Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors

Tenofovir Alafenamide (Vemlidy, TAF)

Tenofovir alafenamide (TAF) is an orally bioavailable form of tenofovir (TFV). TAF is available as a 25 mg single drug tablet for use in hepatitis B and at a dose of 25 mg in several fixed-dose combination tablets without cobicistat for use in HIV. FDC tablets containing 10 mg TAF boosted with cobicistat are also available, but these regimens are not recommended in pregnancy and are therefore not reviewed in this section. For information about tenofovir disoproxil fumarate (TDF), see the TDF section.

Animal Studies

Carcinogenicity

TAF and TDF are both prodrugs of TFV. TAF is converted rapidly to TFV, and TFV exposure in rats and mice is lower after TAF administration than TDF administration. Carcinogenicity studies for TFV were performed with TDF, but given the lower TFV exposure with TAF, the associated carcinogenicity is assumed to be commensurate or lower. Long-term oral carcinogenicity studies of TFV in mice and rats were carried out at TFV exposures that were 167 times (in mice) and 55 times (in rats) the TFV exposures observed in humans who received the recommended doses of TAF; in female mice, liver adenomas were increased.^1,2

Reproduction/Fertility

Reproduction studies have been performed at TAF exposures that in rats were similar to and in rabbits were 53 times higher than the exposure seen in humans who received the recommended dose. These studies revealed no evidence of impaired fertility or mating performance associated with TAF administration.^1,2

Teratogenicity/Adverse Pregnancy Outcomes

No effects on early embryonic development were seen when TAF was administered to male or female rats at doses that produced exposures that were 62 times the exposure seen in humans who received the therapeutic dose.^1,2

Placental and Breast Milk Passage

Rat studies demonstrated secretion of TFV in breast milk after administration of TDF, but whether TAF is present in animal milk is not known.¹

Human Studies in Pregnancy

Pharmacokinetics

TAF pharmacokinetics (PK) do not appear to be significantly affected by pregnancy, and TAF exposures appear adequate in the second and third trimesters. TAF PK were evaluated as part of International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1026s in 27 women who were taking TAF 25 mg.³ Antepartum TAF exposures were 33% to 43% lower compared to postpartum, but comparable with exposures in nonpregnant adults. Another report described TAF PK in 17 women who were taking TAF 25 mg boosted with either cobicistat or ritonavir; plasma exposures for TAF during pregnancy were similar to those seen postpartum.⁴

Placental and Breast Milk Passage

Very limited data exist on the TAF levels in placental and breast milk. One study found that TAF was below the assay limit of quantification (<3.9 ng/mL) in 43 of 44 cord blood samples tested and all infant washout samples; maternal plasma TAF concentrations at delivery were measurable in only 4 of the 45 paired samples.³ No data are available on the breast milk passage of TAF in humans.

Teratogenicity/Adverse Pregnancy Outcomes

The data from the IMPAACT 2010, a randomized trial of dolutegravir (DTG) containing ART regimens in pregnancy, found lower composite adverse outcomes in the group receiving DTG+FTC/TAF (TAF with emtricitabine [FTC] and DTG) than in the group receiving DTG+FTC/TDF (TDF with FTC and DTG) or ]+FTC/TDF (TDF with EFV and FTC), although it is noteworthy that the DTG+FTC/TAF arm of the trial had higher maternal weight gain than the other two arms and a lower neonatal mortality compared with the arm receiving EFV+FTC/TDF (3.7% vs. 1.9%).⁵

The Antiretroviral Pregnancy Registry has monitored sufficient numbers of first-trimester exposures to TAF to detect at least a two-fold increase in the risk of overall birth defects. However, no such increase in the risk of birth defects has been observed with TAF. Among the cases of first-trimester TAF exposure that have been reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 4.2% (22 of 526 live births; 95% confidence interval, 2.64% to 6.27%), not statistically significantly higher than the total prevalence in the U.S. population, according to the Centers for Disease Control and Prevention birth defects surveillance system Metropolitan Atlanta Congenital Defects Program (2.7%; 95% CI: 2.7-2.8) or the Texas Birth Defects Registry (4.2%; 95% CI: 4.15-4.19).⁶

Excerpt from Table 11

Note: When using fixed-dose combination (FDC) tablets, refer to other sections in Appendix B and Table 11 in the Perinatal Guidelines for information about the dosing and safety of individual drug components of the FDC tablet during pregnancy.

References

1. Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208351s010lbl.pdf.
2. Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207561s023lbl.pdf.
3. Brooks KM, Momper JD, Pinilla M, et al. Pharmacokinetics of tenofovir alafenamide with and without cobicistat in pregnant and postpartum women living with HIV. AIDS. 2021;35(3):407-417. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33252495.
4. Brooks K, Pinilla M, Shapiro D, et al. Pharmacokinetics of tenofovir alafenamide 25 mg with PK boosters during pregnancy and postpartum. Presented at: Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs. 2019. Noordwijk, Netherlands.
5. Lockman S, Brummel SS, Ziemba L, et al. Efficacy and safety of dolutegravir with emtricitabine and tenofovir alafenamide fumarate or tenofovir disoproxil fumarate, and efavirenz, emtricitabine, and tenofovir disoproxil fumarate HIV antiretroviral therapy regimens started in pregnancy (IMPAACT 2010/VESTED): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet. 2021;397(10281):1276-1292. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33812487.
6. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 January 1989–31 January 2021. Wilmington, NC: Registry Coordinating Center. 2021. Available at: http://www.apregistry.com/.