Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States
The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.
Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors
Stavudine (Zerit, d4T)
Last Updated: November 14, 2017; Last Reviewed: November 14, 2017
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 non-carcinogenic in doses producing exposures 39 (mice) and 168 (rats) times human exposure at the recommended therapeutic dose. At higher levels of exposure (250 [mice] and 732 [rats] times human exposure at therapeutic doses), benign and malignant liver tumors occurred in mice and rats and urinary bladder tumors occurred in male rats.1
Stavudine has no demonstrated effect on reproduction or fertility in rodents. No evidence of impaired fertility was seen in rats with exposures (based on Cmax) up to 216 times that observed following a clinical dosage of 1 mg/kg/day.1 A dose-related cytotoxic effect has been observed on preimplantation mouse embryos, with inhibition of blastocyst formation at a concentration of 100 µM and of post-blastocyst development at 10 µM.2
Teratogenicity/Adverse Pregnancy Outcomes
No evidence of teratogenicity was noted in rats or rabbits with exposures (based on Cmax) up to 399 and 183 times, respectively, that seen at a clinical dosage of 1 mg/kg/day. In rat fetuses, the incidence of a common skeletal variation—unossified or incomplete ossification of sternebra—was increased at 399 times human exposure, 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 the 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), fetal/maternal plasma concentrations were approximately 0.80.3
Stavudine is excreted into the breast milk of lactating rats.1
Human Studies in Pregnancy
In a Phase I/II 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 stavudine PK parameters similar to those in non-pregnant adults.4
Placental and Breast Milk Passage
Stavudine crosses the human placenta, resulting in a cord/maternal blood concentration of 1.0–1.3.5 Stavudine also crosses into human breast milk, resulting in breast milk/maternal plasma concentrations 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
Lactic acidosis, in some cases fatal, has 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 Antiretroviral Drug-Exposed Infants). Didanosine and stavudine should not be prescribed together for pregnant women.
In a U.S. cohort study evaluation of 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.
|Formulation||Dosing Recommendations||Use in Pregnancy|
Note: Generic products available for all formulations.
|Standard Adult Dosef
Body Weight ≥60 kg:
PK in Pregnancy:
Dosing in Pregnancy:
|High placental transfer.b
No evidence of human teratogenicity (can rule out 2-fold increase in overall birth defects).
d4T is not recommended for pregnant women.
Lactic acidosis, sometimes fatal, has been reported in pregnant women receiving ddI and d4T together.
a Individual ARV drug dosages may need to be adjusted in renal or hepatic insufficiency (for details, see the Adult and Adolescent Guidelines Appendix B, Table 7).
b Placental transfer categories—Mean or median cord blood/maternal delivery plasma drug ratio:
c See Teratogenicity section for discussion of EFV and risks in pregnancy.
d Only indicated for use in chronic HBV infection in adults
e Generic formulation available
f WHO recommends maximum dose of 30 mg regardless of weight.
Key to Acronyms: d4T = stavudine; EFV = efavirenz; PK = pharmacokinetic
- Stavudine [package insert]. Food and Drug Administration. 2012. Available at http://packageinserts.bms.com/pi/pi_zerit.pdf. Accessed October 25, 2017.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989–31 July 2016. Wilmington, NC: Registry Coordinating Center. 2016. Available at http://www. apregistry.com/
- Bristol-Myers Squibb Company. Healthcare Provider Important Drug Warning Letter. January 5, 2001. Available at https://aidsinfo.nih.gov/news/549/fda-bristol-myers-squibb-issues-caution-for-hiv-combination-therapy-with-zerit-and-videx-in-pregnant-women. Accessed October 25, 2017
- 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.
- 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.
- 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.