CIDOFOVIR

Fetal Risk Summary

Cidofovir (HPMPC) is used in the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome. The antiviral agent is converted to the active metabolite, cidofovir diphosphate, by intracellular enzymes. In animals, cidofovir is carcinogenic, embryotoxic, and teratogenic.

Cidofovir was carcinogenic in female rats, producing mammary adenocarcinoma at doses as low as 0.6 mg/kg/week, about 0.04 times the recommended human dose based on an area under the plasma concentration curve (AUC) (1). Reproductive studies with cidofovir have been conducted with rats and rabbits (1). Both maternal toxicity and embryotoxicity (reduced fetal body weights) were observed at IV doses of 1.5 mg/kg/day in rats and 1.0 mg/kg/day in rabbits, administered during organogenesis. The no-observable-effect doses for embryotoxicity in rats and rabbits were 0.5 and 0.25 mg/kg/day, respectively, approximately 0.04 and 0.05 times the recommended human dose, respectively, based on an AUC comparison. Teratogenic effects, consisting of external, soft tissue, and skeletal malformations (meningocele, short snout, and short maxillary bones), were observed in the fetuses of rabbits given 1.0 mg/kg/day during organogenesis.

Pregnant mice inoculated intranasally with equine herpesvirus 1 (EHV-1) in the 2nd or 3rd week of gestation, were treated with a single dose of cidofovir 50 mg/kg SC 1 day prior to inoculation (2). A noninfected control group of pregnant mice was also treated at a similar gestational time with the same dose of cidofovir. In the infected group, cidofovir significantly reduced the incidence of virus transfer to the fetus and subsequent abortion, a predictable effect of the virus. No obvious toxic effects were observed in either group.

No reports describing the use of cidofovir during human pregnancy have been located. It is not known whether the drug crosses the placenta to the fetus, but because of its relatively low molecular weight, approximately 315, passage to the fetus should be expected.

Because of the lack of human data, the risk to the human embryo and fetus cannot be assessed. Some risk may exist because of the adverse effects observed at very low doses in the limited animal studies. Despite this risk, the use of cidofovir after the 1st trimester in a pregnant HIV-positive woman with sight-threatening CMV retinitis may be a rational decision.

Breast Feeding Summary

No reports describing the use of cidofovir during lactation have been located. This antiviral agent should not be used during breast feeding because of the potential severe toxicity in a nursing infant. Moreover, although no studies have been reported in lactating humans, cidofovir has induced mammary cancer with very low doses in female rats.

In addition, the mother's clinical status will usually preclude the use of cidofovir during breast feeding. Cidofovir's only approved indication is for the treatment of CMV retinitis in patients infected with human immunodeficiency virus type 1 (HIV-1). Because HIV-1 is transmitted in milk, breast feeding is not recommended in developed countries where there are available affordable milk substitutes (3,4 and 5).

References

1. Product information. Vistide. Gilead Sciences, 1997.
2. Awan AR, Field HJ. Effects of phosphonylmethoxyalkyl derivatives studied with a murine model for abortion induced by equine herpesvirus 1. Antimicrob Agents Chemother 1993;37:2478–82.
3. Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:276–89.
4. 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;6:991–7.
5. Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast feeding dilemma. Am J Obstet Gynecol 1995;173:483–7.