Antiretroviral pharmacokinetics in mothers and breastfeeding infants from 6 to 24 weeks post-partum: results of the BAN Study

Amanda H Corbett, Dumbani Kayira, Nicole R White, Nicole L Davis, Athena P Kourtis, Charles Chasela, Francis Martinson, Grace Phiri, Bonaface Musisi, Deborah Kamwendo, Michael G Hudgens, Mina C Hosseinipour, Julie Ae Nelson, Sascha R Ellington, Denise J Jamieson, Charles van der Horst, Angela Kashuba, BAN Study Team, Amanda H Corbett, Dumbani Kayira, Nicole R White, Nicole L Davis, Athena P Kourtis, Charles Chasela, Francis Martinson, Grace Phiri, Bonaface Musisi, Deborah Kamwendo, Michael G Hudgens, Mina C Hosseinipour, Julie Ae Nelson, Sascha R Ellington, Denise J Jamieson, Charles van der Horst, Angela Kashuba, BAN Study Team

Abstract

Background: An intensive, prospective, open-label pharmacokinetic (PK) study in a subset of HIV-infected mothers and their uninfected infants enrolled in the Breastfeeding, Antiretroviral and Nutrition (BAN) Study was performed to describe drug exposure and antiviral response.

Methods: Women using Combivir(®) (zidovudine [ZDV] + lamivudine [3TC]) +Aluvia(®) (lopinavir/ritonavir [LPV/RTV]) were enrolled. Breast milk (BM), mother plasma (MP) and infant plasma (IP) samples were obtained over 6 h after observed dosing at 6, 12 or 24 weeks post-partum for drug concentrations and HIV RNA.

Results: A total of 30 mother/infant pairs (10 each at 6, 12 and 24 weeks post-partum) were enrolled. Relative to MP, BM concentrations of ZDV and 3TC were 35% and 21% higher, respectively, whereas LPV and RTV were 80% lower. Only 3TC was detected in IP with concentrations 96% and 98% lower than MP and BM, respectively. Concentrations in all matrices were similar at 6-24 weeks. The majority (98.3%) of BM concentrations were >HIV(wt) IC50, with one having detectable virus. There was no association between PK parameters and MP or BM HIV RNA.

Conclusions: ZDV and 3TC concentrated in BM whereas LPV and RTV did not, possibly due to protein binding and drug transporter affinity. Undetectable to low antiretroviral concentrations in IP suggest prevention of transmission while breastfeeding may be due to antiretroviral effects on systemic or BM HIV RNA in the mother. Low IP 3TC exposure may predispose an infected infant to HIV resistance, necessitating testing and treating infants early.

Figures

Figure 1a
Figure 1a
Median (IQR) Zidovudine Concentation vs Time Profile
Figure 1b
Figure 1b
Median (IQR) Lamivudine Concentration vs Time Profile
Figure 1c
Figure 1c
Median (IQR) Lopinavir Concentration vs Time Profile
Figure 1d
Figure 1d
Median (IQR) Ritonavir Concentration vs Time Profile
Figure 2
Figure 2
Correlations Between Breast Milk Concentrations and Mothers’ Plasma Concentrations

References

    1. Nduati R, Richardson BA, John G, Mbori-Ngacha D, Mwatha A, Ndinya-Achola J, Bwayo J, Onyango FE, Kreiss J. Effect of breastfeeding on mortality among HIV-1 infected women: a randomised trial. Lancet. 2001;357:1651–1655.
    1. Thior I, Lockman S, Smeaton LM, Shapiro RL, Wester C, Heymann SJ, Gilbert PB, Stevens L, Peter T, Kim S, van Widenfelt E, Moffat C, Ndase P, Arimi P, Kebaabetswe P, Mazonde P, Makhema J, Mcintosh K, Novitsky V, Lee TH, Marlink R, Lagakos S, Essex M. Breastfeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus infant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana. A randomized trial: the Mashi Study. JAMA. 2006;296:794–805.
    1. UNAIDS . UNAIDS report on the global AIDS epidemic 2013. WHO; Geneva, Switzerland: 2013. Global Report . available at .
    1. Bedri A, Gudetta B, Isehak A, Kumbi S, Lulseged S, Mengistu Y, Bhore AV, Bhosale R, Varadhrajan V, Gupte N, Sastry J, Suryavanshi N, Tripathy S, Mmiro F, Mubiru M, Onyango C, Taylor A, Musoke P, Nakabiito C, Abashawl A, Adamu R, Antelman G, Bollinger RC, Bright P, Chaudhary MA, Coberly J, Guay L, Fowler MG, Gupta A, Hassen E, Jackson JB, Moulton LH, Nayak U, Omer SB, Propper L, Ram M, Rexroad V, Ruff AJ, Shankar A, Zwerski S. Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials. Lancet. 2008;372:300–313.
    1. Jamieson D, Chasela C, Hudgens M, King C, Kourtis A, Kayira D. Maternal and infant antiretroviral regimens to prevent postnatal HIV-1 transmission: 48-week follow-up of the BAN randomised, controlled trial. The Lancet. 2012:379.
    1. Kesho Bora Study G, de Vincenzi I. Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial. Lancet Infect Dis. 2011;11:171–180.
    1. Kilewo C, Karlsson K, Massawe A, Lyamuya E, Swai A, Mhalu F, Biberfeld G. Prevention of mother-to-child transmission of HIV-1 through breast-feeding by treating infants prophylactically with lamivudine in Dar es Salaam, Tanzania: the Mitra Study. J Acquir Immune Defic Syndr. 2008;48:315–323.
    1. Kilewo C, Karlsson K, Ngarina M, Massawe A, Lyamuya E, Swai A, Lipyoga R, Mhalu F, Biberfeld G. Prevention of mother-to-child transmission of HIV-1 through breastfeeding by treating mothers with triple antiretroviral therapy in Dar es Salaam, Tanzania: the Mitra Plus study. J Acquir Immune Defic Syndr. 2009;52:406–416.
    1. Marazzi CM, Germano P, Liotta G, Guidotti G, Loureiro S, Gomes Ada C, Blazquez MC, Narciso P, Perno CF, Mancinelli S, Altan AD, Nielsen-Saines K, Palombi L. Implementing anti-retroviral triple therapy to prevent HIV mother-to-child transmission: a public health approach in resource-limited settings. Eur J Pediatr. 2007;166:1305–1307.
    1. Peltier CA, Ndayisaba GF, Lepage P, van Griensven J, Leroy V, Pharm CO, Ndimubanzi PC, Courteille O, Arendt V. Breastfeeding with maternal antiretroviral therapy or formula feeding to prevent HIV postnatal mother-to-child transmission in Rwanda. Aids. 2009;23:2415–2423.
    1. Shapiro RL, Hughes MD, Ogwu A, Kitch D, Lockman S, Moffat C, Makhema J, Moyo S, Thior I, Mcintosh K, van Widenfelt E, Leidner J, Powis K, Asmelash A, Tumbare E, Zwerski S, Sharma U, Handelsman E, Mburu K, Jayeoba O, Moko E, Souda S, Lubega E, Akhtar M, Wester C, Tuomola R, Snowden W, Martinez-Tristani M, Mazhani L, Essex M. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med. 2010;362:2282–2294.
    1. Taha TE, Li Q, Hoover DR, Mipando L, Nkanaunena K, Thigpen MC, Taylor A, Kumwenda J, Fowler MG, Mofenson LM, Kumwenda NI. Postexposure prophylaxis of breastfeeding HIV-exposed infants with antiretroviral drugs to age 14 weeks: updated efficacy results of the PEPI-Malawi trial. J Acquir Immune Defic Syndr. 2011;57:319–325.
    1. Thomas TK, Masaba R, Borkowf CB, Ndivo R, Zeh C, Misore A, Otieno J, Jamieson D, Thigpen MC, Bulterys M, Slutsker L, De Cock KM, Amornkul PN, Greenberg AE, Fowler MG. Triple-antiretroviral prophylaxis to prevent mother-to-child HIV transmission through breastfeeding--the Kisumu Breastfeeding Study, Kenya: a clinical trial. PLoS Med. 2011;8:e1001015.
    1. Vyankandondera J, Luchters S, Hassink E, Pakker N, Mmiro F, Okong P. Simba—Stopping Infection from Mother to Child via Breastfeeding in Africa. Program and abstracts of the 3rd International AIDS Society Conference on HIV Pathogenesis. 2003
    1. Organization WHO. The use of antiretroviral drugs for treating and preventing HIV infection. WHO; Jun, 2013.
    1. Corbett A, Martinson F, Rezk N. Lopinavir/ritonavir concentrations in breast milk and breast-feeding infants [abstract no. 947]. 16th Conference on retroviruses and opportunistic infections. 2009
    1. Corbett A, Martinson F, Rezk N, Kashuba A, Jamieson D, Chasela C, Hyde L, Ahmed Y, Tegha G, Joaki G. 15th Conference on retroviruses and opportunistic infections. Boston, MA: Feb, 2008. Antiretroviral drug concentrations in breast milk and breastfeeding infants. [Poster 648]
    1. Mirochnick M, Thomas T, Capparelli E, Zeh C, Holland D, Masaba R, Odhiambo P, Fowler MG, Weidle PJ, Thigpen MC. Antiretroviral concentrations in breast-feeding infants of mothers receiving highly active antiretroviral therapy. Antimicrob Agents Chemother. 2009;53:1170–1176.
    1. Schneider S, Peltier A, Gras A, Arendt V, Karasi-Omes C, Mujawamariwa A, Ndimubanzi PC, Ndayisaba G, Wennig R. Efavirenz in human breast milk, mothers', and newborns’ plasma. J Acquir Immune Defic Syndr. 2008;48:450–454.
    1. Shapiro RL, Holland DT, Capparelli E, Lockman S, Thior I, Wester C, Stevens L, Peter T, Essex M, Connor JD, Mirochnick M. Antiretroviral concentrations in breast-feeding infants of women in Botswana receiving antiretroviral treatment. J Infect Dis. 2005;192:720–727.
    1. Palombi L, Pirillo MF, Andreotti M, Liotta G, ERba F, Sagno JB, Maulidi M, Ceffa S, Jere H, Marchei E, Pichini S, Galluzzo CM, Marazzi MC, Vella S, Guiliano M. Antiretroviral prophylaxis for breastfeeding transmission in Malawi: drug concentrations, virological efficacy and safety. Antivir Ther. 2012;17:1511–1519.
    1. Rezk NL, White N, Bridges AS, Abdel-Megeed MF, Mohamed TM, Moselhy SS, Kashuba AD. Studies on antiretroviral drug concentrations in breast milk: validation of a liquid chromatography-tandem mass spectrometric method for the determination of 7 anti-human immunodeficiency virus medications. Ther Drug Monit. 2008;30:611–619.
    1. National Institute for Allergy and Infectious Diseases Division of AIDS, Clinical Pharmacology Quality Assurance Antiretroviral Proficience Testing Program. available at .
    1. KKGT Association for Quality Assessment in TDM and Clinical Toxicology; A section of the Dutch Foundation for Quality Assessment in Medical Laboratories. available at .
    1. Moore KH, Shaw S, Laurent AL, Lloyd P, Duncan B, Morris DM, O'Mara MJ, Pakes GE. Lamivudine/zidovudine as a combined formulation tablet: bioequivalence compared with lamivudine and zidovudine administered concurrently and the effect of food on absorption. J Clin Pharmacol. 1999;39:593–605.
    1. Kaletra package insert. Abbott Laboratories; North Chicago, IL:
    1. Veldkamp AI, van Heeswijk RP, Mulder JW, Meenhorst PL, Schreij G, van der Geest S, Lange JM, Beijnen JH, Hoetelmans RM. Steady-state pharmacokinetics of twice-daily dosing of saquinavir plus ritonavir in HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2001;27:344–349.
    1. Anderson GD. Using pharmacokinetics to predict the effects of pregnancy and maternal-infant transfer of drugs during lactation. Expert Opin Drug Metab Toxicol. Dec. 2006;2(6):947–60.
    1. Riant P, Urien S, Albengres E, Duche JC, Tillement JP. High plasma protein binding as a parameter in the selection of betablockers for lactating women. Biochem Pharmacol. 1986;35:4579–4581.
    1. Olagunju A, Owen A, Cressey TR. Potential effect of pharmacogenetics on maternal, fetal and infant antiretroviral drug exposure during pregnancy and breastfeeding. Pharmacogenomics. 2012;13:1501–1522.
    1. 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;303:487–496.
    1. Fiscus SA, Aldrovandi GM. Virologic determinants of breast milk transmission of HIV-1. Adv Exp Med Biol. 2012;743:69–80.

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