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Global AIDS Program and Division of HIV/AIDS Prevention, Surveillance and Epidemiology, National Center for HIV, Sexually Transmitted Disease, and Tuberculosis Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
Department of Pediatrics, Harlem Hospital Center
Mother to Child TransmissionPlus Initiative, Mailman School of Public Health, Columbia University, New York, New York
Centers for Disease Control and PreventionZambia, Lusaka, Zambia
Africa's HIV/AIDS epidemic has reached crisis proportions and calls for a rapid expansion of both prevention and treatment services, particularly among young women and children [14]. Mother-to-child transmission (MTCT) is the most important source of HIV-1 infection in children, and prolonged breast-feeding is associated with a near doubling of the risk of MTCT [58]. In resource-limited settings, the majority of HIV-1infected mothers choose to breast-feed because of cultural norms, the high cost of formula, the lack of a safe water supply, and the stigma associated with not breast-feeding [9, 10].
Reducing HIV-1 transmission during lactation remains a pressing global health dilemma confronting HIV-1infected women, health-care providers, and policy makers [1113]. Clinical trials are currently under way to assess whether the use of highly active antiretroviral therapy (HAART) during late pregnancy and during the first 6 months of lactation, followed by early weaning, can substantially reduce the risk of HIV-1 transmission among breast-feeding women [14]. In addition, it is anticipated that eligible HIV-1infected nursing mothers in sub-Saharan Africa will increasingly be able to receive HAART for the maintenance of their own health [1315].
In this issue of the Journal of Infectious Diseases, Shapiro et al. [16, 17] present data on the pharmacokinetics of antiretroviral (ARV) drugs among lactating women and on the effect of HAART on breast milk HIV-1 RNA and DNA. These studies are of vital importance for both biological understanding and health policy. In the first report, detailed pharmacokinetic findings are presented on the magnitude of infant ARV drug exposure from breast milk [16]. Although it was based on a relatively modest sample size (20 mother-infant pairs), this is the first published study to evaluate ARV drug concentrations in breast-feeding infants of women receiving HAART in Africa and is the largest study to date of ARV drug concentrations in breast milk. In the second report, the authors demonstrate that HAART effectively reduces HIV-1 RNA load, but not DNA load, in breast milk [17]. Both studies were conducted in Botswana, where these findings are particularly relevant, given the government's sustained commitment to a nationwide program for MTCT prevention, as well as to the rapid implementation of combination ARV treatment to all those who need it [18].
The pharmacokinetic findings demonstrate that all 3 drugs (lamivudine, zidovudine, and nevirapine) were present in breast milk in significant concentrations [16]. Median nevirapine concentrations in breast-fed infants were many fold higher than the IC50 and were comparable to peak levels achieved after the administration of a single dose of 2 mg/kg of nevirapine at birth [16, 19]. However, drug levels in infants were lower than would be achieved through the standard ARV drug administration used in pediatric HIV treatment. The quantity of ARV drugs that a breast-feeding child ingests is dependent on the concentration of the drug in breast milk, the quantity of breast milk ingested at each feeding, and the frequency of feedings [20]. The apparently relatively stable concentration of ARV drugs in breast milk over a dosing interval reported by Shapiro et al. [16] contrasts with the conventional teaching for drugs with short plasma half-livessuch as zidovudine and lamivudinebut is not unexpected for those with long half-livessuch as nevirapine [21]. Considering their findings and the frequency of breast-feeding throughout the day, it is reasonable to conclude that infants receive relatively consistent, although not necessarily proportional, doses of ARV drugs throughout the day. Infants would be receiving 5%10% of the recommended treatment dose for nevirapine (14 mg/kg/day) and <5% of that for lamivudine (8 mg/kg/day). The quantity of zidovudinethe drug among these with the shortest plasma half-lifereported in breast milk would likely result in the ingestion of <1% of the recommended dose for zidovudine (480 mg/m2/day). Thus, in the absence of parallel administration of zidovudine to the infant, one would expect to find infant serum concentrations of zidovudine that are far below the IC50 for HIV-1. There are few published data on long-term combination ARV treatment available for comparison [22].
The quantities of nevirapine, although perhaps not of lamivudine or zidovudine, that a child ingests through breast milk may not only reduce maternal viral load in breast milk but could potentially also provide infants with drug levels sufficient for prophylaxis against transmission. This may be yet another reason to instruct women to practice exclusive breast-feeding of their infants [12, 2325]. However, these quantities are likely insufficient for the treatment of a child who becomes infected with HIV-1 either before or during a mother's ARV therapy, and this could put the infant at risk for the development of resistant virus, given the therapeutic levels inadequate for the suppression of HIV-1 replication. Infected children should be treated with ARV drugs independent of those ingested through breast milk.
Another interesting finding by Shapiro et al. [16] is that nevirapine serum concentrations were 60% higher in these nursing African women than in comparable postpartum US women or other adult men and women in developed countries [2628]. Similar findings have recently been reported from Malawi [29]. The higher concentrations may increase the risk of drug toxicity in African women receiving long-term nevirapine-based ART, which is the first-line regimen recommended by the World Health Organization for HIV-infected persons in resource-limited settings [15]. Differences in nevirapine metabolism may result from genetic profile [30] and/or environmental factors that potentially lead to a slower clearance of nevirapine during chronic dosing (e.g., traditional herbal remedies [31], medications, concomitant illnesses, diet, and alcohol). Protein malnutrition could potentially lead to higher nevirapine concentrations. These elevated maternal nevirapine concentrations are worrisome in light of recent concerns about the increased rate of nevirapine hypersensitivity and hepatic and cutaneous toxicity, particularly among HIV-1infected women with CD4+ cell counts >250 cells/mm3 [3235]. Women have a 3-fold higher risk than men of developing nevirapine-related hepatic toxicity, and women with CD4+ cell counts >250 cells/mm3 have a 12-fold higher risk of developing this toxicity than women with CD4+ cell counts 250 cells/mm3 [35]. It is important to note that severe toxicity has not been reported in women and infants who have received only a single peripartum dose of nevirapine to prevent MTCT [35].
Further studies are needed to determine the optimal dose of nevirapine for lactating women in Africa, as well as in other resource-poor settings, in which the average maternal weight may be substantially less than that in the United States. For now, women should continue to be treated with the standard doses while being monitored closely for adverse hypersensitivity events. Further research is also needed on possible alternative HAART regimens for lactating women (e.g., combining tenofovir or a protease inhibitor with lamivudine and zidovudine) [36].
The effect of HAART on reducing the HIV-1 RNA load in breast milk provides encouraging support that HAART may, in fact, significantly reduce HIV-1 transmission by this route [17]. The suppression of HIV-1 RNA in breast milk was correlated with suppression in maternal plasma and the use of HAART. However, even among untreated women, more than one-third also had HIV-1 RNA loads below the limit of detection in breast milk. There remains some concern that the risk of transmission may still persist in breast milk even when HIV-1 RNA loads are not detectable. For instance, there is evidence that the HIV-1 DNA load in the female genital tract may be independently associated with HIV-1 transmission by that route [37]. At present, it is unclear whether cell-free or cell-associated virus is more likely to be transmitted through breast milk. The time until sample collection in the present study [17] may have been too short for HAART to have reduced the HIV-1 DNA load in breast milk, but this will be the case in many resource-limited settings, where women may start treatment late during pregnancy and begin breast-feeding shortly after starting HAART.
Perinatal HIV research has reached a critical crossroad. In the United States and other resource-rich settings, where HIV-1infected mothers can safely avoid breast-feeding, MTCT of HIV-1 can be reduced to 1% by use of combination ARV drugs and scheduled cesarean delivery [3, 38]. The goal in resource-limited settings is to achieve similarly low transmission rates, including in HIV-1infected women who, by necessity, opt to breast-feed [2, 39, 40]. Research is currently under way to assess whether maternal HAART used for the prevention of MTCT among breast-feeding women is safe, deliverable, and efficacious; on the relative efficacy of maternal combination ART versus infant ARV prophylaxis; and on whether viral drug resistance from the use of ARVs for prophylaxis may negatively affect later treatment options for mothers and/or infected infants. It is also critical to remember that the primary prevention of HIV-1 infection in young women holds the key to the prevention of MTCT [41].
The studies presented by Shapiro et al. [16, 17] shed light on the magnitude of infant ARV drug exposure from breast milk and the encouraging effect of HAART on the suppression of HIV-1 RNA loads in breast milk. Although we expect that the vast majority of infants born to women who receive HAART during pregnancy and lactation will escape HIV-1 infection, the impact of ARV exposure through breast milk on HIV-1infected children will require thoughtful study. High serum levels of ARV drugs will likely affect viral replication by suppressing infant viral loads during lactation, with possible viral rebound replication on weaning or, alternatively, by inadequately suppressing viral replication during lactation with the resultant development of resistance mutations in the infected child. When drug levels reach the therapeutic threshold, they could theoretically also adversely affect the sensitivity of diagnostic tests in infants, particularly when HIV-1 RNA detection methods are used [42, 43]. We must also assess the potential short-term and long-term adverse effects in uninfected children exposed to sustained high levels of ARV drugs during a critical period of growth and development. Finally, the pharmacokinetic study in this issue [16] highlights the paucity of data on ARV drug levels among HIV-1infected adults and children in resource-limited settings and the need to support further research on the pharmacokinetics of ARV drugs when they are used in diverse populations worldwide.
References
1. De Cock KM, Marum E, Mbori-Ngacha D. A serostatus-based approach to HIV/AIDS prevention and care in Africa. Lancet 2003; 362:18479. First citation in article
2. Bulterys M. Use of antiretroviral drugs to prevent mother-to-child HIV-1 transmission in high-prevalence, resource-poor settings. In: Butera ST, ed. HIV chemotherapy: a critical review. Norwich, UK: Horizon Scientific Press, 2005. First citation in article
3. De Cock KM, Fowler MG, Mercier E, et al. Prevention of mother-to-child HIV transmission in resource-poor countries: translating research into policy and practice. JAMA 2000; 283:117582. First citation in article
4. Weidle PJ, Mastro TD, Grant AD, Nkengasong J, Macharia D. HIV/AIDS treatment and HIV vaccines for Africa. Lancet 2002; 359:22617. First citation in article
5. The Breastfeeding and HIV International Transmission Study Group. Late postnatal transmission of HIV-1 in breast-fed children: an individual patient data meta-analysis. J Infect Dis 2004; 189:215466. First citation in article
6. Nduati R, John G, Mbori-Ngacha D, et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. JAMA 2000; 283:116774. First citation in article
7. Dunn DT, Newell ML, Ades AE, Peckham CS. Risk of human immunodeficiency virus type 1 transmission through breastfeeding. Lancet 1992; 340:5858. First citation in article
8. Kourtis AP, Butera S, Ibegbu C, Belec L, Duerr A. Breast milk and HIV-1: a vector of transmission or vehicle of protection Lancet Infect Dis 2003; 3:78693. First citation in article
9. Fowler MG, Newell ML. Breast-feeding and HIV-1 transmission in resource-limited settings. J Acquir Immune Defic Syndr 2002; 30:2309. First citation in article
10. John-Stewart G, Mbori-Ngacha D, Ekpini R, et al. Breast-feeding and transmission of HIV-1. J Acquir Immune Defic Syndr 2004; 35:196202. First citation in article
11. Bertolli J, Hu DJ, Nieburg P, Macalalad A, Simonds RJ. Decision analysis to guide choice of interventions to reduce mother-to-child transmission of HIV. AIDS 2003; 17:110. First citation in article
12. Rollins N, Meda N, Becquet R, et al. Preventing postnatal transmission of HIV-1 through breast-feeding: modifying infant feeding practices. J Acquir Immune Defic Syndr 2004; 35:18895. First citation in article
13. Bulterys M, Fowler MG, Van Rompay KK, Kourtis AP. Prevention of mother-to-child transmission of HIV-1 through breast-feeding: past, present, and future. J Infect Dis 2004; 189:214953. First citation in article
14. Gaillard P, Fowler MG, Dabis F, et al. Use of antiretroviral drugs to prevent HIV-1 transmission through breastfeeding: from animal studies to randomized clinical trials. J Acquir Immune Defic Syndr 2004; 35:17887. First citation in article
15. World Health Organization. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants: guidelines on care, treatment and support for women living with HIV/AIDS and their children in resource-constrained settings. Geneva, 2004. Available at: http://www.who.int/3by5/publications/. Accessed 12 May 2005. First citation in article
16. Shapiro RL, Ndung'u T, Lockman S, et al. Highly active antiretroviral therapy started in pregnancy or postpartum suppresses HIV-1 RNA, but not DNA, in breast milk. J Infect Dis 2005;192:7139 (in this issue). First citation in article
17. 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;192:7207 (in this issue). First citation in article
18. African Comprehensive HIV/AIDS Partnerships. MASA: the antiretroviral therapy programme. Available at: http://www.achap.org/MASA.htm. Accessed 12 May 2005. First citation in article
19. Mirochnick M, Fenton T, Gagnier P, et al. Pharmacokinetics of nevirapine in human immunodeficiency virus type 1infected pregnant women and their neonates. J Infect Dis 1998; 178:36874. First citation in article
20. Powers NG, Slusser W. Breastfeeding update 2: clinical lactation management. Pediatr Rev 1997; 18:14761. First citation in article
21. Spencer JP, Gonzalez LS, Barnhart DJ. Medications in the breastfeeding mother. Am Fam Phys 2001; 64:11926. First citation in article
22. 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 1infected pregnant women and their offspring. J Infect Dis 1998; 178:132733. First citation in article
23. Coutsoudis A, Pillay K, Kuhn L, Spooner E, Tsai W, Coovadia HM. Methods of feeding and transmission of HIV-1 from mothers to children by 15 months of age: prospective cohort study from Durban, South Africa. AIDS 2001; 15:37987. First citation in article
24. Shapiro RL, Lockman S, Thior I, et al. Low adherence to recommended infant feeding strategies among HIV-infected women: results from the pilot phase of a randomized trial to prevent mother-to-child transmission in Botswana. AIDS Educ Prev 2003; 15:22130. First citation in article
25. Iliff PJ, Piwoz EG, Tavengwa NV, et al. Early exclusive breastfeeding reduces the risk of postnatal HIV-1 transmission and increases HIV-free survival. AIDS 2005; 19:699708. First citation in article
26. Acosta EP, King JR. Methods for integration of pharmacokinetic and phenotypic information in the treatment of infection with human immunodeficiency virus. Clin Infect Dis 2003; 36:3737. First citation in article
27. Riska P, Lamson M, MacGregor T, et al. Disposition and biotransformation of the antiretroviral drug nevirapine in humans. Drug Metab Dispos 1999; 27:895901. First citation in article
28. Haberl A, Hentig N, Carlebach A, Kurowski M, Harder S, Staszewski S. Nevirapine plasma exposure is decreased in pregnant women [abstract TuPeB4644]. In: Program and abstracts of the 15th International AIDS Conference (Bangkok). Geneva: International AIDS Society, 2004. First citation in article
29. Hosseinipour MC, Kanyama C, Mshali I, et al. Pharmacokinetic comparison of generic and trade formulations of lamivudine, stavudine, and nevirapine in 12 HIV-infected Malawian subjects [abstract 631]. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections (Boston). Alexandria, VA: Foundation for Retrovirology and Human Health, 2005. First citation in article
30. Haas DW. Pharmacogenomics and HIV therapeutics. J Infect Dis 2005; 191:1397400. First citation in article
31. Mills E, Foster BC, Van Heeswijk R, et al. Impact of African herbal medicines on antiretroviral metabolism. AIDS 2005; 19:957. First citation in article
32. Fowler MG, Mofenson L, McConnell M. The interface of perinatal HIV prevention, antiretroviral drug resistance, and antiretroviral treatment: what do we really know J Acquir Immune Defic Syndr 2003; 34:30811. First citation in article
33. Dieterich DT, Robinson PA, Love J, Stern JO. Drug-induced liver injury associated with the use of nonnucleoside reverse-transcriptase inhibitors. Clin Infect Dis 2004; 38(Suppl 2):S809. First citation in article
34. Hitti J, Frenkel LM, Stek AM, et al. Maternal toxicity with continuous nevirapine in pregnancy: results from PACTG 1022. J Acquir Immune Defic Syndr 2004; 36:7726. First citation in article
35. US Food and Drug Administration. FDA public health advisory: initiation of nevirapine therapy. Available at: http://www.fda.gov/cder/drug/advisory/nevirapine.htm. Accessed 12 May 2005. First citation in article
36. Mauss S, Milinkovic A, Hoffmann C, et al. Low rate of treatment failure on antiretroviral therapy with tenofovir, lamivudine and zidovudine. AIDS 2005; 19:1012. First citation in article
37. Tuomala RE, O'Driscoll PT, Bremer JW, et al. Cell-associated genital tract virus and vertical transmission of human immunodeficiency virus type 1 in antiretroviral-experienced women. J Infect Dis 2003; 187:37584. First citation in article
38. European Collaborative Study. Mother-to-child transmission of HIV infection in the era of highly active antiretroviral therapy. Clin Infect Dis 2005; 40:45865. First citation in article
39. Dabis F, Bequent L, Ekouevi DK, et al. Field efficacy of zidovudine, lamivudine and single-dose nevirapine to prevent peripartum HIV transmission. AIDS 2005; 19:30918. First citation in article
40. Moodley J, Moodley D. Management of human immunodeficiency virus infection in pregnancy. Best Pract Res Clin Obstet Gynaecol 2005; 19:16983. First citation in article
41. Abrams EJ. Prevention of mother-to-child transmission of HIV: successes, controversies and critical questions. AIDS Rev 2004; 6:13143. First citation in article
42. Nesheim S, Palumbo P, Sullivan K, et al. Quantitative RNA testing for diagnosis of HIV-infected infants. J Acquir Immune Defic Syndr 2003; 32:1925. First citation in article
43. Dunn DT, Simonds RJ, Bulterys M, et al. Interventions to prevent vertical transmission of HIV-1: effect on viral detection rate in early infant samples. AIDS 2000; 14:14218. First citation in article