STAVUDINE

Fetal Risk Summary

Stavudine (2',3'-didehydro-3'-deoxythymidine; d4T) inhibits viral reverse transcriptase and DNA synthesis. It is classified as a nucleoside reverse transcriptase inhibitor (NRTI) used for the treatment of human immunodeficiency virus (HIV) infections. Its mechanism of action is similar to that of five other nucleoside analogues: abacavir, didanosine, lamivudine, zalcitabine, and zidovudine. Stavudine is converted by intracellular enzymes to the active metabolite, stavudine triphosphate.

No evidence of teratogenicity was observed in pregnant rats and rabbits exposed to maximum plasma concentrations up to 399 and 183 times, respectively, of those produced by a human dose of 1 mg/kg/day (1). A dose-related increase in common skeletal variations, post-implantation loss, and early neonatal mortality was observed in one or both species.

Antiretroviral nucleosides have been shown to have a direct dose-related cytotoxic effect on preimplantation mouse embryos. A 1994 report compared this toxicity among zidovudine and three newer compounds, stavudine, didanosine, and zalcitabine (2). Whereas significant inhibition of blastocyst formation occurred with a 1 µmol/L concentration of zidovudine, stavudine and zalcitabine toxicity was not detected until 100 µmol/L, and no toxicity was observed with didanosine up to 100 µmol/L. Moreover, postblastocyst development was severely inhibited in those embryos that did survive exposure to 1 µmol/L zidovudine. As for the other compounds, stavudine, at a concentration of 10 µmol/L (2.24 µg/mL), inhibited postblastocyst development, but no effect was observed with concentrations up to 100 µmol/L of didanosine or zalcitabine. Although there are no human data, the authors of this study concluded that the three newer agents may be safer than zidovudine to use in early pregnancy.

Similar to other nucleoside analogues, stavudine appears to cross the human placenta by simple diffusion (3). The relatively low molecular weight (about 224) is in agreement with this. Stavudine also crosses the placenta in rats, resulting in a fetal:maternal ratio of approximately 0.5 (1). In near-term macaques, the steady-state fetal:maternal plasma ratio was approximately 0.8 (4). A related study found that zidovudine did not affect the placental transfer of stavudine in macaques (5). However, no reports in animals or humans have been located relating to the placental transfer of stavudine triphosphate (the active metabolite) or to the capability of the placenta or the fetus to metabolize stavudine.

Three experimental in vitro models using perfused human placentas to predict the placental transfer of NRTIs (didanosine, stavudine, zalcitabine, and zidovudine) were described in a 1999 publication (6). For each drug, the predicted fetal:maternal plasma drug concentration ratios at steady state with each of the three models were close to those actually observed in pregnant macaques. Based on these results, the authors concluded that their models would accurately predict the mechanism, relative rate, and the extent of in vivo human placental transfer of NRTIs (6).

The Antiretroviral Pregnancy Registry reported, for the period January 1989 through July 2000, prospective data (reported to the Registry before the outcomes were known) involving 526 live births that had been exposed during the 1st trimester to one or more antiretroviral agents (7). Nine of the newborns had congenital defects (1.7%, 95% confidence interval [CI] 0.8–3.3). There were 25 infants with birth defects among 1,256 live births with exposure anytime during pregnancy (2.0%, 95% CI 1.3–3.0). The prevalence rates for the two periods did not differ significantly nor did they differ from the rates expected in a nonexposed population (7).

There were 142 outcomes exposed to stavudine (132 in the 1st trimester and 10 in the 2nd and/or 3rd trimesters) either alone (2 in the 1st trimester) or to stavudine in combination with other antiretroviral agents (7). There were no birth defects observed. In comparing the outcomes of prospectively registered cases to the birth defects among retrospective cases (pregnancies reported after the outcomes were known), the Registry concluded that there was no pattern of anomalies to suggest a common cause (7). (See Lamivudine for required statement.) A 2000 case report described the adverse pregnancy outcomes, including neural tube defects (NTDs), of two pregnant women with HIV infection who were treated with the antiinfective combination trimethoprim/sulfamethoxazole for prophylaxis against Pneumocystsis carinii, concurrently with antiretroviral agents (8). Exposure to stavudine occurred in one of these cases. A 31-year-old woman presented at 15 weeks' gestation. She was receiving trimethoprim/sulfamethoxazole, didanosine, stavudine, nevirapine, and vitamin B supplements (specific vitamins and dosage not given) that had been started before conception. A fetal ultrasound at 19 weeks' gestation revealed spina bifida and ventriculomegaly. The patient elected to terminate her pregnancy. The fetus did not have HIV infection. Defects observed at autopsy included ventriculomegaly, an Arnold-Chiari malformation, sacral spina bifida, and a lumbosacral meningomyelocele. The authors attributed the NTDs in both cases to the antifolate activity of trimethoprim (8).

A 1999 case report described a 26-year-old woman with a 5-year history of HIV infection (9). Two years before her current pregnancy, she had received monotherapy with zidovudine for 19 months followed by 6 months of monotherapy with zalcitabine. She stopped therapy during the first 19 gestational weeks, then started stavudine and lamivudine that was continued until vaginal delivery at term of a healthy 3560-g girl. The infant was not infected with HIV and was doing well at 9 months of age.

No data are available on the advisability of treating pregnant women who have been exposed to HIV via occupational exposure, but one author discourages this use (10).

In summary, although the limited human data does not allow an assessment as to the safety of stavudine during pregnancy, the animal data suggests that the drug may represent a low risk to the developing fetus. Theoretically, exposure to stavudine at the time of implantation could result in impaired fertility because of embryonic cytotoxicity, but this has not been studied in humans. Stavudine peak serum concentrations achievable in humans with therapeutic doses, however, are in the same range that has been found to inhibit postblastocyst development in mice. Mitochondrial dysfunction in offspring exposed in utero or postnatally to NRTIs has been reported (see Lamivudine and Zidovudine), but these findings are controversial and require confirmation.

Two reviews, one in 1996 and the other in 1997, concluded that all women currently receiving antiretroviral therapy should continue to receive therapy during pregnancy and that treatment of the mother with monotherapy should be considered inadequate therapy (11,12). In 1998, the Centers for Disease Control and Prevention (CDC) made a similar recommendation that antiretroviral therapy should be continued during pregnancy, but discontinuation of all therapy during the 1st trimester was a consideration (13). If indicated, therefore, stavudine should not be withheld in pregnancy (with the possible exception of the 1st trimester) because the expected benefit to the HIV-positive mother probably outweighs the unknown risk to the fetus. The efficacy and safety of combined therapy in preventing vertical transmission of HIV to the newborn, however, are unknown, and zidovudine remains the only antiretroviral agent recommended for this purpose (11,12).

Breast Feeding Summary

No reports describing the use of stavudine during lactation have been located. The relatively low molecular weight (about 224), however, suggests that stavudine will be excreted into breast milk. The drug is excreted into the milk of lactating rats (1).

Reports on the use of stavudine during human lactation are unlikely because the antiviral agent is used in the treatment of human immunodeficiency virus (HIV) infections. HIV-1 is transmitted in milk, and in developed countries, breast feeding is not recommended (11,12,14,15 and 16). In developing countries, breast feeding is undertaken, despite the risk, because there are no affordable milk substitutes available. Until 1999, no studies had been published that examined the effect of any antiretroviral therapy on HIV-1 transmission in milk. In that year, a study involving zidovudine was published that measured a 38% reduction in vertical transmission of HIV-1 infection in spite of breast feeding when compared to controls (see Zidovudine).

References

1. Product Information. Zerit. Bristol-Myers Squibb, 2001.
2. Toltzis P, Mourton T, Magnuson T. Comparative embryonic cytotoxicity of antiretroviral nucleosides. J Infect Dis 1994;169:1100–2.
3. Bawdon RE, Kaul S, Sobhi S. The ex vivo transfer of the anti-HIV nucleoside compound d4T in the human placenta. Gynecol Obstet Invest 1994;38:1–4.
4. 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;40:196–202.
5. Odinecs A, Nosbisch C, Unadkat JD. Zidovudine does not affect transplacental transfer or systemic clearance of stavudine (2',3'-didehydro-3'-doxythymidine) in the pigtailed macaque (Macaca nemestrina). Antimicrob Agents Chemother 1996;40:1569–71.
6. Tuntland T, Odinecs A, Pereira CM, Nosbisch C, Unadkat JD. In vitro models to predict the in vivo mechanism, rate, and extent of placental transfer of dideoxynucleoside drugs against human immunodeficiency virus. Am J Obstet Gynecol 1999;180:198–206.
7. The Antiretroviral Pregnancy Registry for abacavir (Ziagen), amprenavir (Agenerase, APV), delavirdine mesylate (Rescriptor), didanosine (Videx, ddl), efavirenz (Sustiva, Stocrin), indinavir (Crixivan, IDV), lamivudine (Epivir, 3TC), lamivudine/zidovudine (Combivir), nelfinavir (Viracept), nevirapine (Viramune), ritonavir (Norvir), saquinavir (Fortovase, SQV-SGC), saquinavir mesylate (Invirase, SQV-HGC), stavudine (Zerit, d4T), zalcitabine (Hivid, ddC), zidovudine (Retrovir, ZDV). Interim Report. 1 January 1989 through 31 July 2000. 2000(December);11(No. 2):1–55.
8. Richardson MP, Osrin D, Donaghy S, Brown NA, Hay, Sharland M. Spinal malformations in the fetuses of HIV infected women receiving combination antiretroviral therapy and co-trimoxazole. Eur J Obstet Gynecol Reprod Biol 2000;93:215–7.
9. Ristola M, Salo E, Ammala P, Suni J. Combined stavudine and lamivudine during pregnancy. AIDS 1999;13:285.
10. Gerberding JL. Management of occupational exposures to blood-borne viruses. N Engl J Med 1995;332:444–51.
11. Carpenter CCJ, Fischi MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JSG, Richman DD, Saag MS, Schooley RT, Thompson MA, Vella S, Yeni PG, Volberding PA. Antiretroviral therapy for HIV infection in 1996. JAMA 1996;276;146–54.
12. Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:478–89.
13. Centers for Disease Control and Prevention. Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR 1998;47:No. RR–2.
14. Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:276–89.
15. de Martino M, Tovo P-A, Tozzi AE, Pezzotti P, Galli L, Livadiotti S, Caselli D, Massironi E, Ruga E, Fioredda F, Plebani A, Gabiano C, Zuccotti GV. HIV-1 transmission through breast-milk: appraisal of risk according to duration of feeding. AIDS 1992;6:991–7.
16. Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast-feeding dilemma. Am J Obstet Gynecol 1995;173:483–7.