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 prodrug form of tenofovir (TFV). For information about tenofovir disoproxil fumarate (TDF), see the TDF section.

Summary

• No dose adjustments are required for TAF during pregnancy.
• First-trimester exposure to TAF is not associated with increased risk of congenital anomalies.

Human Studies in Pregnancy

Pharmacokinetics

TAF pharmacokinetics (PK) can differ during pregnancy, depending on the concomitant antiretroviral (ARV) drugs administered. However, TAF exposures appear to be adequate in the second and third trimesters based on comparisons with historical data in nonpregnant adults.

TAF PK were evaluated as part of International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network P1026s in 31 women taking TAF 10 mg with cobicistat, 27 women taking TAF 25 mg without a pharmacoenhancer,¹ and 29 women taking TAF 25 mg with a pharmacoenhancer (cobicistat or ritonavir).² TAF area under the concentration-time curve (AUC) did not differ between pregnancy and postpartum for women taking TAF 10 mg with cobicistat¹ or those taking TAF 25 mg with a pharmacoenhancer.² TAF AUC at a 25 mg dose without a pharmacoenhancer was 33% to 43% lower during pregnancy compared to postpartum but comparable to exposures in nonpregnant adults.¹ The Pharmacokinetics of newly developed ANtiretroviral agents in pregNAnt women with HIV (PANNA) Network also evaluated TAF and TFV PK in 20 pregnant and postpartum European women receiving TAF 10 mg with cobicistat or TAF 25 mg without a pharmacoenhancer.³ PK results from both dosing combinations were pooled and showed that TAF and TFV AUCs were 46% and 33% lower during pregnancy, respectively, than postpartum. Despite these decreases, 94% of pregnant women remained above the predefined TAF AUC efficacy target of 53.1 ng•h/mL. A separate study in pregnant women receiving TAF 25 mg with bictegravir and emtricitabine (FTC) showed that the total TAF AUC was approximately 22% to 43% lower during pregnancy than postpartum, but the unbound AUC was approximately 6% to 17% lower.⁴ Trough concentrations of the active tenofovir-diphosphate form in peripheral blood mononuclear cells were comparable but variable between pregnancy and postpartum.

Placental and Breast Milk Passage

Limited data exist on TAF and TFV concentrations in placental blood and breast milk. 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 in women receiving TAF 25 mg without a pharmacoenhancer¹ and in all cord blood and infant washout samples in women receiving TAF 25 mg with ritonavir or cobicistat. Maternal plasma TAF concentrations at delivery were measurable in only 4 of 45 paired samples in women receiving TAF 25 mg without a pharmacoenhancer¹ and in 2 of 25 paired samples in women receiving TAF 25 mg with ritonavir or cobicistat.² A separate study also did not detect TAF in any paired cord blood or maternal delivery samples, but it was able to quantify TFV and estimated a median placental transfer ratio of 0.81 from 13 paired samples.³

TAF breast milk transfer has been examined in smaller PK studies. One study examined TAF breast milk transfer in five breastfeeding women with HIV and identified a breast milk–to-plasma ratio of 4.09 for TAF⁵ and a median estimated infant daily dose of 0.007 mg/kg. A separate PK study in eight breastfeeding women with hepatitis B virus (HBV) infection receiving TAF for at least 4 weeks estimated breast milk–to-plasma ratios for TAF and TFV to be 0.029 and 2.809, respectively.⁶ The relative TAF dose was estimated at 0.005% of the maternal dose. TFV was detectable in the urine of three of seven infants at a median steady-state concentration of 5 ng/mL, which was 300 times less than urine concentrations measured in adults on TAF. TFV breast milk transfer was examined in 12 women receiving TAF 25 mg and 4 women receiving TDF 300 mg for HBV treatment.⁷ TFV exposures in breast milk through 8 hours postdose were approximately fivefold higher at Day 3 postdelivery in women taking TAF than in women taking TDF. TFV concentrations with TAF decreased by 43% and 47% at 15 and 30 days postpartum, respectively, compared with Day 3. TFV has poor oral bioavailability, and TAF and infant plasma concentrations were not quantified, so the clinical relevance of higher TFV in breast milk with TAF is unclear.

Teratogenicity

The Antiretroviral Pregnancy Registry (APR) provides updated birth defect data for TAF and other ARV drugs twice a year through an interim report released in June and December. The APR has monitored sufficient numbers of first-trimester TAF exposures to detect at least a 1.5-fold increase in the risk of overall birth defects and at least a twofold increase in the risk of cardiovascular and genitourinary defects (the more common classes of birth defects in the general population). No such increase in the risk of birth defects has been observed with TAF. In the APR interim report, Figure 1. Summary of Birth Defects Among First Trimester Exposures provides a summary of the number and prevalence of birth defects per live births among cases of first-trimester exposure to TAF and other ARV drugs reported to the APR where there are sufficient data to determine 95% confidence intervals. The data in Figure 1 can be compared with the prevalence of birth defects in the U.S. population (2.72 birth defects per 100 live births) based on the Centers for Disease Control and Prevention birth defects surveillance system (Metropolitan Atlanta Congenital Defects Program [MACDP]) and with the Texas Birth Defects Registry (TBDR; 4.17 birth defects per 100 live births).

Adverse Pregnancy Outcomes

IMPAACT 2010/Virologic Efficacy and Safety of ART Combinations with TAF/TDF, EFV, and DTG (VESTED) was a randomized trial of dolutegravir (DTG)- and efavirenz (EFV)-containing antiretroviral therapy regimens in pregnancy, which found lower composite adverse outcomes in the group receiving DTG and FTC with TAF (DTG+FTC/TAF) than in the group receiving DTG and FTC with TDF (DTG+FTC/TDF) or EFV and FTC with TDF (EFV+FTC/TDF), and lower neonatal mortality than the arm receiving EFV+FTC/TDF (3.7% vs. 1.9%).⁸ A posthoc risk–benefit analysis of weighted infant outcomes showed a more favorable overall tradeoff for infants born to mothers in the DTG+TAF/FTC arm than in the DTG+TDF/FTC and EFV+TDF/FTC arms.^9,10 

Other Safety Data

Maternal Safety Outcomes

The DTG+FTC/TAF arm of IMPAACT 2010/VESTED had higher maternal weight gain than the other two arms.⁸ Although greater weight gain was seen in mothers receiving DTG+FTC/TAF, the extent of average weekly weight gain that occurred was still below the recommended amount by the Institute of Medicine. Follow-up analyses did not identify significant differences in metabolic issues between study arms as measured by hemoglobin A1C or random glucose levels among pregnant women or infants,¹¹ and they also showed that lower antepartum weight gain was associated with a higher risk of adverse pregnancy outcomes.¹² However, the potential implications of excessive weight gain and other adverse safety outcomes when TAF-containing regimens are prescribed during pregnancy have also been evaluated^13-15 in U.S.-based cohorts with variable findings. A systematic analysis^12,16 of these collective studies identified a higher risk of excessive maternal weight gain and hypertensive disorders among pregnant women on TAF/integrase strand transfer inhibitor (INSTI) ART regimens in comparison to those not on a TAF/INSTI ART regimen but did not identify any differences in the risk of gestational diabetes mellitus. However, because TAF was administered with an INSTI across these studies, the effect of TAF alone could not be examined. 

Renal safety also has been examined in a separate retrospective cohort of 100 pregnant women with HIV receiving TAF- or TDF-containing ART, and no significant differences in renal function, toxicity, or treatment discontinuations due to renal toxicity among regimens were identified.¹⁵

Infant Safety Outcomes

Length-for-age z-scores and weight-for-age z-scores among infants exposed to DTG+TAF/FTC in utero did not significantly differ from those exposed to DTG+TDF/FTC at 26 or 50 weeks of age but were higher than those measured in infants exposed to EFV+TDF/FTC.¹⁷ There were no differences in weight-for-length z-scores between treatment regimens. All infants showed severely stunted growth through the first year of age.

Animal Studies

Carcinogenicity

Carcinogenicity studies for TFV have only been performed with TDF, but given the lower TFV exposure with TAF, the associated carcinogenicity is assumed to be commensurate or lower. Refer to the TDF section for more information.

Reproduction/Fertility

There is no evidence of impaired fertility or mating performance with TAF administration in rats or rabbits at exposures up to 53 times those seen in humans.¹⁸

Teratogenicity/Adverse Pregnancy Outcomes

No effects on early embryonic development were seen in rats at TAF doses that produced exposures that were 62 times those seen in humans who received the therapeutic dose.¹⁸

Placental and Breast Milk Passage

Rat studies demonstrated secretion of TFV in breast milk after administration of TDF, but secretion of TAF or TFV in animal milk after administration of TAF has not been evaluated.¹⁸

Excerpt from Table 14

Note: When using fixed-dose combination (FDC) tablets, refer to other sections in Appendix B and Table 14 in the Perinatal Guidelines for information about the dosing and safety of individual drug components of the FDC tablet during pregnancy.

References

1. 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://pubmed.ncbi.nlm.nih.gov/33252495.
2. Brooks KM, Pinilla M, Stek AM, et al. Pharmacokinetics of tenofovir alafenamide with boosted protease inhibitors in pregnant and postpartum women living with HIV: results from IMPAACT P1026s. J Acquir Immune Defic Syndr. 2022;90(3):343-350. Available at: https://pubmed.ncbi.nlm.nih.gov/35195573.
3. Bukkems VE, Necsoi C, Hidalgo Tenorio C, et al. Tenofovir alafenamide plasma concentrations are reduced in pregnant women living with human immunodeficiency virus (HIV): data from the PANNA network. Clin Infect Dis. 2022;75(4):623-629. Available at: https://pubmed.ncbi.nlm.nih.gov/34864950/.
4. Zhang H, Hindman JT, Lin L, et al. A study of the pharmacokinetics, safety, and efficacy of bictegravir/emtricitabine/tenofovir alafenamide in virologically suppressed pregnant women with HIV. AIDS. 2023. Available at: https://pubmed.ncbi.nlm.nih.gov/37939141.
5. Aebi-Popp K, Kahlert CR, Crisinel PA, et al. Transfer of antiretroviral drugs into breastmilk: a prospective study from the Swiss Mother and Child HIV Cohort Study. J Antimicrob Chemother. 2022;77(12):3436-3442. Available at: https://pubmed.ncbi.nlm.nih.gov/36177836.
6. Kayes T, Crane H, Symonds A, et al. Plasma and breast milk pharmacokinetics of tenofovir alafenamide in mothers with chronic hepatitis B infection. Aliment Pharmacol Ther. 2022;56(3):510-518. Available at: https://pubmed.ncbi.nlm.nih.gov/35599363.
7. Yang N, Zhou G, Cheng X, et al. Distribution evaluation of tenofovir in the breast milk of mothers with HBeAg-positive chronic HBV infection after treatment with tenofovir alafenamide and tenofovir disoproxil fumarate by a sensitive UPLC-MS/MS method. Front Pharmacol. 2021;12:734760. Available at: https://pubmed.ncbi.nlm.nih.gov/34483946/.
8. 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://pubmed.ncbi.nlm.gov/33812487.
9. Brummel S, Ziemba L, Coletti A, et al. Risk-benefit trade-off for pregnancy and infant outcomes: DTG, EFV, TAF, and TDF. Presented at The Conference on Retroviruses and Opportunistic Infections; 12-16 February, 2022, Virtual Conference. Available at: https://www.impaactnetwork.org/sites/default/files/inline-files/IMPAACT2010_Brummel_DOOR_CROI2022_poster_0.pdf.
10. Fairlie L, Brummel S, Ziemba L, et al. Adverse outcomes in subsequent pregnancies in the IMPAACT 2010 trial. Presented at The Conference on Retroviruses and Opportunistic Infections; 12-16 February,2022, Virtual Conference. Available at: https://www.impaactnetwork.org/sites/default/files/inline-files/IMPAACT2010_Fairlie_Subsequent-pregnancies_CROI2022-poster_0.pdf.
11. Chinula L, Ziemba L, Brummel S, et al. Efficacy and safety of three antiretroviral therapy regimens started in pregnancy up to 50 weeks post partum: a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet HIV. 2023;10(6):e363-e374. Available at: https://pubmed.ncbi.nlm.nih.gov/37167996.
12. Hoffman RM, Brummel S, Ziemba L, et al. Weight changes and adverse pregnancy outcomes with dolutegravir- and tenofovir alafenamide fumarate-containing antiretroviral treatment regimens during pregnancy and postpartum. Clin Infect Dis. 2024;78(6):1617-1628. Available at: https://pubmed.ncbi.nlm.nih.gov/38180851.
13. Joseph NT, Satten GA, Williams RE, et al. The effect of antiretroviral therapy for the treatment of human immunodeficiency virus (HIV)-1 in pregnancy on gestational weight gain. Clin Infect Dis. 2022;75(4):665-672. Available at: https://pubmed.ncbi.nlm.nih.gov/34864949.
14. Nissim OA, Haney A, Lazenby GB. Effect of tenofovir alafenamide in combination with and without integrase inhibitors on weight gain, diabetes, and hypertensive disorders of pregnancy. Pregnancy Hypertens. 2023;34:47-52. Available at: https://pubmed.ncbi.nlm.nih.gov/37804587.
15. Thimm MA, Eke AC. Tenofovir, pregnancy and renal function changes in pregnant women living with HIV. AIDS. 2021;35(8):1319-1320. Available at: https://pubmed.ncbi.nlm.nih.gov/33710027/.
16. Eke AC, Ramaiyer M, Eleje GU, et al. A systematic review and meta-analysis of maternal weight changes and pregnancy outcomes associated with integrase inhibitors and tenofovir alafenamide in pregnant women with HIV. Am J Obstet Gynecol MFM. 2024;6(8):101406. Available at: https://pubmed.ncbi.nlm.nih.gov/38866134.
17. Stranix-Chibanda L, Ziemba L, Brummel S, et al. Growth of infants with perinatal exposure to maternal DTG vs EFV and TDF vs TAF: the randomized. IMPAACT 2010 trial. Presented at Conference on Retroviruses and Opportunistic Infections; Feb 12-16, 2022, Virtual. Available at: https://www.hivandmore.de/kongresse/croi2022/slides/gilead/Stranix-Chibanda_Perinatal-exposure-DTG--EFV--TDF--TAF_CROI2022_Oral-30.pdf.
18. Descovy (emtricitabine and tenofovir alafenamide) [package insert]. Food and Drug Administration. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208215s020lbl.pdf.