Is Tenofovir Alafenamide safe while breastfeeding?

Summary of use during breastfeeding

Tenofovir is available in the U.S. in two forms, tenofovir disoproxil fumarate and tenofovir alafenamide. Both release tenofovir, but tenofovir disoproxil fumarate releases tenofovir in the bloodstream whereas tenofovir alafenamide enters cells before releasing tenofovir. Exposure of the breastfed infant to tenofovir is trivial in HIV-positive mothers and in HIV-negative mothers treated for HIV prophylaxis or hepatitis B infection. Among HIV-positive mothers who have breastfed during tenofovir disoproxil fumarate therapy, no infant adverse effects have occurred up to 2 years of age. Tenofovir alafenamide results in even lower milk levels and infant dosages than tenofovir disoproxil fumarate. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.[1,2] Pre-exposure prophylaxis (PrEP) regimens containing tenofovir are acceptable for use in HIV-negative nursing mothers.[3]

In hepatitis B, expert reviews of available data and professional guidelines state that there is no justification for contraindicating the use of tenofovir during breastfeeding.[4-7] No differences exist in infection rates between breastfed and formula-fed infants born to hepatitis B-infected women, as long as the infant receives hepatitis B immune globulin and hepatitis B vaccine at birth.

Effects on the breastfed infant

Numerous studies have demonstrated the safety of tenofovir disoproxil fumarate for breastfed infants.[14-25] See the LactMed record on tenofovir disoproxil fumarate for more information.

An open-label, controlled, multicenter phase 3 trial women who were confirmed HIV-positive were randomized to receive one of 3 regimens: dolutegravir, emtricitabine, and tenofovir alafenamide (n = 208); dolutegravir, emtricitabine, and tenofovir disoproxil fumarate (n = 202); or efavirenz, emtricitabine, and tenofovir disoproxil fumarate (n = 207). The regimens were started at 14 to 28 weeks of pregnancy and continued postpartum. Of the 617 liveborn infants, 99% were breastfeeding at time of last infant HIV test, which was as late as 50 weeks of age. The mean infant duration on the study was 47.6 weeks of age. Infants who had any clinical or laboratory adverse event of grade 3 or higher ranged from 25 to 31%, but was not statistically significant between groups. Dolutegravir-containing regimens resulted in lower rates of virological failure, HIV drug resistance, and infant mortality up to 50 weeks postpartum compared with efavirenz, emtricitabine, and tenofovir disoproxil fumarate.[26]

Effects on milk supply

No information is available on tenofovir alafenamide, but some studies on tenofovir disoproxil fumarate found that mothers breastfed at lower rates when taking antiviral combination therapies that included tenofovir disoproxil fumarate. See tenofovir disoproxil fumarate.

Levels in milk

Tenofovir has poor bioavailability. The more bioavailable tenofovir alafenamide enters cells before releasing tenofovir. Tenofovir is metabolized intracellularly to the active metabolite tenofovir diphosphate. The bioavailability of tenofovir and tenofovir diphosphate from breastmilk are not known, but presumed to be extremely low.

Maternal Levels. Fifty-two pregnant women with hepatitis B were given either tenofovir alafenamide (n = 26) or tenofovir disoproxil fumarate (n = 26) from 28 weeks of pregnancy to delivery to prevent mother-to-child transmission. Dosages were not stated. Milk samples obtained 6 hours after delivery from the women taking tenofovir alafenamide contained no detectable (<0.5 mcg/L) tenofovir. Milk samples obtained 6 hours after delivery from the women taking tenofovir disoproxil fumarate contained a median of 12.83 (IQR 7.46-29.46) mcg/L of tenofovir.[8]

Thirty-six lactating women with hepatitis B were given tenofovir alafenamide 25 mg once a day with food and another 36 were given 300 mg of tenofovir disoproxil fumarate once a day. Breast milk samples from both groups were collected at 48 hours postpartum, but the time with respect to doses was not reported. Tenofovir measured by mass spectrometry was undetectable (lower limit of assay not specified) in breastmilk in all of the women given tenofovir alafenamide, while only 4 of the women who received tenofovir disoproxil fumarate had undetectable tenofovir levels. The average milk tenofovir levels in the remaining 32 mothers was 19.2 mcg/L.[9]

Women with hepatitis B received either tenofovir alafenamide 25 mg (n = 12) or tenofovir disoproxil fumarate 300 mg (n = 4) daily from 24 to 28 weeks of gestation until the 4th week postpartum. Milk samples were collected before the dose and 1, 2, 4, 6, 8 hours after the dose on the 3rd day postpartum. Trough and 1-hour post-dose milk samples were also collected on days 15 and 30 postpartum in mothers who received tenofovir alafenamide. Mothers who received tenofovir alafenamide had an average peak milk concentration of 101 mcg/L at a median peak time of 4 hours after the dose. Trough and 1-hour milk tenofovir levels decreased by about 45% at 15 and 30 days postpartum in the tenofovir alafenamide group.[10] Using the highest milk level on day 3 postpartum, infants would receive a maximum of 15 mcg/kg daily; the average level would be considerably lower.

Eight women with chronic hepatitis B took oral tenofovir alafenamide 25 mg daily. Milk samples were taken pre-dose, and 0.5 hours, 1 to 1.5 hours, 2,5 to 3.5 hours, 5 to 6 hours, 8 hours and 24 hours after a dose and analyzed for tenofovir alafenamide and tenofovir. For tenofovir alafenamide, the median steady-state peak breastmilk level was 1.7 mcg/L (IRQ 0.22 to 5.65 mcg/L) at a median of 0.5 hours after a dose. The median half-life in milk was 0.5 hours and by 6 to 8 hours milk levels were undetectable (<0.05 mcg/L) in 7 of the 8 women. The median breastmilk tenofovir alafenamide concentration was 0.125 mcg/L (range 0.06 to 11.6 mcg/L), which resulted in an estimated infant dose of 18.75 ng/kg daily and a relative infant dose of 0.005% of the maternal weight-adjusted dose. For tenofovir, the median steady-state peak breastmilk level was 53.1 mcg/L (IRQ 29.6 to 57.8 mcg/L) at a median of 5.5 hours after a dose. The median half-life of tenofovir in milk was 27.7 hours. The mean tenofovir concentration in milk was 33.3 mcg/L in breastmilk, which would result in an estimated infant dosage of about 5 mcg/kg daily.[11]

Three mothers taking tenofovir alafenamide 25 mg once daily provided 5 milk samples at a median of 8.5 hours after a dose. The median drug concentration in milk was 45 mcg/L, which resulted in an estimated infant dosage of 7 mcg/kg daily.[12]

Women in a 9-country clinical trial were randomly assigned to receive either dolutegravir 50 mg once daily with a fixed-dose combination of emtricitabine 200 mcg plus tenofovir alafenamide 25 mg once daily, or dolutegravir 50 mg once daily with a fixed-dose combination of emtricitabine 200 mg plus tenofovir disoproxil fumarate 300 mg once daily. One milk sample was obtained at 6 weeks postpartum (n = 98). Tenofovir was below the limit of quantification in nearly all samples. The median RID was 0.0%.[13]

Infant Levels. Eight mothers with chronic hepatitis B who were predominantly breastfeeding took oral tenofovir alafenamide 25 mg daily. Infant urine was collected from the time of the dose to 8 hours after the dose. Tenofovir was detectable in 3 of 7 infant urine samples with the remaining 4 samples having undetectable (<10 mcg/L) levels. The three detectable infant urine concentrations of tenofovir were 12, 24 and 25 mcg/L.[11]

An infant was breastfed by a mother taking tenofovir alafenamide 25 mg daily, although the extent of breastfeeding was not sated. The infant’s serum tenofovir concentration taken19 hours after maternal drug intake at 1 month of age was undetectable.[12]

Women in a 9-country clinical trial were randomly assigned to receive either dolutegravir 50 mg once daily with a fixed-dose combination of emtricitabine 200 mcg plus tenofovir alafenamide 25 mg once daily, or dolutegravir 50 mg once daily with a fixed-dose combination of emtricitabine 200 mg plus tenofovir disoproxil fumarate 300 mg once daily. One infant blood sample was obtained at 6 weeks postpartum (n = 180). The concentration in infant plasma was below the limit of quantification in nearly all infants.[13]

Alternatives LactMed lists

• Lamivudine