Lopinavir use while Breastfeeding

Drugs containing Lopinavir: Kaletra, AccessPak for HIV PEP Expanded with Kaletra

Lopinavir 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 with triple antiretroviral therapy 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] Lopinavir has been successfully used as part of a regimen that decreases mother-to-child transmission of HIV.[6][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] 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. One study measured lopinavir in breastmilk samples from nursing mothers who had been randomized to receive the drug as part of a clinical trial to evaluate maternal to child transmission of HIV infection. The dosages, dosage regimens and time of breastmilk sample collection times were not reported. Lopinavir was not detected in any of 60 breastmilk samples.[13]

Nine mothers who were receiving lopinavir 400 mg plus ritonavir 100 mg twice daily as part of a combination antiretroviral regimen provided a total of 23 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 lopinavir concentration was 1834 mcg/L (range 557 to 3950 mcg/L).[14]

Fifteen women had been taking lopinavir 400 mg twice daily for 53 to 182 days as part of a drug combination that included ritonavir, zidovudine, and lamivudine. Breastmilk samples were collected at just before a dose at a median of 1 month postpartum. Whole breastmilk levels contained a median of 0.06 mg/L of lopinavir, which was a median of 0.7% of maternal blood levels.[15]

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 seventeen of the 121 breastmilk samples contained detectable quantities (10 mcg/L or greater) of lopinavir, with a median breastmilk concentration of 1.43 mg/L over the 6 hours.[16]

Infant Levels. Breastfed infants of 9 mothers who were receiving lopinavir 400 mg plus ritonavir 100 mg twice daily as part of a combination antiretroviral regimen had a total of 6 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' median lopinavir plasma concentrations was 105 mcg/L (range 12 to 518 mcg/L), which was a median of 8% (range 0 to 16%) of the maternal serum concentration.[14]

Five infants were breastfed either partially or exclusively by their mothers who had been taking lopinavir 400 mg twice daily for 53 to 182 days as part of a drug combination that included ritonavir, zidovudine, and lamivudine. Infant blood was collected at a median of 1 month postpartum at 11 to 16 hours after the last dose and a median of 1 hour (range 6 minutes to 35 hours) after the last breastfeeding. Two of five infants had measurable lopinavir plasma levels of <1 mg/L.[15]

Lopinavir was measured in 117 breastfed (90% exclusive) infants whose mothers were taking lopinavir plus ritonavir for HIV infection during pregnancy and postpartum. At 8 weeks postpartum, only 2% had detectable lopinavir in their plasma at a mean concentration of 0.17 mg/L. At 12 weeks postpartum, none of the infants had detectable lopinavir in their plasma, and 96% of infants had detectable lopinavir in their hair samples at a mean concentration of 5.1 ng/mg of hair (range 0.13 to 15.8 ng/mg). The authors interpreted the results to mean that infants receive negligible exposure to lopinavir during breastfeeding.[17]

Thirty nursing mothers were studied at 6, 12 or 24 weeks postpartum (10 at each time). Each mother was taking lopinavir 400 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. Lopinavir was undetectable (<10 mcg/L) in all of the 115 infant plasma samples.[16]

Effects in Breastfed Infants

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.[18]

Possible Effects on Lactation

Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen.[19][20][21] Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients,[22][23] although this has been disputed.[24] 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

Lamivudine, 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. 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

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. 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

14. 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

15. 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

16. 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

17. Gandhi M, Mwesigwa J, Aweeka F et al. Hair and plasma data show that lopinavir, ritonavir, and efavirenz all transfer from mother to infant in utero, but only efavirenz transfers via breastfeeding. J Acquir Immune Defic Syndr. 2013;63:578-84. PMID: 24135775

18. 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

19. 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

20. Pantanowitz L, Evans D, Gross PD, Dezube BJ. HIV-related gynecomastia. Breast J. 2003;9:131-2. PMID: 12603389

21. Evans DL, Pantanowitz L, Dezube BJ, Aboulafia DM. Breast enlargement in 13 men who were seropositive for human immunodeficiency virus. Clin Infect Dis. 2002;35:1113-9. PMID: 12384846

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

23. 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

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

Lopinavir Identification

Substance Name

Lopinavir

CAS Registry Number

192725-17-0

Drug Class

  • Antiinfective Agents
  • Anti-HIV Agents
  • Antiviral Agents
  • Anti-Retroviral Agents
  • HIV Protease Inhibitors

Administrative Information

LactMed Record Number

659

Information from the National Library of Medicine's LactMed Database.

Last Revision Date

2014-02-04

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