Abacavir

Risk Factor: CM
Class: Anti-infectives / Antivirals

Fetal Risk Summary

Abacavir is a synthetic carbocyclic nucleoside analogue that is converted by cellular enzymes to the active metabolite, carbovir triphosphate. It is a nucleoside reverse transcriptase inhibitor (NRTI) used for the treatment of human immunodeficiency virus type 1 (HIV-1). Other drugs in this class are didanosine, lamivudine, stavudine, zalcitabine, and zidovudine.

In reproduction studies, doses of abacavir up to eight times the human therapeutic dose based on body surface area (HTD) comparisons had no effect on the fertility or mating performance of male and female rats (1). However, embryo toxicity (increased resorptions, decreased body weight) was observed. During organogenesis, doses up to 35 times the human exposure based on AUC (about 16 times the HTD) resulted in fetal growth retardation (reduced body weight and grown-rump length), and increased incidences of fetal anasarca and skeletal malformations. Offspring exposed from implantation through weaning had an increased incidence of stillbirth and, in survivors, decreased body weights throughout life. In contrast, no developmental toxicity or malformations were observed in rabbits at doses up to 8.5 times the human exposure based on AUC (1).

Abacavir is transferred across the rat placenta to the fetus (1). In an ex vivo human placental model, the antiviral agent also readily crossed to the fetal side with a high clearance index of about 50% that of antipyrine (2). This result is consistent with the relatively low molecular weight (about 671) and high lipophilic properties of the compound. No accumulation of the drug was found on the fetal side.

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 to one or more antiretroviral agents during the 1st trimester (3). Nine of the newborns had congenital defects (1.7%, 95% confidence interval [CI] 0.83.3). There were 25 infants with birth defects among 1,256 live births with exposure anytime during pregnancy (2.0%, 95% CI 1.33.0). The prevalence rates for the two periods did not differ significantly, nor did they differ from the rates expected in a nonexposed population (3).

There were 19 outcomes exposed to abacavir (11 in the 1st trimester and 8 in the 2nd and/or the 3rd trimesters) in combination with other antiretroviral agents (3). There were no birth defects in these infants. 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 (3). (See Lamivudine for required statement.) In summary, the animal and human data are too limited to determine the safety of abacavir during pregnancy. The agent did cause embryo and fetal toxicity and skeletal malformations in rats, but no developmental toxicity was observed in rabbits. Other antiretroviral nucleosides have been shown to have a direct dose-related cytotoxic effect on preimplantation mouse embryos (see Didanosine, Stavudine, Zalcitabine, and Zidovudine). This toxicity has not been studied in humans. 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 (4,5). 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 (6). If indicated, therefore, abacavir 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 (4,5).

Breast Feeding Summary

No reports have been located that describe the use of abacavir during human lactation. The molecular weight (about 671) is suggestive that the drug will be excreted into breast milk. The antiviral agent is excreted into the milk of lactating rats (1).

Reports on the use of abacavir during human lactation are unlikely because the drug is used in the treatment of HIV-1 infections. HIV-1 is transmitted in milk, and in developed countries, breast feeding is not recommended (4,5,7,8 and 9). 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. Ziagen. Glaxo Wellcome, 2000.
2. Bawdon RE. The ex vivo human placental transfer of the anti-HIV nucleoside inhibitor abacavir and the protease inhibitor amprenavir. Infect Dis Obstet Gynecol 1998;6:2446.
3. 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). 1 January 1989 through 31 July 2000. Interim Report. 2000(December);11(No. 2):155.
4. 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;14654.
5. Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:47889.
6. 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.
7. Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:27689.
8. de Martino M, Tovo P-A, Pezzotti P, Galli L, Massironi E, Ruga E, Floreea F, Plebani A, Gabiano C, Zuccotti GV. HIV-1 transmission through breast-milk: appraisal of risk according to duration of feeding. AIDS 1992;6:9917.
9. Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast feeding dilemma. Am J Obstet Gynecol 1995;173:4837.