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

Archived Drugs

Stavudine (Zerit, d4T)

Stavudine is classified as Food and Drug Administration (FDA) Pregnancy Category C.

Stavudine is not recommended for use in pregnant women with HIV due to its toxicity.

Animal Studies

Carcinogenicity
Stavudine is clastogenic in in vitro and in vivo assays but not mutagenic in in vitro assays. In 2-year carcinogenicity studies in mice and rats, stavudine was noncarcinogenic at doses that produced exposures 39 times (in mice) and 168 times (in rats) the human exposure observed at the recommended therapeutic dose. At higher levels of exposure (250 times [in mice] and 732 times [in rats] the human exposure seen at therapeutic doses), benign and malignant liver tumors occurred in mice and rats, and urinary bladder tumors occurred in male rats.¹

Reproduction/Fertility
Stavudine has no demonstrated effect on reproduction or fertility in rodents. No evidence of impaired fertility was seen in rats with exposures (based on C_max) up to 216 times the exposures observed following a clinical dosage of stavudine 1 mg/kg/day.¹ A dose-related cytotoxic effect has been observed on preimplantation mouse embryos, with inhibition of blastocyst formation occurring at a concentration of 100 µM and inhibition of post-blastocyst development occurring at 10 µM.²

Teratogenicity/Adverse Pregnancy Outcomes
No evidence of teratogenicity was noted in rats or rabbits with stavudine exposures (based on C_max) up to 399 times and 183 times, respectively, the exposures seen at a clinical dosage of stavudine 1 mg/kg/day. In rat fetuses, the incidence of a common skeletal variation—unossified or incomplete ossification of sternebra—increased at 399 times human exposure (i.e., the exposure in adult humans who received a standard dose), although no effect was observed at 216 times human exposure. A slight post-implantation loss was noted at 216 times human exposure, with no effect noted at approximately 135 times human exposure. An increase in early rat neonatal mortality (birth to day 4) occurred at 399 times human exposure, although survival of neonates was unaffected at approximately 135 times human exposure.¹

Placental and Breast Milk Passage
A study in rats showed that stavudine is transferred to the fetus through the placenta. The concentration in fetal tissue was approximately one-half the concentration in maternal plasma.¹ In primates (pig-tailed macaques), the ratio of fetal plasma concentrations/maternal plasma concentrations was approximately 0.80.³

Stavudine is excreted into the breast milk of lactating rats.¹

Human Studies in Pregnancy

Pharmacokinetics
In a Phase 1/2 short-term safety and pharmacokinetic (PK) study of combination stavudine and lamivudine in pregnant women living with HIV and their infants (PACTG 332), both drugs were well tolerated, with maternal stavudine PK parameters similar to those seen in nonpregnant adults.⁴

Placental and Breast Milk Passage
Stavudine crosses the human placenta, resulting in cord blood concentration/maternal blood concentration ratios of 1.0 to 1.3.⁵ Stavudine also crosses into human breast milk, resulting in breast milk concentration/maternal plasma concentration ratios of 1.0 to 1.76. Concentrations in nursing infants were negligible.^6,7

Teratogenicity/Adverse Pregnancy Outcomes
No association was found between first-trimester exposure to stavudine and birth defects in a large French cohort study that had 70% power to detect an increased adjusted odds ratio of 1.5.⁸ In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to stavudine in humans have been monitored to be able to detect at least a two-fold increased risk of overall birth defects. No such increase in birth defects has been observed with stavudine. Among cases of first-trimester stavudine exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.6% (21 of 811 births; 95% CI, 1.6% to 3.9%) compared with a total prevalence in the U.S. population of 2.7%, based on Centers for Disease Control and Prevention surveillance.⁹

Other Safety Data
Cases of lactic acidosis, including some fatal cases, have been described in pregnant women receiving the combination of didanosine and stavudine along with other antiretroviral (ARV) agents.10-12 The FDA and Bristol-Myers Squibb issued a warning to health care professionals that pregnant women may be at increased risk of fatal lactic acidosis when prescribed didanosine and stavudine in combination (see Recommendations for Use of Antiretroviral Drugs During Pregnancy and Long-Term Follow-Up of Infants Exposed to Antiretroviral Drugs). Didanosine and stavudine should not be prescribed together for pregnant women.

In a U.S. cohort study evaluation of the safety of ARV drugs used during pregnancy, children without HIV born to women with HIV who received didanosine plus stavudine during the pregnancy had an increased risk of both adverse neurodevelopmental (relative risk [RR] of 12.40; 95% CI, 5.29–29.08) and language (RR of 4.84, 95%CI, 1.14–20.51) outcomes compared to children whose mothers did not receive these drugs during pregnancy.¹³

Stavudine is not recommended for use in pregnant women with HIV due to its toxicity.

 References

1. Stauvidine [package insert]. Food and Drug Administration. 2017. Available at: http://packageinserts.bms.com/pi/pi_zerit.pdf
2. Toltzis P, Mourton T, Magnuson T. Comparative embryonic cytotoxicity of antiretroviral nucleosides. J Infect Dis. 1994;169(5):1100-1102. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8169400.
3. Odinecs A, Nosbisch C, Keller RD, Baughman WL, Unadkat JD. In vivo maternal-fetal pharmacokinetics of stavudine (2',3'-didehydro-3'-deoxythymidine) in pigtailed macaques (Macaca nemestrina). Antimicrob Agents Chemother. 1996;40(1):196-202. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8787905.
4. Wade NA, Unadkat JD, Huang S, et al. Pharmacokinetics and safety of stavudine in HIV-infected pregnant women and their infants: pediatric AIDS clinical trials group protocol 332. J Infect Dis. 2004;190(12):2167-2174. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15551216.
5. McCormack SA, Best BM. Protecting the fetus against HIV infection: a systematic review of placental transfer of antiretrovirals. Clin Pharmacokinet. 2014;53(11):989-1004. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25223699.
6. Fogel JM, Taha TE, Sun J, et al. Stavudine concentrations in women receiving postpartum antiretroviral treatment and their breastfeeding infants. J Acquir Immune Defic Syndr. 2012;60(5):462-465. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22614899.
7. Palombi L, Pirillo MF, Andreotti M, et al. Antiretroviral prophylaxis for breastfeeding transmission in Malawi: drug concentrations, virological efficacy and safety. Antivir Ther. 2012;17(8):1511-1519. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22910456.
8. Sibiude J, Mandelbrot L, Blanche S, et al. Association between prenatal exposure to antiretroviral therapy and birth defects: an analysis of the French perinatal cohort study (ANRS CO1/CO11). PLoS Med. 2014;11(4):e1001635. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24781315.
9. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 January 1989–31 January 2018.Wilmington, NC: Registry Coordinating Center. 2018. Available at: http://www.apregistry.com/.
10. Bristol-Myers Squibb Company. Healthcare provider important drug warning letter. 2001.
11. Sarner L, Fakoya A. Acute onset lactic acidosis and pancreatitis in the third trimester of pregnancy in HIV-1 positive women taking antiretroviral medication. Sex Transm Infect. 2002;78(1):58-59. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11872862.
12. Mandelbrot L, Kermarrec N, Marcollet A, et al. Case report: nucleoside analogue-induced lactic acidosis in the third trimester of pregnancy. AIDS. 2003;17(2):272-273. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12545093.
13. Williams PL, Hazra R, Van Dyke RB, et al. Antiretroviral exposure during pregnancy and adverse outcomes in HIV-exposed uninfected infants and children using a trigger-based design. AIDS. 2016;30(1):133-144. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26731758.