Antiretroviral concentrations in breast-feeding infants of mothers receiving highly active antiretroviral therapy

Mark Mirochnick, Timothy Thomas, Edmund Capparelli, Clement Zeh, Diane Holland, Rose Masaba, Prisca Odhiambo, Mary Glenn Fowler, Paul J Weidle, Michael C Thigpen, Mark Mirochnick, Timothy Thomas, Edmund Capparelli, Clement Zeh, Diane Holland, Rose Masaba, Prisca Odhiambo, Mary Glenn Fowler, Paul J Weidle, Michael C Thigpen

Abstract

There are limited data describing the concentrations of zidovudine, lamivudine, and nevirapine in nursing infants as a result of transfer via breast milk. The Kisumu Breastfeeding Study is a phase IIb open-label trial of prenatal, intrapartum, and postpartum maternal treatment with zidovudine, lamivudine, and nevirapine from 34 weeks of gestation to 6 months postpartum. In a pharmacokinetic substudy, maternal plasma, breast milk, and infant dried blood spots were collected for drug assay on the day of delivery and at 2, 6, 14, and 24 weeks after delivery. Sixty-seven mother-infant pairs were enrolled. The median concentrations in breast milk of zidovudine, lamivudine, and nevirapine during the study period were 14 ng/ml, 1,214 ng/ml, and 4,546 ng/ml, respectively. Zidovudine was not detectable in any infant plasma samples obtained after the day of delivery, while the median concentrations in infant plasma samples from postpartum weeks 2, 6, and 14 were 67 ng/ml, 32 ng/ml, and 24 ng/ml for lamivudine and 987 ng/ml, 1,032 ng/ml, and 734 ng/ml for nevirapine, respectively. Therefore, lamivudine and nevirapine, but not zidovudine, are transferred to infants via breast milk in biologically significant concentrations. The extent and effect of infant drug exposure via breast milk must be well understood in order to evaluate the benefits and risks of maternal antiretroviral use during lactation.

Figures

FIG. 1.
FIG. 1.
Infant concentrations (conc) of zidovudine (ZDV), lamivudine (3TC), and nevirapine (NVP) on day of delivery (DEL) and at 2, 6, 14, and 24 weeks postpartum, Kisumu Breastfeeding Study, Kenya, 2004 to 2007. For comparative purposes, the IC50 for wild-type HIV type 1, subtype B, is ∼0.6 to 21 ng/ml for lamivudine and ∼17 ng/ml for nevirapine.
FIG. 2.
FIG. 2.
Maternal plasma and breast milk concentrations (conc) of zidovudine (ZDV), lamivudine (3TC), and nevirapine (NVP) plotted against time since last maternal dose, Kisumu Breastfeeding Study, Kenya, 2004 to 2007. Dashed lines are regression lines for maternal plasma data, and solid lines are regression lines for breast milk data.
FIG. 3.
FIG. 3.
Zidovudine (ZDV), lamivudine (3TC), and nevirapine (NVP) breast milk (BM)-to-maternal plasma ratio plotted against time since last maternal dose, Kisumu Breastfeeding Study, 2004 to 2007. The filled circles represent samples with zidovudine breast milk concentrations below the limit of detection and represent the highest possible breast milk/plasma ratio. The P values represent the probability that the slope of the line is different than zero as calculated by linear mixed-effects regression analysis.
FIG. 4.
FIG. 4.
Proportion of breast-feeding infants receiving a cumulative breast milk nevirapine dose of 2 mg/kg plotted against number of days of breast feeding (estimated from day-of-delivery breast milk nevirapine concentrations), Kisumu Breastfeeding Study, Kenya, 2004 to 2007.
FIG. 5.
FIG. 5.
Observed and model-predicted infant dried blood spot (DBS) nevirapine (NVP) concentrations (conc) at weeks 2, 6, and 14 postpartum, Kisumu Breastfeeding Study, Kenya, 2004 to 2007.

References

    1. Back, D., T. Blaschke, C. Boucher, et al. 2006. Optimizing TDM in HIV clinical care. .
    1. Bailey, B., and S. Ito. 1997. Breast-feeding and maternal drug use. Pediatr. Clin. N. Am. 44:41-54.
    1. Boucher, F. D., J. F. Modlin, S. Weller, A. Ruff, M. Mirochnick, S. Pelton, C. Wilfert, R. McKinney, Jr., M. J. Crain, M. M. Elkins, et al. 1993. Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus. J. Pediatr. 122:137-144.
    1. Coates, J. A., N. Cammack, H. J. Jenkinson, A. J. Jowett, M. I. Jowett, B. A. Pearson, C. R. Penn, P. L. Rouse, K. C. Viner, and J. M. Cameron. 1992. (−)−2′-Deoxy-3′-thiacytidine is a potent, highly selective inhibitor of human immunodeficiency virus type 1 and type 2 replication in vitro. Antimicrob. Agents Chemother. 36:733-739.
    1. Colebunders, R., B. Hodossy, D. Burger, T. Daems, K. Roelens, M. Coppens, B. Van Bulck, Y. Jacquemyn, E. Van Wijngaerden, and K. Fransen. 2005. The effect of highly active antiretroviral treatment on viral load and antiretroviral drug levels in breast milk. AIDS 19:1912-1915.
    1. Coutsoudis, A., F. Dabis, W. Fawzi, P. Gaillard, G. Haverkamp, D. R. Harris, J. B. Jackson, V. Leroy, N. Meda, P. Msellati, M. L. Newell, R. Nsuati, J. S. Read, and S. Wiktor. 2004. Late postnatal transmission of HIV-1 in breast-fed children: an individual patient data meta-analysis. J. Infect. Dis. 189:2154-2166.
    1. De Cock, K. M., M. G. Fowler, E. Mercier, I. de Vincenzi, J. Saba, E. Hoff, D. J. Alnwick, M. Rogers, and N. Shaffer. 2000. Prevention of mother-to-child HIV transmission in resource-poor countries: translating research into policy and practice. JAMA 283:1175-1182.
    1. Giuliano, M., G. Guidotti, M. Andreotti, M. F. Pirillo, P. Villani, G. Liotta, M. C. Marazzi, M. G. Mancini, M. Cusato, P. Germano, S. Loureiro, S. Ceffa, M. Regazzi, S. Vella, and L. Palombi. 2007. 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. 44:286-291.
    1. Guay, L. A., P. Musoke, T. Fleming, D. Bagenda, M. Allen, C. Nakabiito, J. Sherman, P. Bakaki, C. Ducar, M. Deseyve, L. Emel, M. Mirochnick, M. G. Fowler, L. Mofenson, P. Miotti, K. Dransfield, D. Bray, F. Mmiro, and J. B. Jackson. 1999. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 354:795-802.
    1. Havlir, D., S. H. Cheeseman, M. McLaughlin, R. Murphy, A. Erice, S. A. Spector, T. C. Greenough, J. L. Sullivan, D. Hall, M. Myers, et al. 1995. High-dose nevirapine: safety, pharmacokinetics, and antiviral effect in patients with human immunodeficiency virus infection. J. Infect. Dis. 171:537-545.
    1. Holland, D. T., R. DiFrancesco, J. D. Connor, and G. D. Morse. 2006. Quality assurance program for pharmacokinetic assay of antiretrovirals: ACTG proficiency testing for pediatric and adult pharmacology support laboratories, 2003 to 2004: a requirement for therapeutic drug monitoring. Ther. Drug Monit. 28:367-374.
    1. Kent, J. C., L. Mitoulas, D. B. Cox, R. A. Owens, and R. E. Hartmann. 1999. Breast volume and milk production during extended lactation in women. Exp. Physiol. 84:435-447.
    1. Kumwenda, N. I., D. R. Hoover, L. M. Mofenson, M. C. Thigpen, G. Kafulafula, Q. Li, L. Mipando, K. Nkanaunena, T. Mebrahtu, M. Bulterys, M. G. Fowler, and T. E. Taha. 2008. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. N. Engl. J. Med. 359:119-129.
    1. McNamara, P. J., and M. Abbassi. 2004. Neonatal exposure to drugs in breast milk. Pharm. Res. 21:555-566.
    1. Mei, J. V., J. R. Alexander, B. W. Adam, and W. H. Hannon. 2001. Use of filter paper for the collection and analysis of human whole blood specimens. J. Nutr. 131:1631S-1636S.
    1. Mei, J. V., W. H. Hannon, T. L. Dobbs, C. J. Bell, C. Spruill, and M. Gwinn. 1998. Radioimmunoassay for monitoring zidovudine in dried blood spot specimens. Clin. Chem. 44:281-286.
    1. Mirochnick, M., E. Capparelli, K. Nielsen, J. Pilotto, P. Musoke, A. Shetty, and K. Luzuriaga. 2006. Nevirapine pharmacokinetics during the first year of life: a population analysis across studies, abstr. E-PAS2006:59:5523.135. Abstr. Pediatr. Acad. Soc. Meet., San Francisco, CA.
    1. Mirochnick, M., S. Siminski, T. Fenton, M. Lugo, and J. L. Sullivan. 2001. Nevirapine pharmacokinetics in pregnant women and in their infants after in utero exposure. Pediatr. Infect. Dis. J. 20:803-805.
    1. Moodley, J., D. Moodley, K. Pillay, H. Coovadia, J. Saba, R. van Leeuwen, C. Goodwin, P. R. Harrigan, K. H. Moore, C. Stone, R. Plumb, and M. A. Johnson. 1998. 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. 178:1327-1333.
    1. Moorthy, A., A. Gupta, R. Bhosale, S. Tripathy, J. Sastry, S. Kulkarni, M. Thakar, R. Bharadwaj, A. Kagal, A. V. Bhore, S. Patil, V. Kulkarni, V. Venkataramani, U. Balasubramaniam, N. Suryavanshi, C. Ziemniak, N. Gupte, R. Bollinger, and D. Persaud. 2009. Nevirapine resistance and breast-milk HIV transmission: effects of single and extended-dose nevirapine prophylaxis in subtype C HIV-infected infants. PLoS ONE 4:e4096.
    1. Musoke, P., L. A. Guay, D. Bagenda, M. Mirochnick, C. Nakabiito, T. Fleming, T. Elliott, S. Horton, K. Dransfield, J. W. Pav, A. Murarka, M. Allen, M. G. Fowler, L. Mofenson, D. Hom, F. Mmiro, and J. B. Jackson. 1999. 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 13:479-486.
    1. Naver, L., S. Lindgren, E. Belfrage, K. Gyllensten, K. Lidman, M. Gisslen, A. Ehrnst, M. Arneborn, and A. B. Bohlin. 2006. Children born to HIV-1-infected women in Sweden in 1982-2003: trends in epidemiology and vertical transmission. J. Acquir. Immune Defic. Syndr. 42:484-489.
    1. Nduati, R., G. John, D. Mbori-Ngacha, B. Richardson, J. Overbaugh, A. Mwatha, J. Ndinya-Achola, J. Bwayo, F. E. Onyango, J. Hughes, and J. Kreiss. 2000. Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. JAMA 283:1167-1174.
    1. O'Sullivan, M. J., P. J. Boyer, G. B. Scott, W. P. Parks, S. Weller, M. R. Blum, J. Balsley, Y. J. Bryson, et al. 1993. The pharmacokinetics and safety of zidovudine in the third trimester of pregnancy for women infected with human immunodeficiency virus and their infants: phase I acquired immunodeficiency syndrome clinical trials group study (protocol 082). Am. J. Obstet Gynecol. 168:1510-1516.
    1. Ruprecht, R. M., A. H. Sharpe, R. Jaenisch, and D. Trites. 1990. Analysis of 3′-azido-3′-deoxythymidine levels in tissues and milk by isocratic high-performance liquid chromatography. J. Chromatogr. 528:371-383.
    1. Schneider, S., A. Peltier, A. Gras, V. Arendt, C. Karasi-Omes, A. Mujawamariwa, P. C. Ndimubanzi, G. Ndayisaba, and R. Wennig. 2008. Efavirenz in human breast milk, mothers', and newborns’ plasma. J. Acquir. Immune Defic. Syndr. 48:450-454.
    1. Shapiro, R. L., D. T. Holland, E. Capparelli, S. Lockman, I. Thior, C. Wester, L. Stevens, T. Peter, M. Essex, J. D. Connor, and M. Mirochnick. 2005. Antiretroviral concentrations in breast-feeding infants of women in Botswana receiving antiretroviral treatment. J. Infect. Dis. 192:720-727.
    1. Shapiro, R. L., T. Ndung'u, S. Lockman, L. M. Smeaton, I. Thior, C. Wester, L. Stevens, G. Sebetso, S. Gaseitsiwe, T. Peter, and M. Essex. 2005. Highly active antiretroviral therapy started during pregnancy or postpartum suppresses HIV-1 RNA, but not DNA, in breast milk. J. Infect. Dis. 192:713-719.
    1. Shetty, A. K., H. M. Coovadia, M. M. Mirochnick, Y. Maldonado, L. M. Mofenson, S. H. Eshleman, T. Fleming, L. Emel, K. George, D. A. Katzenstein, J. Wells, C. C. Maponga, A. Mwatha, S. A. Jones, S. S. Abdool Karim, and M. T. Bassett. 2003. Safety and trough concentrations of nevirapine prophylaxis given daily, twice weekly, or weekly in breast-feeding infants from birth to 6 months. J. Acquir. Immune Defic. Syndr. 34:482-490.
    1. Sinkala, M., L. Kuhn, C. Kankasa, P. Kasonde, C. Vwalika, M. Mwiya, N. Scott, K. Semrau, G. Aldrovani, D. Thea, and Z. E. B. S. Group. 2007. No benefit of early cessation of breastfeeding at 4 months on HIV-free survival of infants born to HIV-infected mothers in Zambia: the Zambia Exclusive Breastfeeding Study, abstr. 74LB. 14th Conf. Retrovir. Opportun. Infect., Los Angeles, CA.
    1. Thomas, T., R. Masaba, R. Ndivo, C. Zeh, C. Borkowf, M. Thigpen, et al. 2008. PMTCT of HIV-1 among breastfeeding mothers using HAART: the Kisumu breastfeeding study, Kisumu, Kenya, 2003-2007, abstr. 45aLB. Abstr. 15th Conf. Retrovir. Opportun. Infect., Boston, MA.
    1. Tremoulet, A. H., E. V. Capparelli, P. Patel, E. P. Acosta, K. Luzuriaga, Y. Bryson, D. Wara, C. Zorrilla, D. Holland, and M. Mirochnick. 2007. Population pharmacokinetics of lamivudine in human immunodeficiency virus-exposed and -infected infants. Antimicrob. Agents Chemother. 51:4297-4302.
    1. Wilfert, C. M., and M. G. Fowler. 2007. Balancing maternal and infant benefits and the consequences of breast-feeding in the developing world during the era of HIV infection. J. Infect. Dis. 195:165-167.
    1. Wilson, J. T., R. D. Brown, J. L. Hinson, and J. W. Dailey. 1985. Pharmacokinetic pitfalls in the estimation of the breast milk/plasma ratio for drugs. Annu. Rev. Pharmacol. Toxicol. 25:667-689.
    1. Zeh, C., P. Weidle, L. Nafisa, H. Musuluma, J. Okonji, E. Anyango, P. Bondo, R. Masaba, M. Thigpen, and T. Thomas. 2008. Emergence of HIV-1 drug resistance among breastfeeding infants born to HIV-infected mothers taking antiretrovirals for prevention of mother-to-child transmission of HIV: the Kisumu Breastfeeding Study, Kenya, abstr. 84LB. 15th Conf. Retrovir. Opportun. Infect., Boston, MA.

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