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:9/14/2011)
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 DF 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 due to tenofovir. There were also no effects on fertility, mating performance, or early embryonic development when tenofovir DF was administered to male rats (600 mg/kg/day; equivalent to 10 times the human dose based on body surface area) for 28 days prior to mating and to female rats for 15 days prior to 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 20–150 of gestation did not result in gross structural abnormalities [1]. However, significantly lower fetal circulating insulin-like growth factor-1 (a primary regulator of linear growth) and higher insulin-like growth factor
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 6–10 times that achieved with therapeutic dosing in humans) to severe, pathologic osteomalacia (with subcutaneous dosing given to monkeys). Juvenile monkeys given chronic subcutaneous 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 subcutaneous 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 12–50 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 2.4% (26 of 1,092 births, 95% CI, 1.6%–3.5%) 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 3 studies of pregnant women on chronic dosing, the cord-to-maternal blood ratio ranged from 0.60 to 0.99, indicating high placental transfer [4-6]. In 2 studies of single-dose tenofovir (in some cases with emtricitabine) in labor that included 82 mother-infant pairs, the drugs were well tolerated and cord-to-maternal blood ratios were 0.61–0.67 [7-9].
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 [9]. 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
In study P1026s, tenofovir PKs were evaluated in 19 pregnant women receiving tenofovir-based combination therapy at 30–36 weeks’ gestation and 6–12 weeks postpartum [4]. The percentage of women with tenofovir AUC exceeding the target of 2 μg*hour/mL (the 10th percentile in nonpregnant adults) was lower in the third trimester (74%, 14 of 19 women) than postpartum (86%, 12 of 14 women) (P = 0.02); however, trough levels were similar in the two groups.
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 [11]. 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 2 years of age [12]. A retrospective review of 16 pregnancy outcomes among 15 heavily ARV experienced women demonstrated that tenofovir was well tolerated by the women and associated with normal growth and development in the infants [13].
References
1. Tarantal AF, Castillo A, Ekert JE, et al. Fetal and maternal outcome after administration of tenofovir to gravid rhesus monkeys (Macaca mulatta). J Acquir Immune Defic Syndr. 2002;29(3):207-220.
2. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 Jan 1989 - 31 January 2011. Wilmington, NC: Registry Coordinating Center; 2010. Available from URL: http://www.APRegistry.com. 2011.
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. 1999 Apr 1;20(4):323-333.
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);Feb. 25-28, 2007; Los Angeles, CA.
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); Feb 25-28, 2007; Los Angeles, CA.
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. 2009 Mar;53(3):1067-1073.
7. Rodman J, Flynn P, Shapiro D, et al. Pharmacokinetics and safety of tenofovir disoproxil fumarate in HIV-1-infected pregnant women and their infants. Paper presented at: 13th Conference on Retoviruses and Opportunistic Infections (CROI); Feb.5-8, 2006; Denver, CO.
8. Flynn P, Mirochnick M, Shapiro D, et al. Single dose tenofovir disoproxil fumarate (TDF) with and without emtricitabine (FTC) in HIV-1 infected pregnant women and their infants: pharmacokinetics (PK) and safety. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections (CROI); Feb. 8-11, 2009; Montreal, Canada.
9. Mirochnick M, Kafulafula G, et al. The pharmacokinetics (PK) of tenofovir disoproxil fumarate (TDF) after administration to HIV-1 infected pregnant women and their newborns. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections (CROI); Feb. 8-11, 2009; Montreal, Canada.
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. 2011 Mar;55(3):1315-1317.
11. Habert 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);Feb. 3-8, 2008; Boston, MA.
12. 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); Feb. 16-19, 2010; San Francisco, CA.
13. 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 Nov;42(11):1581-1585.