Efavirenz use while Breastfeeding
Drugs containing Efavirenz: Atripla, Sustiva
Efavirenz 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. Published experience with efavirenz during breastfeeding is limited. In countries in which no acceptable, feasible, sustainable and safe replacement feeding is available, World Health Organization guidelines recommend that all women with an HIV infection who are pregnant or breastfeeding should be maintained on antiretroviral therapy for at least the duration of risk for mother-to-child transmission. Mothers should exclusively breastfeed their infants for the first 6 months of life; breastfeeding with complementary feeding should continue through 12 months of life. The first choice regimen for nursing mothers is tenofovir, efavirenz and either lamivudine or emtricitabine. If these drugs are unavailable, alternative regimens include: 1) zidovudine, lamivudine and efavirenz; 2) zidovudine, lamivudine and nevirapine; or 3) tenofovir, nevirapine and either lamivudine or emtricitabine. Exclusively breastfed infants should also receive 6 weeks of prophylaxis with nevirapine.
Maternal Levels. Thirteen mothers who averaged 15.8 weeks (range 6 to 25 weeks) postpartum were treated with efavirenz 600 mg daily plus zidovudine and lamivudine. Milk and plasma samples were taken 3 to 4 hours after the last dose. Skimmed breastmilk efavirenz concentrations averaged 3.5 mg/L (range 1.3 to 7.4 mg/L).
Fifty-one HIV-positive nursing mothers receiving efavirenz 600 mg once daily as part of their antiretroviral regimens. Breastmilk was obtained 12 to 14 hours after a dose and dried. The median breastmilk concentration was 2280 mcg/L (interquartile range 1180 to 3270 mcg/L). The maternal CYP2B6 rs3745274 genotype affected the breastmilk levels with the TT genotype having statistically significantly higher milk levels than either the GG or GT genotypes. The authors estimated a median infant dose of 340 mcg/kg daily.
Five mothers who were taking oral efavirenz 600 mg daily as part of an antiretroviral regimen collected mid-feed milk samples at 0.5, 1, 2, 4, 8, 12 and 24 hours after an evening dose at an average of 146 days after delivery. The average peak level of 4.5 mg/L occurred at about 4 hours after the dose and the average trough milk value was 2.5 mg/L.
Infant Levels. Thirteen mothers who averaged 15.8 weeks (range 6 to 25 weeks) postpartum were treated with efavirenz 600 mg daily plus lamivudine and zidovudine (n = 12) or stavudine (n = 1). Plasma samples were taken from their breastfed infants 3 to 4 hours after the last dose. Infant plasma concentrations averaged 0.86 mg/L (range 0.4 to 1.5 mg/L). Infant plasma concentrations averaged 13% of maternal plasma concentrations, but there was no statistically significant correlation between them. Average plasma levels were slightly below the plasma level considered effective for suppression of HIV in adults.
Efavirenz was measured in 117 breastfed (90% exclusive) infants whose mothers were taking efavirenz for HIV infection during pregnancy and postpartum. All infants had detectable efavirenz in their plasma samples at 0 (mean 1.7 mg/L), 8 (mean 0.3 mg/L) and 12 (mean 0.3 mg/L) weeks postpartum. All infants had detectable efavirenz in their hair samples at 12 weeks postpartum at a mean concentration of 1.9 mcg/gram of hair (range 0.34 to 11 mcg/gram). The authors interpreted the results to mean that infants receive substantial exposure to efavirenz during breastfeeding.
Fifty-one HIV-positive nursing mothers receiving efavirenz 600 mg once daily as part of their antiretroviral regimens. Blood samples were obtained 12 to 14 hours after a dose from their exclusively breastfed infants. Dried blood spots were analyzed for efavirenz concentrations. The median infant plasma concentration was 178 mcg/L (interquartile range 88 to 340 mcg/L). The maternal CYP2B6 rs3745274 genotype affected the infant plasma levels with the TT and GT genotypes having statistically significantly higher infant plasma levels than the GG genotype.
Effects in Breastfed Infants
Thirteen mothers nursed their infants while they were taking efavirenz 600 mg daily, lamivudine 150 mg and zidovudine 300 mg daily (n = 12) or stavudine 60 mg daily (n = 1) . No adverse reactions were reported in the infants after 6 months of breastfeeding, none had developed HIV infection and all were developing normally.
An unblinded study in Uganda compared the outcomes of breastfed infants and their HIV-positive mothers who were randomized to receive antiretrovial therapy that was based either on efavirenz 600 mg once daily or lopinavir 400 mg plus ritonavir 100 mg twice daily during breastfeeding. All mothers received lamivudine 150 mg, zidovudine 300 mg twice daily and trimethoprim-sulfamethoxazole once daily. All infants received prophylaxis with either zidovudine for 1 week or nevirapine for 6 weeks, plus trimethoprim-sulfamethoxazole from 6 weeks of age to 6 weeks after weaning. Almost all of the infants were exclusively breastfed until 6 months of age and about 73% were partially breastfed until 12 months of age. There was no statistical difference in hospitalizations or adverse events including anemia, neutropenia or deaths among infants in the two groups.
Effects on Lactation and Breastmilk
Gynecomastia has been reported among men and at least one woman receiving efavirenz therapy. Efavirenz appears to be much more likely to cause gynecomastia than other antiretroviral agents. Gynecomastia is unilateral initially, but can progress to bilateral. Spontaneous resolution usually occurred within one year, even with continuation of the regimen. 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.
1. World Health Organization. HIV and infant feeding: update. 2007. http://whqlibdoc.who.int/publications/2007/9789241595964_eng.pdf
2. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Geneva: World Health Organization. 2013. http://www.who.int/hiv/pub/guidelines/arv2013/en
3. Schneider S, Peltier A, Gras A et al. Efavirenz in human breast milk, mothers', and newborns' plasma. J Acquir Immune Defic Syndr. 2008;48:450-4. PMID: 18614925
4. Olagunju A, Siccardi M, Okafor O et al. Pharmacogenetics of efavirenz excretion into human breast milk and transfer to breastfed infants. Top Antivir Med. 2014;22 (e-1):464. Abstract. https://www.iasusa.org/tam/april-2014
5. Olagunju A, Bolaji OO, Amara A et al. Development, validation and clinical application of a novel method for the quantification of efavirenz in dried breast milk spots using LC-MS/MS. J Antimicrob Chemother. 2015;70:555-61. PMID: 25326089
6. 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
7. Cohan D, Natureeba P, Koss CA et al. Efficacy and safety of lopinavir/ritonavir versus efavirenz-based antiretroviral therapy in HIV-infected pregnant Ugandan women. AIDS. 2015;29:183-91. PMID: 25426808
8. Jover F, Cuadrado JM, Roig P et al. Efavirenz-associated gynecomastia: report of five cases and review of the literature. Breast J. 2004;10:244-6. PMID: 15125753
9. Rahim S, Ortiz O, Maslow M, Holzman R. A case-control study of gynecomastia in HIV-1-infected patients receiving HAART. AIDS Read. 2004;14:23-4, 29-32, 35-40. PMID: 14959701
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