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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:March 28, 2014; last reviewed:March 28, 2014)

Tenofovir disoproxil fumarate (hereafter, tenofovir) is classified as Food and Drug Administration 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 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. A retrospective analysis of 7,275 women (1,199 receiving tenofovir-based combination antiretroviral therapy) demonstrated a slight reduction in pregnancy rates but the findings were limited by the observational nature of the data and additional studies are needed for confirmation.1

Teratogenicity/Developmental Toxicity
Chronic exposure of fetal monkeys to tenofovir at high doses (i.e., exposure equivalent to 25 times the area under the curve achieved with therapeutic dosing in humans) resulted in lower fetal circulating insulin-like growth factor (IGF)-1, higher IGF binding protein-3 levels, and were associated with lower overall body weights. 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.2 In newborn macaques exposed to tenofovir at high dose over a prolonged period, similar changes have been noted, as well as osteomalacia, bone fracture, hypophosphatemia, and nephrotoxicity.

These toxicities appear to be dose- and age-related and are reversible. In contrast, no detectable effects on growth have been seen with administration of tenofovir for shorter durations or at lower doses to newborn or infant macaques.3,4 

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 increased 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% to 3.2%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance.5 In addition, no association was seen between tenofovir administration and birth defects in two large U.S. cohorts, PACT 219/219C (n = 2,202) and P1025 (n = 1,112).6,7

Placental and Breast Milk Passage
Intravenous administration of tenofovir to pregnant cynomolgus monkeys resulted in a fetal/maternal concentration of 17%, demonstrating that tenofovir does cross the placenta.8 In studies of pregnant women on chronic tenofovir dosing, the cord-to-maternal-blood ratio ranged from 0.60 to 1.03, indicating high placental transfer.9-12 In studies of 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 ranged from 0.55 to 0.73.13,14 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 disoproxil fumarate with 400 mg emtricitabine, but intracellular tenofovir diphosphate was detectable in only 2 (5.5%) of 36.15 Two studies of neonatal dosing of tenofovir disoproxil fumarate resulted in tenofovir and tenofovir diphosphate levels similar to those in adults following either a single neonatal dose of 13 mg/kg or a regimen of 6 mg/kg administered daily for 7 days.14,15 

Sixteen breast milk samples were obtained from five 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 disoproxil fumarate for neonates.16

Human Studies in Pregnancy
A retrospective population pharmacokinetic (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.17 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.9 The percentage of women with tenofovir area under the curve 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. A study of 34 women receiving tenofovir plus emtricitabine in the third trimester and postpartum has recently been reported.11 Although similar decreases in PK parameters were observed during pregnancy, they were not associated with virologic failure. At the present time, standard dosing during pregnancy continues to be recommended.

A case series found tenofovir to be well tolerated in 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.18 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.19 A retrospective review of 16 pregnancy outcomes in 15 heavily antiretroviral- experienced women demonstrated that tenofovir was well tolerated by the women and associated with normal growth and development in the infants.20 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 2 groups and evaluation of quantitative bone ultrasound and parameters of bone metabolism gave similar measures between groups.21 Among 382 pregnancies occurring in 302 women in Uganda and Zimbabwe participating in the DART trial—approximately two-thirds of whom received tenofovir through more than 90% of their pregnancies—there were no differences noted in mortality, birth defects, or growth.22 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 HIV-uninfected infants.23 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 in 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. Maskew M, Westreich D, Firnhaber C, Sanne I. Tenofovir use and pregnancy among women initiating HAART. AIDS. 2012;26(18):2393-2397. Available at http://www.ncbi.nlm.nih.gov/pubmed/22951630.
  2. 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. 2002;29(3):207-220. Available at http://www.ncbi.nlm.nih.gov/pubmed/11873070.
  3. Van Rompay KK, Durand-Gasselin L, Brignolo LL, et al. Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy: summary of pharmacokinetics and biological and virological effects. Antimicrob Agents Chemother. 2008;52(9):3144-3160. Available at http://www.ncbi.nlm.nih.gov/pubmed/18573931.
  4. Van Rompay KK, Brignolo LL, Meyer DJ, et al. Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques. Antimicrob Agents Chemother. 2004;48(5):1469-1487. Available at http://www.ncbi.nlm.nih.gov/pubmed/15105094.
  5. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 Jan 1989–31 July 2013. 2013. Available at http://www.APRegistry.com. Accessed March 5, 2014.
  6. Brogly SB, Abzug MJ, Watts DH, et al. Birth defects among children born to human immunodeficiency virus-infected women: pediatric AIDS clinical trials protocols 219 and 219C. Pediatr Infect Dis J. 2010;29(8):721-727. Available at http://www.ncbi.nlm.nih.gov/pubmed/20539252.
  7. Knapp KM, Brogly SB, Muenz DG, et al. Prevalence of congenital anomalies in infants with in utero exposure to antiretrovirals. Pediatr Infect Dis J. 2012;31(2):164-170. Available at http://www.ncbi.nlm.nih.gov/pubmed/21983213.
  8. 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. 1999;20(4):323-333. Available at http://www.ncbi.nlm.nih.gov/pubmed/10096575.
  9. 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; 2007; Los Angeles, CA.
  10. 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; 2007; Los Angeles, CA.
  11. 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; 2012; Barcelona, Spain.
  12. Hirt D, Urien S, Ekouevi DK, et al. Population pharmacokinetics of tenofovir in HIV-1-infected pregnant women and their neonates (ANRS 12109). Clin Pharmacol Ther. 2009;85(2):182-189. Available at http://www.ncbi.nlm.nih.gov/pubmed/18987623.
  13. 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. 2011;55(12):5914-5922. Available at http://www.ncbi.nlm.nih.gov/pubmed/21896911.
  14. Nielsen-Saines K, al. e. Tenofovir disoproxil fumarate (TDF) pharmacokinetics (PK) with daily dosing in the first week of life (HPTN 057). Abstract no. TUAB0201. Paper presented at: 19th International AIDS Conference; 2012; Washington, DC.
  15. Hirt D, Ekouevi DK, Pruvost A, et al. Plasma and intracellular tenofovir pharmacokinetics in the neonate (ANRS 12109 trial, step 2). Antimicrob Agents Chemother. 2011;55(6):2961-2967. Available at http://www.ncbi.nlm.nih.gov/pubmed/21464249.
  16. 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(3):1315-1317. Available at http://www.ncbi.nlm.nih.gov/pubmed/21173182.
  17. Benaboud S, Hirt D, Launay O, et al. Pregnancy-related effects on tenofovir pharmacokinetics: a population study with 186 women. Antimicrob Agents Chemother. 2012;56(2):857-862. Available at http://www.ncbi.nlm.nih.gov/pubmed/22123690.
  18. Habert A, Linde R, Reittner A, al e. Safety and efficacy of tenofovir in pregnant women. 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008, 2008; Boston, MA.
  19. 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. 17th Conference on Retoviruses and Opportunistic Infections; February 27-March 2, 2010, 2010; San Francisco, CA.
  20. 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. 2008;42(11):1581-1585. Available at http://www.ncbi.nlm.nih.gov/pubmed/18957630.
  21. 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.
  22. 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(5):e1001217. Available at http://www.ncbi.nlm.nih.gov/pubmed/22615543.
  23. Siberry GK, Williams PL, Mendez H, et al. Safety of tenofovir use during pregnancy: early growth outcomes in HIV-exposed uninfected infants. AIDS. 2012;26(9):1151-1159. Available at http://www.ncbi.nlm.nih.gov/pubmed/22382151.

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