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Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors

Tenofovir disoproxil fumarate (Viread, TDF)

(Last updated:7/31/2012; last reviewed:7/31/2012)

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Tenofovir disoproxil fumarate (Viread, TDF)  is classified as FDA Pregnancy Category B.
 
Animal carcinogenicity studies
Tenofovir is mutagenic in one of two in vitro assays and has no evidence of clastogenic activity. Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were carried out at 16 times (mice) and 5 times (rats) human exposure. In female mice, liver adenomas were increased at exposures 16 times that observed in humans at therapeutic doses. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.

Reproduction/fertility
Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus associated with tenofovir. There were also no effects on fertility, mating performance, or early embryonic development when tenofovir disoproxil fumarate was administered to male rats (600 mg/kg/day; equivalent to 10 times the human dose based on body surface area) for 28 days before mating and to female rats for 15 days before mating through Day 7 of gestation. There was, however, an alteration of the estrous cycle in female rats administered 600 mg/kg/day.

Teratogenicity/developmental toxicity
Chronic exposure of fetal monkeys to tenofovir at a high dose of 30 mg/kg (exposure equivalent to 25 times the AUC achieved with therapeutic dosing in humans) from Days 20 to 150 of gestation did not result in gross structural abnormalities.1 However, significantly lower fetal circulating insulin-like growth factor (IGF)-1 (a primary regulator of linear growth) and higher IGF binding protein-3 levels were shown and were associated with overall body weights approximately 13% lower than untreated controls. A slight reduction in fetal bone porosity was also observed. Effects on these parameters were observed within 2 months of maternal treatment. Significant changes in maternal monkey bone biomarkers were noted but were primarily limited to the treatment period and were reversible.

Continued administration of tenofovir at 30 mg/kg/day to infant monkeys resulted in significant growth restriction and severe bone toxicity in 2 of 8 (25%) infants and effects on bone biomarkers and defective bone mineralization in all animals. Chronic administration of tenofovir to immature animals of multiple species has resulted in reversible bone abnormalities; these effects were dose, exposure, age, and species specific. Abnormalities ranged from minimal decrease in bone mineral density and content (with oral dosing in rats and dogs that achieved drug exposures 6 to 10 times that achieved with therapeutic dosing in humans) to severe, pathologic osteomalacia (with subcutaneous [SQ] dosing given to monkeys). Juvenile monkeys given chronic SQ tenofovir at 30 mg/kg/day (exposure equivalent to 25 times the AUC achieved with therapeutic dosing in humans) developed osteomalacia, bone fractures, and marked hypophosphatemia. However, no clinical or radiologic bone toxicity was seen when juvenile monkeys received SQ dosing of 10 mg/kg/day (exposure equivalent to 8 times the AUC achieved with therapeutic dosing in humans). Evidence of nephrotoxicity was observed in newborn and juvenile monkeys given tenofovir in doses resulting in exposures 12 to 50 times higher than the human dose, based on body surface area comparisons.

In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to tenofovir in humans have been monitored to be able to detect at least a 2-fold increase in risk of overall birth defects. No such increase in birth defects has been observed with tenofovir. Among cases of first-trimester tenofovir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.3% (31 of 1,370 births; 95% CI, 1.5%–3.2%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance.2

Placental and breast milk passage
Studies in rats have demonstrated that tenofovir is secreted in milk. Intravenous administration of tenofovir to pregnant cynomolgus monkeys resulted in a fetal/maternal concentration of 17%, demonstrating that tenofovir does cross the placenta.3 In studies of pregnant women on chronic dosing, the cord-to-maternal blood ratio ranged from 0.60 to 1.03, indicating high placental transfer.4-7 In a study of 31 pregnant women receiving single-dose tenofovir (with and without emtricitabine) in labor, the drugs were well-tolerated and the median tenofovir cord-to maternal blood ratio at delivery was 0.73 (range, 0.26 to 1.95).8 In a study evaluating intracellular tenofovir levels in newborns, intracellular tenofovir concentrations were detected in the peripheral blood mononuclear cells from cord blood in all infants after a maternal single dose of 600 mg tenofovir with 400 mg emtricitabine, but intracellular tenofovir diphosphate was detectable in only 2 (5.5%) of 36.9 Neonatal dosing of tenofovir resulted in tenofovir and tenofovir diphosphate levels similar to those in adults.9

Among women receiving a single 600-mg dose during labor, tenofovir was detectable in only 4 of 25 (16%) breast milk samples during the first week after delivery, with a median concentration of 13 (range 6–18) ng/mL.8 In another study, 16 breast milk samples were obtained from 5 women who received 600 mg of tenofovir at the start of labor followed by 300 mg daily for 7 days. Tenofovir levels in breast milk ranged from 5.8 to 16.3 ng/mL, and nursing infants received an estimated 0.03% of the proposed oral dose of tenofovir for neonates.10

Human studies in pregnancy
A retrospective population PK study was performed on samples collected for therapeutic drug monitoring from 46 pregnant women and 156 non-pregnant women receiving combination regimens including tenofovir.11 Pregnant women had a 39% higher apparent clearance compared with non-pregnant women, which decreased slightly but significantly with increasing age. In study P1026s, tenofovir PKs were evaluated in 19 pregnant women receiving tenofovir-based combination therapy at 30 to 36 weeks’ gestation and 6 to 12 weeks postpartum.4 The percentage of women with tenofovir AUC exceeding the target of 2 μg*hour/mL (the 10th percentile in non-pregnant adults) was lower in the third trimester (74%, 14 of 19 women) than postpartum (86%, 12 of 14 women) (P = .02); however, trough levels were similar in the two groups. At the present time, standard dosing during pregnancy continues to be recommended.

A recent case series found tenofovir to be well tolerated among 76 pregnant women, with only 2 stopping therapy, 1 for rash and the other for nausea. All 78 infants were healthy with no signs of toxicity, and all were HIV uninfected.12 A follow-up study of 20 of the tenofovir-exposed infants and 20 controls found no differences between the groups in renal function, including cystatin C levels, through age 2 years.13 A retrospective review of 16 pregnancy outcomes in 15 heavily ARV experienced women demonstrated that tenofovir was well tolerated by the women and associated with normal growth and development in the infants.14 In a cross-sectional study of 68 HIV-exposed uninfected infants who had in utero exposure to combination regimens with (N = 33) or without (N = 35) tenofovir, the incidence of low birth weight and length measurements (<10th percentile) was comparable in the two groups and evaluation of quantitative bone ultrasound and parameters of bone metabolism gave similar measures between groups.15 The Pediatric HIV/AIDS Cohort Study from the United States reported on the association of tenofovir use during pregnancy with early growth parameters in 449 HIV-exposed but -uninfected infants.16 Of 2,029 infants, 449 (21%) had in utero exposure to tenofovir. There was no difference at birth between those exposed to combination drug regimens with or without tenofovir for low birth weight, small-for-gestational-age, and newborn length-for-age and head circumference-for-age z-scores (LAZ and HCAZ, respectively). At age 1 year, infants exposed to combination regimens with tenofovir had a slight but significantly lower adjusted mean LAZ and HCAZ than those without tenofovir exposure (LAZ: -0.17 vs. -0.03, P = .04; HCAZ: 0.17 vs. 0.42, P = .02), but not lower weight-for-age z-score. However, there were no significant differences between those with and without tenofovir exposure at age 1 year when defining low LAZ or HCAZ as <-1.5 z-score. Thus, these slightly lower mean LAZ and HCAZ scores are of uncertain significance.

References

  1. Tarantal AF, Castillo A, Ekert JE, Bischofberger N, Martin RB. Fetal and maternal outcome after administration of tenofovir to gravid rhesus monkeys (Macaca mulatta). J Acquir Immune Defic Syndr. Mar 1 2002;29(3):207-220. Available at http://www.ncbi.nlm.nih.gov/pubmed/11873070.
  2. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available at http://www.APRegistry.com.
  3. Tarantal AF, Marthas ML, Shaw JP, Cundy K, Bischofberger N. Administration of 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) to gravid and infant rhesus macaques (Macaca mulatta): safety and efficacy studies. J Acquir Immune Defic Syndr Hum Retrovirol. Apr 1 1999;20(4):323-333. Available at http://www.ncbi.nlm.nih.gov/pubmed/10096575.
  4. Burchett S, Best B, Mirochnick M, et al.Tenofovir pharmacokinetics during pregnancy, at delivery, and postpartum. Paper presented at: 14th Conference on Retroviruses and Opportunistic Infections (CROI); February 25-28,  2007; Los Angeles, CA. Abstract 738b.
  5. Bonora S, de Requena DG, Chiesa E, et al.Transplacental passage of tenofovir and other ARVs at delivery. Paper presented at: 14th Conference on Retoviruses and Opportunistic Infections (CROI); February 25-28, 2007; Los Angeles, CA. Abstract 738a.
  6. Hirt D, Urien S, Rey E, et al. Population pharmacokinetics of emtricitabine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Antimicrob Agents Chemother. Mar 2009;53(3):1067-1073. Available at http://www.ncbi.nlm.nih.gov/pubmed/19104016.
  7. Colbers A, Taylor G, et al.A comparison of the pharmacokinetics of tenofovir during pregnancy and post-partum. Paper presented at: 13th International Workshop on Clinical Pharmacology of HIV Therapy; April 16-18, 2012; Barcelona, Spain. Abstract P34
  8. Flynn PM, Mirochnick M, Shapiro DE, et al. Pharmacokinetics and safety of single-dose tenofovir disoproxil fumarate and emtricitabine in HIV-1-infected pregnant women and their infants. Antimicrob Agents Chemother. Dec 2011;55(12):5914-5922. Available at http://www.ncbi.nlm.nih.gov/pubmed/21896911.
  9. Hirt D, Ekouevi DK, Pruvost A, et al. Plasma and intracellular tenofovir pharmacokinetics in the neonate (ANRS 12109 trial, step 2). Antimicrob Agents Chemother. Jun 2011;55(6):2961-2967. Available at http://www.ncbi.nlm.nih.gov/pubmed/21464249.
  10. 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. Mar 2011;55(3):1315-1317. Available at http://www.ncbi.nlm.nih.gov/pubmed/21173182.
  11. Benaboud S, Hirt D, Launay O, et al. Pregnancy-related effects on tenofovir pharmacokinetics: a population study with 186 women. Antimicrob Agents Chemother. Feb 2012;56(2):857-862. Available at http://www.ncbi.nlm.nih.gov/pubmed/22123690.
  12. Haberl A, Linde R, Reittner A, et al. Safety and efficacy of tenofovir in pregnant women. Paper presented at: 15th Conference on Retroviruses and Opportunistic Infections (CROI); February 3-6, 2008; Boston, MA. Abstract 627a.
  13. Linde R, Konigs C, Rusicke E, Haberl A, Reitter A, Dreuz W. Tenofovir therapy during pregnancy does not affect renal function in HIV-exposed children. Paper presented at: 17th Conference on Retoviruses and Opportunistic Infections (CROI); February 27-March 2, 2010; San Francisco, CA. Abstract 925.
  14. Nurutdinova D, Onen NF, Hayes E, Mondy K, Overton ET. Adverse effects of tenofovir use in HIV-infected pregnant women and their infants. Ann Pharmacother. Nov 2008;42(11):1581-1585. Available at http://www.ncbi.nlm.nih.gov/pubmed/18957630.
  15. Vigano A, Mora S, Giacomet V, et al. In utero exposure to tenofovir disoproxil fumarate does not impair growth and bone health in HIV-uninfected children born to HIV-infected mothers. Antivir Ther. 2011;16(8):1259-1266. Available at http://www.ncbi.nlm.nih.gov/pubmed/22155907.
  16. Siberry GK, Williams PL, Mendez H, et al. Safety of tenofovir use during pregnancy: early growth outcomes in HIV-exposed uninfected infants. AIDS. Jun 1 2012;26(9):1151-1159. Available at http://www.ncbi.nlm.nih.gov/pubmed/22382151.