hepatocytes. Biopharm Drug Dispos 2010; 31: 178-88.
[175]
Zembruski NC, Haefeli WE, Weiss J. Interaction potential of etravirine with drug transporters assessed in vitro. Antimicrob Agents Chemother 2011; 55: 1282-4.
[176]
Bailey H, Zash R, Rasi V, Thorne C. HIV treatment in pregnancy. Lancet HIV 2018; 5: e457-67.
[177]
Sibiude J, Warszawski J, Tubiana R, et al. Premature delivery in HIV-infected women starting protease inhibitor therapy during pregnancy: role of the ritonavir boost? Clin Infect Dis 2012; 54: 1348-60.
[178]
Powis KM, Kitch D, Ogwu A, et al. Increased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy. J Infect Dis 2011; 204: 506-14.
[179]
Ravizza M, Martinelli P, Bucceri A, et al. Italian Group on Surveillance on Antiretroviral Treatment in P. Treatment with protease inhibitors and coinfection with hepatitis C virus are independent predictors of preterm delivery in HIV-infected pregnant women. J Infect Dis 2007; 195: 913-4.
[180]
Fiore S, Ferrazzi E, Newell ML, Trabattoni D, Clerici M. Protease inhibitor-associated increased risk of preterm delivery is an immunological complication of therapy. J Infect Dis 2007; 195: 914-6.
[181]
Fowler MG, Qin M, Fiscus SA, et al. Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention. N Engl J Med 2016; 375: 1726-37.
[182]
Jao J, Abrams EJ, Phillips T, Petro G, Zerbe A, Myer L. In utero tenofovir exposure is not associated with fetal long bone growth. Clin Infect Dis 2016; 62: 1604-9.
[183]
Siberry GK, Jacobson DL, Kalkwarf HJ, et al. Lower Newborn Bone Mineral Content Associated With Maternal Use of Tenofovir Disoproxil Fumarate During Pregnancy. Clin Infect Dis 2015; 61: 996-1003.
[184]
Vigano A, Mora S, Giacomet V, et al. In utero exposure to tenofovir disoproxil fumarate does not impair growth and bone health in HIV-uninfected children born to HIV-infected mothers. Antivir Ther 2011; 16: 1259-66.
[185]
Denneman L, Cohen S, Godfried MH, et al. In-utero exposure to tenofovir is associated with impaired fetal and infant growth: need for follow-up studies in combination antiretroviral therapy/HIV-exposed infants. AIDS 2016; 30: 2135-7.
[186]
Liotta G, Floridia M, Andreotti M, et al. Growth indices in breastfed infants pre and postnatally exposed to tenofovir compared with tenofovir-unexposed infants. AIDS 2016; 30: 525-7.
[187]
Ransom CE, Huo Y, Patel K, et al. Group PTotIMPAACT. Infant growth outcomes after maternal tenofovir disoproxil fumarate use during pregnancy. J Acquir Immune Defic Syndr 2013; 64: 374-81.
[188]
Williams PL, Hazra R, Van Dyke RB, et al. Antiretroviral exposure during pregnancy and adverse outcomes in HIV-exposed uninfected infants and children using a trigger-based design. AIDS 2016; 30: 133-44.
[189]
Kourtis AP, Wiener J, Wang L, et al. Tenofovir disoproxil fumarate use during pregnancy and infant bone health: the Tenofovir in Pregnancy Pilot Study. Pediatr Infect Dis J 2018.
[190]
Bristol-Myers Squibb Pharma Company. SUSTIVA package insert 2005.Available from: . https://www.accessdata.fda.gov/ drugsatfda_docs/label/2005/020972s026,021360s013lbl.pdf
[191]
Ford N, Mofenson L, Shubber Z, et al. Safety of efavirenz in the first trimester of pregnancy: An updated systematic review and meta-analysis. AIDS 2014; 28(Suppl. 2): S123-31.
[192]
Zash R, Jacobson DL, Diseko M, et al. Comparative Safety of Antiretroviral Treatment Regimens in Pregnancy. JAMA Pediatr 2017; 171: e172222.
[193]
Antiretroviral Pregnancy Registry. Last accessed: Available from: http://www.apregistry.com/
[194]
Zash R, Makhema J, Shapiro RL. Neural-Tube Defects with Dolutegravir Treatment from the Time of Conception. N Engl J Med 2018; 379: 979-81.
[195]
Shi L, Chia SE. A review of studies on maternal occupational exposures and birth defects, and the limitations associated with these studies. Occup Med (Lond) 2001; 51: 230-44.
[196]
Hofer CB, Keiser O, Zwahlen M, et al. In Utero Exposure to Antiretroviral Drugs: Effect on Birth Weight and Growth Among HIV-exposed Uninfected Children in Brazil. Pediatr Infect Dis J 2016; 35: 71-7.
[197]
Suchard MS, Mayne E, Green VA, et al. FOXP3 expression is upregulated in CD4T cells in progressive HIV-1 infection and is a marker of disease severity. PLoS One 2010; 5: e11762.
[198]
Rasmussen SA, Barfield W, Honein MA. Protecting Mothers and Babies - A Delicate Balancing Act. N Engl J Med 2018; 379(10): 907-9.
[199]
Brocklehurst P, French R. The association between maternal HIV infection and perinatal outcome: A systematic review of the literature and meta-analysis. Br J Obstet Gynaecol 1998; 105: 836-48.
[200]
Wedi CO, Kirtley S, Hopewell S, Corrigan R, Kennedy SH, Hemelaar J. Perinatal outcomes associated with maternal HIV infection: A systematic review and meta-analysis. Lancet HIV 2016; 3: e33-48.
[201]
Ito S, Alcorn J. Xenobiotic transporter expression and function in the human mammary gland. Adv Drug Deliv Rev 2003; 55: 653-65.
[202]
Alcorn J, Lu X, Moscow JA, McNamara PJ. Transporter gene expression in lactating and nonlactating human mammary epithelial cells using real-time reverse transcription-polymerase chain reaction. J Pharmacol Exp Ther 2002; 303: 487-96.
[203]
Jonker JW, Merino G, Musters S, et al. The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk. Nat Med 2005; 11: 127-9.
[204]
Vlaming ML, Lagas JS, Schinkel AH. Physiological and pharmacological roles of ABCG2 (BCRP): recent findings in Abcg2 knockout mice. Adv Drug Deliv Rev 2009; 61: 14-25.
[205]
Gilchrist SE, Alcorn J. Lactation stage-dependent expression of transporters in rat whole mammary gland and primary mammary epithelial organoids. Fundam Clin Pharmacol 2010; 24: 205-14.
[206]
McNamara PJ, Abbassi M. Neonatal exposure to drugs in breast milk. Pharm Res 2004; 21: 555-66.
[207]
United States Department of Health and Human Services (DHHS), Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) https://www.fda.gov/downloads/ regulatoryinformation/guidances/ucm127505.pdf
[208]
Olagunju A, Bolaji O, Amara A, et 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.
[209]
Begg EJ, Duffull SB, Hackett LP, Ilett KF. Studying drugs in human milk: time to unify the approach. J Hum Lact 2002; 18: 323-32.
[210]
Waitt CJ, Garner P, Bonnett LJ, Khoo SH, Else LJ. 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.
[211]
Ito S. Drug therapy for breast-feeding women. N Engl J Med 2000; 343: 118-26.
[212]
Fogel J, Li Q, Taha TE, et al. Initiation of antiretroviral treatment in women after delivery can induce multiclass drug resistance in breastfeeding HIV-infected infants. Clin Infect Dis 2011; 52: 1069-76.
[213]
United States Department of Health and Human Services (DHHS), Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Center for Biologics Evaluation and Research (CBER). Pregnant Women Scientific and Ethical Considerations for Inclusion in Clinical Trials. Guidance for Industry. Draft Guidance. 2018. Available from: https://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM603873.pdf
[214]
Colbers A, Schalkwijk S, Konopnicki D, et al. Timing of the postpartum curve in pharmackinetc studies in pregnancy should not be too early 2016.17th edition of the International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy. Washington DC, USA Available from:. http://regist2.virology-education.com/ 2016/17HIVHEPPK/04_Colbers.pdf
[215]
De Sousa Mendes M, Hirt D, Urien S, et al. Physiologically-based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women. Br J Clin Pharmacol 2015; 80: 1031-41.
[216]
Colbers A, Greupink R, Litjens C, Burger D, Russel FG. Physiologically based modelling of darunavir/ritonavir pharmacokinetics during pregnancy. Clin Pharmacokinet 2016; 55: 381-96.
[217]
Schalkwijk S, Buaben AO, Freriksen JJM, et al. Prediction of fetal darunavir exposure by integrating human ex-vivo placental transfer and physiologically based pharmacokinetic modeling. Clin Pharmacokinet 2018; 57: 705-16.
[218]
Lyerly AD, Little MO, Faden R. The second wave: Toward responsible inclusion of pregnant women in research. Int J Fem Approaches Bioeth 2008; 1: 5-22.
[219]
Sheffield JS, Siegel D, Mirochnick M, et al. Designing drug trials: considerations for pregnant women. Clin Infect Dis 2014; 59(Suppl. 7): S437-44.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 25
ISSUE: 5
Year: 2019
Published on: 03 June, 2019
Page: [556 - 576]
Pages: 21
DOI: 10.2174/1381612825666190320162507
Price: $65

Article Metrics

PDF: 59
HTML: 12
EPUB: 1
PRC: 1