Zidovudine

Drug Levels and Effects:




Summary of Use during Lactation:


In the United States and other developed countries, HIV-infected mothers should generally not breastfeed their infants. In countries in which no acceptable, feasible, sustainable and safe replacement feeding is available, exclusive breastfeeding for 6 months is recommended for HIV-infected mothers to reduce the risk of HIV transmission from the mother to the infant compared with mixed feeding.[1][2][3] In these settings, abrupt weaning at 4 months does not reduce the risk of HIV transmission or produce an overall health benefit compared to continued breastfeeding, and increases the risk of infant death in HIV-infected infants.[4] Zidovudine is often used as part of a regimen that decreases mother-to-child transmission of HIV and is generally well tolerated by the breastfed infant.[1][2][3][5][6][7] Extended antiretroviral prophylaxis in breastfed infants with antiretroviral drugs appears to reduce the rate of HIV transmission during breastfeeding by about half, but the optimal regimen and duration of prophylaxis has not yet been defined.[8][9][10][11][12] The infants who do become HIV infected during breastfeeding by mothers receiving a HAART regimen that includes zidovudine are often infected with multi-class resistant HIV.[13][14] Breastfed infants whose mothers receive highly active antiretroviral therapy (HAART) have higher rates of neutropenia during the first month and severe anemia during the first 6 months of life.


Drug Levels:


Maternal Levels.

Six women were given a single oral dose of 200 mg of zidovudine. Milk samples were collected 1, 2, 4 and 6 hours after the dose. The peak milk concentration occurred 1 to 2 hours after the dose in 4 women and occurred 1 hour later in the others. The average peak milk concentration was 857 mcg/L (range 472 to 1043 mcg/L).[15]

Eighteen women who were receiving oral zidovudine 300 mg twice daily as part of a combination antiretroviral regimen had their milk analyzed at either 2 or 5 months postpartum. Milk samples were provided at a median of 4 hours (range 1 to 8.5 hours) after the last dose. The median zidovudine concentration in breastmilk was 207 mcg/L.[16]

Forty women were given postpartum prophylaxis with unstated dosages of lamivudine, nevirapine and zidovudine (or stavudine if the hemoglobin <8 g/dl).="" blood="" and="" milk="" samples="" were="" collected="" once="" during="" the="" first="" 3="" days="" postpartum="" and="" once="" at="" 7="" days="" postpartum.="" the="" median="" times="" after="" a="" dose="" that="" samples="" were="" collected="" were="" 5.3="" hours="" (range="" 0="" to="" 99="" hours)="" for="" the="" first="" sample="" and="" 6="" hours="" (range="" 4.3="" to="" 20="" hours)="" for="" the="" 7-day="" sample.="" average="" breastmilk="" zidovudine="" concentrations="" were="" calculated="" only="" for="" samples="" that="" had="" detectable="" (="">20 mcg/L) concentrations of zidovudine. The mean breastmilk concentrations were 130 (n = 11) and 150 mcg/L (n = 13), respectively, at the two sampling times, which was equal to the simultaneous maternal serum concentrations.[17]

Fifty-eight mothers who were taking a combination regimen of lamivudine, nevirapine and zidovudine had their serum and breastmilk analyzed for the presence of these drugs. Mothers took zidovudine 200 mg twice daily starting at 34 to 36 weeks postpartum and continuing until 6 months postpartum. Breastmilk was collected within 24 hours after delivery and at 2, 6, 14 and 24 weeks postpartum at variable times after the previous dose. The median breastmilk zidovudine concentration in 35 selected samples across all visits was 9 mcg/L.[18]

Thirty-eight mothers who were receiving zidovudine 300 mg twice daily as part of a combination antiretroviral regimen provided a total of 114 milk samples at birth, 1 month, 3 months and/or 6 months postpartum. Milk samples were collected at a median of 4.5 hours (range 3.5 to 6 hours) after the previous dose. The median breastmilk zidovudine concentration was 33 mcg/L (range 5 to 117 mcg/L).[19]

Infant Levels.

Eighteen nursing mothers were receiving oral zidovudine 300 mg twice daily as part of a combination antiretroviral regimen. Their infants had serum concentrations determined at either 2 or 5 months postpartum. Serum samples were provided at a median of 4 hours (range 1 to 8.5 hours) after the last dose. The infants were also receiving oral zidovudine 4 or 6 mg/kg 3 times daily, depending on their age. The median infant serum zidovudine concentration was 123 mcg/L (range 14 to 3302 mcg/L). The average value was 25 times the IC50 for HIV.[16]

Fifty-eight infants whose mothers were taking a combination regimen of lamivudine, nevirapine and zidovudine had their serum analyzed for the presence of these drugs. Mothers took zidovudine 200 mg twice daily starting at 34 to 36 weeks postpartum and continuing until 6 months postpartum and were instructed to exclusively breastfeed for 5.5 months. Serum samples were collected within 24 hours after delivery and at 2, 6, 14 and 24 weeks postpartum. Median serum concentration of 16 selected dried blood spot samples was 24 mcg/L. At later times postpartum, zidovudine was not detectable (<30 mcg/L) in 66 infant dried blood spots.[18]

Breastfed infants of 38 mothers who were receiving zidovudine 300 mg twice daily as part of a combination antiretroviral regimen had a total of 34 blood samples analyzed at 1 month, 3 months and/or 6 months postpartum. Samples were collected at a median of 4.5 hours (range 3.5 to 6 hours) after the previous maternal dose and a median of 30 minutes (range 20 to 60 minutes) after the previous nursing. The infants' zidovudine plasma concentrations ranged from 0 to 2.5 mcg/L, which was a median of 2% (range 0 to 5%) of the maternal serum concentration.[19]


Effects in Breastfed Infants:


A study assigned pregnant women to zidovudine alone or highly-active antiretroviral therapy (HAART: zidovudine, lamivudine and nevirapine) to prevent maternal-to-child transmission of HIV infection. After delivery, All infants received one month of zidovudine prophylaxis; some infants were breastfed and others were formula fed. A higher percentage of infants in the HAART-exposed group had neutropenia than those in the unexposed group at 1 month of age (15.9 and 3.7%, respectively). Hematologic toxicity was transient and asymptomatic. From 2 to 6 months postpartum, no differences in hematologic toxicity were seen between breastfed and formula-fed infants. No statistical difference in hepatic toxicity was seen between the breastfed and formula-fed infants.[20]

A study compared the rates of severe anemia in 3 groups of infants who received postpartum prophylaxis with zidovudine for prevention of maternal-to-child transmission of HIV infection. Through 6 months of age, breastfed infants whose mothers received HAART had a higher rate of severe anemia (7.4%) than breastfed infants whose mothers received only zidovudine (5.3%). Formula-fed infants had the lowest rate of severe anemia (2.5%). The anemia generally responded well to iron and multivitamin supplementation, and discontinuation of zidovudine.[21]


Possible Effects on Lactation:


Relevant published information was not found as of the revision date.


Alternate Drugs to Consider:


Lamivudine,Nelfinavir,Nevirapine


References:


1. World Health Organization. HIV and infant feeding: update. 2007.
2. Dao H, Mofenson LM, Ekpini R et al. International recommendations on antiretroviral drugs for treatment of HIV-infected women and prevention of mother-to-child HIV transmission in resource-limited settings: 2006 update. Am J Obstet Gynecol. 2007;197 (3 Suppl):S42-55. PMID:17825650
3. Branson BM, Handsfield HH, Lampe MA et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep. 2006;55 (RR-14):1-17. PMID:16988643
4. Kuhn L, Aldrovandi GM, Sinkala M et al. Effects of early, abrupt weaning on HIV-free survival of children in Zambia. N Engl J Med. 2008;359:130-41. PMID:18525036
5. Chasela CS, Hudgens MG, Jamieson DJ et al. Maternal or infant antiretroviral drugs to reduce HIV-1 transmission. N Engl J Med. 2010;362:2271-81. PMID:20554982
6. Shapiro RL, Hughes MD, Ogwu A et al. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med. 2010;362:2282-94. PMID:20554983
7. Meda N, Fao P, Ky-Zerbo O et al. Triple antiretroviral compared with zidovudine and single-nose 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;11:171-80. PMID:21237718
8. Kumwenda NI, Hoover DR, Mofenson LM et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. N Engl J Med. 2008;359:119-29. PMID:18525035
9. Mofenson LM. Antiretroviral prophylaxis to reduce breast milk transmission of HIV type 1: new data but still questions. J Acquir Immune Defic Syndr. 2008;48:237-40. PMID:18545160
10. Bedri A, Gudetta B, Isehak A et al. 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;372:300-13. PMID:18657709
11. Chigwedere P, Seage GR, Lee TH, Essex M. Efficacy of antiretroviral drugs in reducing mother-to-child transmission of HIV in Africa: a meta-analysis of published clinical trials. AIDS Res Hum Retroviruses. 2008;24:827-37. PMID:18544018
12. Thomas TK, Masaba R, Borkowf CB et al. 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. PMID:21468300
13. Zeh C, Weidle PJ, Nafisa L et al. HIV-1 drug resistance emergence among breastfeeding infants born to HIV-infected mothers during a single-arm trial of triple-antiretroviral prophylaxis for prevention of mother-to-child transmission: a secondary analysis. PLoS Med. 2011;8:e1000430. PMID:21468304
14. 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. PMID:21460326
15. Ruff A, Hamzeh F, Lietman P et al. Excretion of zidovudine (ZDV) in human breast milk. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. Orlando FL. October 4-7, 1995. Abstract I11.
16. 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. PMID:16088821
17. Giuliano M, Guidotti G, Andreotti M et al. Triple antiretroviral prophylaxis administered during pregnancy and after delivery significantly reduces breast milk viral load study within the Drug Resource Enhancement Against AIDS and Malnutrition Program. J Acquir Immune Defic Syndr. 2006 ;14:459-60. PMID:17146372
18. 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. PMID:19114673
19. Palombi L, Pirillo MF, Andreotti M et al. Antiretroviral prophylaxis for breastfeeding transmission in Malawi: drug concentrations, virological efficacy and safety. Antivir Ther. 2012. PMID:22910456
20. Bae WH, Wester C, Smeaton LM et al. Hematologic and hepatic toxicities associated with antenatal and postnatal exposure to maternal highly active antiretroviral therapy among infants. AIDS. 2008;22:1633-40. PMID:18670224
21. Dryden-Peterson S, Shapiro RL, Hughes MD et al. Increased risk of severe infant anemia following exposure to maternal HAART, Botswana. J Acquir Immune Defic Syndr. 2011;56:428-36. PMID:21266910



Substance Identification:




Substance Name:

Zidovudine

CAS Registry Number:

30516-87-1

Drug Class:


  • Antiinfective Agents

  • Anti
  • -HIV Agents

  • Antiviral Agents

  • Anti
  • -Retroviral Agents

  • Reverse Transcriptase
  • Inhibitors

    Administrative Information:




    LactMed Record Number:


    649


    Last Revision Date:


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