Risk Factor: CM
Class: Anti-infectives/ Antivirals
Fetal Risk Summary
The synthetic nonnucleoside reverse transcriptase inhibitor (nnRTI), delavirdine, is used in the treatment of the human immunodeficiency virus type 1 (HIV-1). Because resistant viruses emerge rapidly with delavirdine monotherapy, the drug should always be used in combination with other antiretroviral agents (1). Other drugs in this class are efavirenz and nevirapine.
Reproductive studies with delavirdine have been conducted in rats and rabbits. Ventricular septal defects were produced when pregnant rats were administered the agent during organogenesis at doses producing systemic levels equal to or lower than the expected human exposure at the recommended dose (1). Reduced pup survival on the day of birth was also noted at this dose. At doses producing 5 times the expected human exposure at the recommended dose, marked maternal toxicity, embryo toxicity, fetal developmental delay, and reduced pup survival were observed. Delavirdine administered during organogenesis to rabbits caused maternal toxicity, embryo toxicity, and abortions (1). The lowest dose producing these effects was about 6 times the expected human exposure at the recommended dose. No malformations were observed in the surviving rabbit offspring, but only a few were available for examination (1).
It is not known if delavirdine crosses the human placenta. The molecular weight (about 553 for the mesylate salt) is low enough, however, that passage to the fetus should be expected.
During premarketing clinical studies, seven unplanned pregnancies occurred resulting in three ectopic pregnancies, three healthy live births, and one premature infant with a birth defect (1). The infant, exposed early in gestation to about 6 weeks of delavirdine and zidovudine, had a small muscular ventricular septal defect.
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 (2). 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 (2).
There were six outcomes (all exposed during the 1st trimester) that were exposed to delavirdine in combination with other antiretroviral agents (2). No birth defects were observed in these infants. (See Lamivudine for required statement.) In summary, the limited human data do not allow a prediction as to the safety of delavirdine during pregnancy. However, the animal data indicates that the drug may represent a risk to the developing human fetus. Moreover, one exposed newborn had a ventricular septal defect, an anomaly identical to that seen in rats. 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 (3,4). 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 (5). Whether these recommendations to continue therapy apply to delavirdine, however, is unknown. If possible, another agent should be substituted for delavirdine if pregnancy is planned or occurs while the mother is undergoing treatment with this agent. However, if combination therapy with delavirdine is mandatory, it should not be withheld (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 mother should be counseled on the risk to her fetus. The efficacy and safety of combined therapy in preventing vertical transmission of HIV to the newborn are unknown, and zidovudine remains the only antiretroviral agent recommended for this purpose (3,4).
Breast Feeding Summary
No reports describing the use of delavirdine during lactation have been located. The molecular weight (about 553 for the mesylate salt) is low enough that excretion into breast milk should be expected. Delavirdine is concentrated (35 times the maternal plasma level) in the milk of lactating rats (1).
Reports on the use of delavirdine during human lactation are unlikely, however, 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 (3,4,6,7 and 8). 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 despite breast feeding when compared to controls (see Zidovudine).
- Product information. Rescriptor. Agouron Pharmaceuticals, 2001.
- 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):155.
- 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.
- Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:47889.
- 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.
- Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:27689.
- 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.
- Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast feeding dilemma. Am J Obstet Gynecol 1995;173:4837.