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Drugs and Lactation Database (LactMed) [Internet].

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Tenofovir

Last Revision: December 21, 2020.

Estimated reading time: 10 minutes

CASRN: 147127-20-6

image 135078595 in the ncbi pubchem database

Drug Levels and Effects

Summary of Use during Lactation

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. Most published experience is with tenofovir disoproxil fumarate in HIV therapy and prophylaxis. Exposure of the breastfed infant to tenofovir is trivial in HIV-positive mothers and HIV-negative mothers treated for HIV prophylaxis or hepatitis B infection.[1] Some data indicate that tenofovir alfenamide produces lower milk levels of tenofovir than tenofovir disoproxil fumarate. Among HIV-positive mothers who have breastfed during tenofovir disoproxil fumarate therapy no infant adverse effects have occurred up to 2 years of age. Pre-exposure prophylaxis (PrEP) regimens containing tenofovir are acceptable for use in HIV-negative nursing mothers.[2] Maternal use of prophylactic vaginal tenofovir (investigational in the U.S.) also does not appear to present a risk to the breastfed infant.[3]

In hepatitis B, expert reviews of available data and most professional guidelines state that there is no justification for contraindicating the use of tenofovir during breastfeeding.[4-8] One guideline suggests discussing the lack of long-term safety data with the mother.[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.

Drug Levels

Tenofovir has very poor bioavailability and is available commercially as the more bioavailable tenofovir disoproxil fumarate and tenofovir alfenamide. Tenofovir disoproxil fumarate releases tenofovir in the bloodstream whereas tenofovir alafenamide enters cells before releasing tenofovir. Both are metabolized intracellularly to the active metabolite tenofovir diphosphate. The bioavailabilities of tenofovir and tenofovir diphosphate from breastmilk are not known, but presumed to be very low. Tenofovir (not a salt form) is also being investigated as a gel for vaginal use in prophylaxis.

Maternal Levels. Tenofovir disoproxil fumarate. Five exclusively breastfeeding mothers received oral tenofovir disoproxil fumarate 300 mg plus emtricitabine 200 mg and nevirapine 200 mg at the start of labor, then oral tenofovir tenofovir disoproxil fumarate 300 mg daily and emtricitabine 200 mg for 7 days postpartum. A total of 16 concurrent maternal blood and milk samples were collected on days 1, 2, 3, and 7 postpartum between 10 minutes and 21 hours after the mothers’ doses. Median peak and trough tenofovir concentrations in breastmilk were 14.1 mcg/L and 6.8 mcg/L, respectively. The authors estimated that an exclusively breastfed infant would receive about 0.03% of the proposed infant dose for tenofovir and achieve trivial infant serum concentrations that would likely have no adverse consequences.[9]

In a multicenter study in Malawi and Brazil, mothers were given a single dose of either 600 mg or 900 mg of tenofovir disoproxil fumarate during labor. Breastmilk samples were collected from mothers at various times postpartum. Tenofovir was detected (>2.5 mcg/L) in three-fourths of samples collected from 25 mothers during the first 2 days postpartum. Levels ranged from 6.3 to 17.8 mcg/L. At 4 to 6 days postpartum, only one milk sample of 21 had a detectable tenofovir level of 15.7 mcg/L.[10]

Women in Malawi received the option B+ regimen for prevention of mother-to-child transmission of HIV consisting of tenofovir disoproxil fumarate, lamivudine and efavirenz between 6 and 8 pm daily. The tenofovir disoproxil fumarate dose was not stated, but was presumably 300 mg daily. Milk samples collected in the morning from 33 women at month 1 postpartum had a median tenofovir concentration of 5 mcg/L (IQR 0 to 6.1 mcg/L). Milk samples collected in the morning from 47 women at month 12 postpartum had a median tenofovir concentration of 2.5 mcg/L (IQR 0 to 5.5 mcg/L).[11]

Fifty HIV-negative women who were nursing their infants were given pre-exposure prophylaxis daily with the combination of tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg by directly observed therapy for 10 days. On days 7 and 10 of therapy, peak milk samples were obtained 1 to 2 hours after a dose and trough samples were obtained 23 to 24 hours after the previous dose. The median peak milk tenofovir concentration was 3.2 mcg/L and the trough concentration was 3.3 mcg/L. These values represent an estimated daily dosage of 0.47 to 0.49 mcg/kg, which is less than 0.01% of the proposed infant therapeutic dosage.[12]

Tenofovir was measured in 6 HIV-positive nursing mothers after a 300 mg dose of tenofovir disoproxil fumarate during ongoing therapy. Tenofovir reached a peak breastmilk concentration of 5.9 mcg/L (range 5.5 to 8.0 mcg/L) at an average of 3 hours (range 1 to 7) hours after the dose.[13]

Forty-eight Nigerian and Ugandan women took 300 mg of tenofovir disoproxil fumarate once daily as part of a combination therapy for HIV. Expressed milk samples were taken before the dose and at several times in the 12 hours after the morning dose (n = 30) or at 12, 16 and 20 hours after a dose given the previous evening (n = 18). The median peak breastmilk concentration from dried breastmilk spots was 5.98 mcg/L (IQR 0 to 8.05 mcg/L) at a median of 4 hours after the dose (IQR 1 to 6 hours).[14]

Eleven mothers taking tenofovir disoproxil fumarate for chronic hepatitis B. The dosage of the drug and timing of milk samples were not specified in the abstract. Median milk levels were 6.69 mcg/L (IQR 4.88 to 7.03 mcg/L).[15]

A meta-analysis of 4 previous studies[9,11,12,14] calculated that breastfed infants would receive ony 0.03% of the recommend dose of tenofovir.[1]

Tenofovir alfenamide. Fifty-two pregnant women with hepatitis B were given either tenofovir alfenamide (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 alfenamide 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.[16]

Tenofovir gel. Seventeen women received 40 mg vaginal doses of 1% tenofovir gel daily for 6 days, with the first and last doses applied in clinic under observation. Two women reported using four doses at home, eleven women reported five doses, and two reported six doses. Breastmilk samples were collected before and 2, 4, and 6 hours after the first and last doses. Only 25% of milk samples contained detectable (>1 mcg/L) tenofovir post-dose on day 0, 12.5% at pre-dose on day 6, and 37.5% post-dose on day 6. Breastmilk tenofovir concentrations ranged from 0 to 0.75 mcg/L on day 0 and from 0 to 1.6 mcg/L on day 6.[3]

Infant Levels. Tenofovir disoproxil fumarate. Five infants were exclusively breastfed by 4 mothers who took tenofovir 245 mg (presumably 300 mg of tenofovir disoproxil fumarate) daily. At an average of 1.8 months of age, infant serum tenofovir concentrations were measured. Tenofovir was undetectable (<0.005 mg/L) in the serum of 4 of the infants, and 0.0055 mg/L in the serum of one infant.[17]

In a study of women and their infants receiving antiretroviral therapy for HIV infection, mothers who received a tenofovir disoproxil fumarate-containing regimen were compared to those who did not. The risk of infant death was reduced by 57% among infants who were breastfed and exposed to tenofovir compared to those who were not breasted. No alterations in growth and development were seen among breastfed infants in 2 years of follow-up.[18]

Blood samples were taken from 25 breastfed infants of mothers who were receiving option B+ regimen for prevention of mother-to-child transmission of HIV consisting of tenofovir disoproxil fumarate, lamivudine and efavirenz between 6 and 8 pm daily. The tenofovir dose was not stated, but was presumably 300 mg daily. The median morning infant plasma concentration of tenofovir at 6 months of age was 24 mcg/L (IQR 0 to 51.6 mcg/L). The median morning infant plasma concentration of tenofovir at 12 months of age was 0 mcg/L.[11]

Fifty HIV-negative women who were nursing their infants were given pre-exposure prophylaxis daily with the combination of tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg by directly observed therapy for 10 days. A single infant blood sample was obtained after the mother’s 7th dose. Of 49 infant blood samples collected, 46 had an undetectable (<0.31 mcg/L) concentration of tenofovir. The 3 with detectable levels contained 0.9, 0.9 and 17.4 mcg/L of tenofovir.[12]

Tenofovir disoproxil fumarate 300 mg daily was given to 6 HIV-positive nursing mothers. None of the breastfed infants had detectable tenofovir serum levels.[13]

Forty-eight Nigerian and Ugandan women took 300 mg of tenofovir disoproxil fumarate once

daily either in the morning or evening as part of a combination therapy for HIV. Their exclusively breastfed infants were fed on demand and had blood samples taken at 2 and 8 hours after the dose. Dried blood spots were analyzed and no infants had a measurable (>4.2 mcg/L) tenofovir blood concentration.[14]

Eleven infants breastfed (extent not stated) of mothers taking tenofovir disoproxil fumarate for chronic hepatitis B had undetectable (<4 mcg/L) tenofovir in their plasma. Timing of the samples was not stated.[15]

Tenofovir gel. Seventeen women received 40 mg vaginal doses of 1% tenofovir gel daily for 6 days, with the first and last doses applied in clinic under observation. Two women reported four doses at home, eleven women reported inserting five doses, and two reported six doses. Infant blood was collected 6 hours after the maternal dose, which ranged from 1 to 4 hours after breastfeeding. Six infants (37.5%) had detectable tenofovir levels after the maternal dose on day 0, and 12 (75%) of infants post-dose on day 6. In infants with detectable tenofovir serum concentrations, day 6 levels were higher (median 2.4 mcg/L) than on day 0 concentrations (median 0). No difference was seen in the anti-HIV activity of breastmilk between day 0 and day 6.[3]

Effects in Breastfed Infants

Two newborn infants whose mothers were treated with tenofovir 245 mg (presumably 300 mg of tenofovir disoproxil fumarate) daily were exclusively breastfed for 3 months. At 4 months of age, neither showed any adverse outcomes on standard developmental parameters.[17]

Five women with hepatitis B infection were treated with tenofovir disoproxil fumarate 300 mg daily beginning in the third trimester of pregnancy and continuing postpartum. Although instructed not to breastfeed, 5 mothers breastfed (extent not stated) their newborn infants. No short-term adverse reactions were seen and the infants’ HBsAg was negative between 28 and 36 weeks of age.[19]

Fourteen mothers were treated with tenofovir disoproxil fumarate (dosage unspecified) during pregnancy (12 beginning in the first trimester) for hepatitis B. Three of the mothers breastfed while taking tenofovir. No adverse outcomes were noted in their breastfed infants up to 1 year of age.[20]

In a study of 50 infants breastfed by HIV-negative women who were given pre-exposure prophylaxis daily with the combination of tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg by directly observed therapy for 10 days, 2 infants reportedly had diarrhea lasting 2 to 3 days. No other side effects were reported.[12]

A study of 136 breastfed infants of mothers who took tenofovir disoproxil fumarate, efavirenz and lamivudine during pregnancy and postpartum (Option B+) in Malawi measured bone markers at 1, 6 and 12 months of age. Markers included bone-specific alkaline phosphatase and C-terminal telopeptide of type I collagen. Although tenofovir is known to affect bone density and bone mineral density in adults, no effects were seen on infants’ bone markers in the study.[21]

In a long-term study of tenofovir disoproxil fumarate for chronic hepatitis B, 3 women reportedly breastfed their infants (extent not stated). None of the infants had any adverse effects up to 1 year of age.[22]

A prospective cohort study compared the growth and development of infants of HIV-negative mothers and infants of HIV-positive mothers taking tenofovir disoproxil fumarate and efavirenz as part of Option B+ HIV treatment. Infants were followed up to 12 months of age. No differences in the groups was found in any growth parameters.[23]

A study of pregnant women with hepatitis B infection in China enrolled 143 women. Tenofovir disoproxil fumarate 300 mg daily was given starting at 22 to 33 weeks of pregnancy and continued postpartum. Thirty-one mothers breastfed (extent not stated) their infants who received standard hepatitis B prophylaxis. At 28 weeks postpartum, infant physical and neurologic development was within national standards and none had developed hepatitis B infection. Mild side effects of cough and fever were reported in >5% of infants. Less frequent reactions included skin rash, diarrhea, vomiting, jaundice and pneumonia. All adverse effects were judged not to be related to the drug by the authors.[24]

In a study of 17 nursing mothers who receive 40 mg of 1% vaginal tenofovir gel daily for 6 days, 4 of 17 infants had one or more adverse effects. There were a total of 8 adverse reactions. Seven were mild, and one had diarrhea that was thought to be related to tenofovir exposure.[3]

A study in Malawi compared the infants of HIV+ mothers taking tenofovir disoproxil fumarate and efavirenz (n = 260) to infants of mothers who were HIV negative (n = 125). Infants were followed for growth and development for up to 18 months at which time there were 169 mother-infant pairs in the treatment group and 54 in the HIV-negative group. No difference was found in the growth and development of the breastfed infants of treated women compared to the infants of untreated mothers.[25]

Effects on Lactation and Breastmilk

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

Alternate Drugs to Consider

(Hepatitis B) Interferon Alfa, Lamivudine

References

1.
Bierhoff M, Smolders EJ, Tarning J, et al. Pharmacokinetics of oral tenofovir disoproxil fumarate in pregnancy and lactation: A systematic review. Antivir Ther. 2019;24:529–40. [PubMed: 31868655]
2.
Hodges-Mameletzis I, Fonner VA, Dalal S, et al. Pre-exposure prophylaxis for HIV prevention in women: Current status and future directions. Drugs. 2019;79:1263–76. [PubMed: 31309457]
3.
Noguchi LM, Montgomery ET, Biggio JR, et al. Detectable tenofovir levels in breastfeeding infants of mothers exposed to topical tenofovir. Antimicrob Agents Chemother. 2016;60:5616–9. [PMC free article: PMC4997886] [PubMed: 27401570]
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Ehrhardt S, Xie C, Guo N, et al. Breastfeeding while taking lamivudine or tenofovir disoproxil fumarate: A review of the evidence. Clin Infect Dis. 2015;60:275–8. [PubMed: 25313254]
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Mofenson LM, Baggaley RC, Mameletzis I. Tenofovir disoproxil fumarate safety for women and their infants during pregnancy and breastfeeding. Aids. 2017;31:213–32. [PubMed: 27831952]
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Hu X, Wang L, Xu F. Guides concerning tenofovir exposure via breastfeeding: A comparison of drug dosages by developmental stage. Int J Infect Dis. 2019;87:8–12. [PubMed: 31357055]
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Terrault NA, Bzowej NH, Chang KM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63:261–83. [PMC free article: PMC5987259] [PubMed: 26566064]
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9.
Benaboud S, Pruvost A, Coffie PA, et al. Concentrations of tenofovir and emtricitabine in breast milk of HIV-1-infected women in Abidjan, Cote d'Ivoire, in the ANRS 12109 TEMAA Study, step 2. Antimicrob Agents Chemother. 2011;55:1315–7. [PMC free article: PMC3067089] [PubMed: 21173182]
10.
Mirochnick M, Taha T, Kreitchmann R, et al. Pharmacokinetics and safety of tenofovir in HIV-infected women during labor and their infants during the first week of life. J Acquir Immune Defic Syndr. 2014;65:33–41. [PMC free article: PMC3912736] [PubMed: 23979002]
11.
Palombi L, Pirillo MF, Marchei E, et al. Concentrations of tenofovir, lamivudine and efavirenz in mothers and children enrolled under the Option B-Plus approach in Malawi. J Antimicrob Chemother. 2016;71:1027–30. [PubMed: 26679247]
12.
Mugwanya KK, Hendrix CW, Mugo NR, et al. Pre-exposure prophylaxis use by breastfeeding HIV-uninfected women: A prospective short-term study of antiretroviral excretion in breast milk and infant absorption. PLoS Med. 2016;13:e1002132. [PMC free article: PMC5038971] [PubMed: 27676257]
13.
Waitt C, Diliiy Penchala S, Olagunju A, et al. Development, validation and clinical application of a method for the simultaneous quantification of lamivudine, emtricitabine and tenofovir in dried blood and dried breast milk spots using LC–MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2017;1060:300–7. [PMC free article: PMC5588985] [PubMed: 28651173]
14.
Waitt C, Olagunju A, Nakalema S, et al. Plasma and breast milk pharmacokinetics of emtricitabine, tenofovir and lamivudine using dried blood and breast milk spots in nursing African mother-infant pairs. J Antimicrob Chemother. 2018;73:1013–9. [PMC free article: PMC5890695] [PubMed: 29309634]
15.
Erturk US, Mete B, Ozaras R, et al. The determination of tenofovir level in breast milk of nursing mothers under tenofovir therapy. Hepatology 2018;68 (Suppl 1):256A-7A. Abstract. doi:10.1002/hep.30257. [CrossRef]
16.
Bojun L, Ye G, Yan W, et al. Tenofovir (TFV) or tenofovir alafenamide (TAF) concentration in breast milk and infants' cord blood, with tenofovir disoproxil fumarate (TDF) or TAF treatment in pregnancy. Hepatol Int 2020;14 (Suppl 1):S78. Abstract. doi:10.1007/s12072-020-10030-4. [CrossRef]
17.
Gouraud A, Millaret A, Bernard N, et al. Tenofovir exposure through breast feeding: Serum concentrations in neonates and clinical follow-up. Fundam Clin Pharmacol 2012;26 (Suppl 1):9. Abstract. doi:10.1111/j.1472-8206.2012.01032.x. [CrossRef]
18.
Gibb DM, Kizito H, Russell EC, et al. Pregnancy and infant outcomes among HIV-infected women taking long-term ART with and without tenofovir in the DART trial. PLoS Med. 2012;9:e1001217. [PMC free article: PMC3352861] [PubMed: 22615543]
19.
Pan CQ, Mi LJ, Bunchorntavakul C, et al. Tenofovir disoproxil fumarate for prevention of vertical transmission of hepatitis B virus infection by highly viremic pregnant women: A case series. Dig Dis Sci. 2012;57:2423–9. [PMC free article: PMC7469074] [PubMed: 22543886]
20.
Ganne-Carrie N, Causse X, Zarski JP, et al. Efficacy and safety results of tenofovir DF (TDF) treatment from the first trimester in HBV pregnant women in real-life clinical practice. Hepatology. 2013;58 Suppl 1:664A–5A. [CrossRef]
21.
Floridia M, Liotta G, Andreotti M, et al. Levels of bone markers in a population of infants exposed in utero and during breastfeeding to tenofovir within an Option B+ programme in Malawi. J Antimicrob Chemother. 2016;71:3206–11. [PubMed: 27494909]
22.
Marcellin P, Zoulim F, Hezode C, et al. Effectiveness and safety of tenofovir disoproxil fumarate in chronic hepatitis B: A 3-year, prospective, real-world study in France. Dig Dis Sci. 2016;61:3072–83. [PMC free article: PMC5020114] [PubMed: 26821154]
23.
Kapito-Tembo AP, Wesevich A, Bauleni A, et al. Growth in infants exposed to EFV and TDF through breastmilk: Malawi PMTCT option B+. Top Antiviral Med. 2017;25(1) Suppl 1:333s–4s. Abstract.
24.
Wang M, Bian Q, Zhu Y, et al. Real-world study of tenofovir disoproxil fumarate to prevent hepatitis B transmission in mothers with high viral load. Aliment Pharmacol Ther. 2019;49:211–7. [PubMed: 30506691]
25.
Kapito-Tembo AP, Bauleni A, Wesevich A, et al. Growth and neurodevelopment outcomes in HIV, tenofovir and efavirenz exposed breastfed infants in PMTCT Option B+ program in Malawi. J Acquir Immune Defic Syndr. 2021;86:81–90. [PubMed: 33027153]

Substance Identification

Substance Name

Tenofovir

CAS Registry Number

147127-20-6

Drug Class

Breast Feeding

Lactation

Anti-Infective Agents

Anti-HIV Agents

Antiviral Agents

Anti-Retroviral Agents

Reverse Transcriptase Inhibitors

Disclaimer: Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.

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