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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

Stavudine (Zerit, d4T)

(Last updated: March 28, 2014; last reviewed: March 28, 2014)

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

Animal Carcinogenicity Studies

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.

Reproduction/Fertility

Stavudine has not been shown to have an effect on reproduction or fertility in rodents. A dose-related cytotoxic effect has been observed on pre-implantation mouse embryos, with inhibition of blastocyst formation at a concentration of 100 µM and of post-blastocyst development at 10 µM.1

Teratogenicity/Developmental Toxicity Studies

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. 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.

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 2.5% (20 of 801 births; 95% CI, 1.5% to 3.8%) compared with a total prevalence in the U.S. population of 2.7%, based on CDC surveillance.2

Placental and Breast Milk Passage

Stavudine crosses the rat placenta in vivo and the human placenta ex vivo, resulting in a fetal/maternal concentration of approximately 0.50. In primates (pig-tailed macaques), fetal/maternal plasma concentrations were approximately 0.80.3 Stavudine is excreted into the breast milk of lactating rats. Stavudine also crosses into human breast milk, resulting in breast milk/maternal plasma concentrations of 1.0–1.76. Concentrations in nursing infants were negligible.4,5

Human Studies in Pregnancy

A Phase I/II safety and pharmacokinetic (PK) study has been conducted of combination stavudine and lamivudine in pregnant HIV-infected women and their infants (PACTG 332). Both drugs were well tolerated, with stavudine PKs similar to those in non-pregnant adults.6 Data from primate studies also indicated that pregnancy did not affect the PKs of stavudine.7

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.8-10 The FDA and Bristol-Myers Squibb have 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 NRTI Drugs and Mitochondrial Toxicity). These drugs should be prescribed together for pregnant women only when the potential benefit clearly outweighs the potential risk. Clinicians should prescribe this ARV combination in pregnancy with caution and generally only when other nucleoside analog drug combinations have failed or have caused unacceptable toxicity or side effects.

Although the standard adult dosing in the U.S. is weight-based, the World Health Organization recommends 30 mg, twice-daily dosing regardless of body weight.11

References

  1. 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.
  2. 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.
  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. 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.
  5. 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.
  6. 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.
  7. Odinecs A, Pereira C, Nosbisch C, Unadkat JD. Prenatal and postpartum pharmacokinetics of stavudine (2',3'-didehydro-3'-deoxythymidine) and didanosine (dideoxyinosine) in pigtailed macaques (Macaca nemestrina). Antimicrob Agents Chemother. 1996;40(10):2423-2425. Available at http://www.ncbi.nlm.nih.gov/pubmed/8891157.
  8. Bristol-Myers Squibb Company. Healthcare Provider Important Drug Warning Letter. 2001. New York, NY; 2001. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm173947.htm. Last accessed on February 14, 2014. 
  9. 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.
  10. 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.
  11. World Health Organization. Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach: 2010 Revision. Geneva, Switzerland; 2010.

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