Lamivudine use while Breastfeeding

Drugs containing Lamivudine: Combivir, Epivir, Triumeq, Epzicom, Trizivir, Epivir-HBV

Lamivudine Levels and Effects while Breastfeeding

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][4][5][6] 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.[7] Lamivudine is recommended by the World Health Organization to be given as part of a 3-drug combination to all antiretroviral-naive women who are breastfeeding their infants.[8] 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.[9][10][11][12][13] The infants who do become HIV infected during breastfeeding by mothers receiving a HAART regimen that includes lamivudine are often infected with multi-class resistant HIV.[14][15] Lamivudine 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][16] 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.

Lamivudine has not been studied in HIV-negative nursing mothers being treated for hepatitis B infection, but the low doses used would not be expected to cause any serious adverse effects in breastfed infants. Some sources recommend not breastfeeding during lamivudine therapy for hepatitis B.[17] In a survey, 226 physicians with a practice interest in liver disease in the United States responded. Of these, 31% stated that they recommend breastfeeding for their patients with hepatitis B who are taking antiviral therapy, 44% stated that they do not recommend breastfeeding during antiviral therapy and 25% stated that they were unsure.[18]

Drug Levels

Maternal Levels. Milk samples were taken daily before breastfeeding from women receiving lamivudine from 2 groups of women. In the group (n = 10) receiving lamivudine 300 mg twice daily (n = 10), the average milk concentration was 1.2 mg/L (range <0.5 to 6.1 mg/L). In the group receiving 150 mg twice daily plus zidovudine (n = 10), the average milk lamivudine concentration was 0.9 mg/L (range <0.5 to 8.2 mg/L).[19]

Twenty women who were receiving oral lamivudine 150 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 lamivudine concentration in breastmilk was 1.8 mg/L.[20]

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 lamivudine concentrations were calculated only for samples that had detectable (>20 mcg/L) concentrations of nevirapine. The mean breastmilk concentrations were 0.4 (n = 20) and 0.4 mg/L (n = 30), respectively, at the two sampling times, which was 2.9 to 3.3 times the simultaneous maternal serum concentrations.[21]

Forty-seven samples of breastmilk and maternal serum were obtained at 6, 12 and 24 weeks postpartum from mothers taking lamivudine as part of a combination of antiretrovirals. The lamivudine dosage the mothers were taking was not stated in the abstract. The median breastmilk concentrations of lamivudine at a median of 14 hours after the last maternal dose were 510 (17 samples), 387 (17 samples) and 310 mcg/L (13 samples). Median milk concentrations were 2.6 times (interquartile range 1.1 to 3.5 times) the maternal plasma concentrations.[22] In a related study by the same authors, the lamivudine milk to plasma ratio was found to be 2.96 in 49 patients.[23]

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 lamivudine 150 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 lamivudine concentration across all visits was 1214 mcg/L. The authors estimated that a fully breastfed infant would receive a daily dosage of 182 mcg/kg of lamivudine.[24]

Sixty-six mothers who were receiving lamivudine 150 mg twice daily as part of a combination antiretroviral regimen provided a total of 206 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 lamivudine concentration was 446 mcg/L (range 269 to 683 mcg/L).[25]

Fifteen women had been taking lamivudine 150 mg twice daily for 53 to 182 days as part of a drug combination that included either abacavir and zidovudine or lopinavir, ritonavir, and zidovudine. Breastmilk samples were collected at just before a dose at a median of 1 month postpartum. Whole breastmilk levels contained a median of 0.14 mg/L of lamivudine, which was a median of 74% of maternal blood levels.[26]

Thirty women were studied at 6, 12 or 24 weeks postpartum (10 at each time). Each mother was taking zidovudine 300 mg, lamivudine 150 mg, lopinavir 400 mg, and ritonavir 100 mg twice daily by mouth starting at delivery. On the study day, at a median of 14.9 hours after the previous evening's dose, maternal plasma and breastmilk samples were obtained prior to the morning dose and 2, 4 and 6 hours after the dose. One hundred seven of the 121 breastmilk samples contained detectable quantities (10 mcg/L or greater) of lamivudine, with an median breastmilk concentration of 0.94 mg/L over the 6 hours.[27]

Infant Levels. Twenty nursing mothers were receiving oral lamivudine 150 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 median infant serum lamivudine concentration was 28 mcg/L (range <14 to 53 mcg/L). The average value was 5% of the IC50 for HIV.[20]

The infants of postpartum mothers taking nevirapine as part of a combination of antiretrovirals had undetectable serum nevirapine concentrations by HPLC/MS analysis. The lamivudine dosage the mothers were taking and times of infant plasma sampling were not stated in the abstract. Infant serum concentrations were measured at 6 (17 samples), 12 (17 samples), and 24 (13 samples) weeks of age at an average of 14 hours after the last maternal dose. Median infant serum lamivudine concentrations were 13, 10, and 5 mcg/L, respectively, which was 6% of the maternal serum concentration.[22]

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 lamivudine 150 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. The median infant dried blood spot lamivudine concentrations were 67 mcg/L at delivery, 32 mcg/L at week 2, 24 mcg/L at week 6, 20 mcg/L at week 14 and not measurable (<16 mcg/L) at week 24 postpartum.[24]

Breastfed infants of 66 mothers who were receiving lamivudine 150 mg twice daily as part of a combination antiretroviral regimen had a total of 64 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 medial infants' lamivudine plasma concentration was 18 mcg/L (range 7 to 35 mcg/L), which was a median of 2% (range 0 to 4%) of the maternal serum concentration.[25]

Twenty-four infants were breastfed either partially or exclusively by their mothers who had been taking lamivudine 150 mg twice daily for 53 to 182 days as part of a drug combination that included either abacavir and zidovudine or lopinavir, ritonavir, and zidovudine. Infant blood was collected at a median of 1 month postpartum at 11 to 18 hours after the last dose and a median of 1 hour (range 6 minutes to 35 hours) after the last breastfeeding. All of the infant plasma samples had undetectable (<7 mcg/L) plasma levels of lamivudine.[26]

Thirty nursing mothers were studied at 6, 12 or 24 weeks postpartum (10 at each time). Each mother was taking lamivudine 150 mg twice daily by mouth starting at delivery. Infant plasma samples were obtained before their mother's first dose and at 2, 4 and 6 hours after the mother's dose. Infants were allowed to breastfeed ad libitum during the study period. Lamivudine was detectable (10 mcg/L or greater) in 107 of the 115 infant plasma samples, at a median concentration of 180 mcg/L.[27]

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.[28]

Effects on Lactation and Breastmilk

Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients,[29][30] although this has been disputed.[31] One case series found an incidence of gynecomastia of 2.4 cases per person annually among men receiving highly active antiretroviral therapy; 51% of the affected patients were taking lamivudine. Gynecomastia was unilateral initially, but progressed to bilateral in 53% of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen.[32] The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

Alternate Drugs to Consider

(Hepatitis B) Interferon Alfa, Tenofovir, (HIV) Nelfinavir, Nevirapine, Zidovudine

References

1. World Health Organization. HIV and infant feeding: update. 2007. http://whqlibdoc.who.int/publications/2007/9789241595964_eng.pdf

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. McIntyre J, Dabis F, Mofenson LM et al. Rapid advice: Use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. World Health Organization. Geneva. 2009;1-23.

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. 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

8. Hirnschall G, Harries AD, Easterbrook PJ et al. The next generation of the World Health Organization's global antiretroviral guidance. J Int AIDS Soc. 2013;16:18757. PMID: 23819908

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. Bzowej NH. Optimal management of the hepatitis B patient who desires pregnancy or is pregnant. Curr Hepat Rep. 2012;11:82-9. PMID: 22707918

18. Ahn J, Salem SB, Cohen SM. Evaluation and management of hepatitis B in pregnancy: a survey of current practices. Gastroenterol Hepatol (N Y). 2010;6:570-8. PMID: 21088746

19. 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. PMID: 9780252

20. 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

21. 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

22. Corbett A, Kashuba A, Rezk N et al. Antiretroviral drug concentrations in breast milk and breastfeeding infants. 15th Annual Conference on Retroviruses and Opportunistic Infections (CROI) 2/3/2008 to 2/6/2008; Boston, MA. Poster # 648. 2008.

23. Rezk NL, White N, Bridges AS et al. 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;30:611-9. PMID: 18758393

24. 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

25. 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. PMID: 22910456

26. 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. PMID: 23183881

27. 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. PMID: 24464632

28. 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

29. Hutchinson J , Murphy M, Harries R, Skinner CJ. Galactorrhoea and hyperprolactinaemia associated with protease-inhibitors. Lancet. 2000;356:1003-4. PMID: 11041407

30. Orlando G, Brunetti L, Vacca M. Ritonavir and saquinavir directly stimulate anterior pituitary prolactin secretion, in vitro. Int J Immunopathol Pharmacol. 2002;15:65-8. PMID: 12593790

31. Montero A, Bottasso OA, Luraghi MR et al. Galactorrhoea, hyperprolactinaemia, and protease inhibitors. Lancet. 2001;357:473-4; author reply 475. PMID: 11273087

32. Garcia-Benayas T, Blanco F, Martin-Carbonero L et al. Gynecomastia in HIV-infected patients receiving antiretroviral therapy. AIDS Res Hum Retroviruses. 2003;19:739-41. PMID: 14585204

Lamivudine Identification

Substance Name

Lamivudine

CAS Registry Number

134678-17-4

Drug Class

Antiinfective Agents

Anti-HIV Agents

Antiviral Agents

Anti-Retroviral Agents

Reverse Transcriptase Inhibitors

Administrative Information

LactMed Record Number

646

Last Revision Date

20140204

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