EFAVIRENZ

Fetal Risk Summary

Efavirenz is an orally active, nonnucleoside reverse transcriptase inhibitor (nnRTI) that is specific for human immunodeficiency virus, type 1 (HIV-1). It is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infections. Other drugs in this class are delavirdine and nevirapine. Efavirenz has a terminal half-life of 52–76 hours after a single dose and 40–55 hours after multiple dosing (1). The shorter elimination time after chronic dosing is a result of P450 enzyme induction that induces its own metabolism.

In reproduction studies, cynomolgus monkeys were administered oral efavirenz (60 mg/kg/day) throughout pregnancy (post-coital days 20–150) (1). This dose produced plasma drug concentrations similar to those achieved in humans with 600 mg/day. Three of 20 exposed newborns had major congenital malformations, compared with 0 of 20 in nonexposed control monkeys. The defects observed were 1 case each of anencephaly and unilateral anophthalmia, microphthalmia, and cleft palate. In pregnant rats, doses producing plasma concentrations similar to those in humans resulted in an increase in fetal resorptions (1). Neither mating nor fertility was impaired in rats at these doses. No teratogenic or toxic effects were observed in rabbits given doses producing plasma concentrations similar to those in humans (1).

It is not known if efavirenz crosses the human placenta to the fetus. The relatively low molecular weight (about 316), however, suggests that the drug is transferred to the fetus. Placental transfer of efavirenz has been documented in cynomolgus monkeys, rats, and rabbits, with fetal blood concentrations approximately the same as maternal plasma concentrations (1).

The Antiretroviral Pregnancy Registry reported prospective data (reported to the Registry before the outcomes were known) for January 1989 through July 2000 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] 0.8–3.3). There were 25 infants with birth defects among 1256 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 (2).

There were 24 outcomes (21 in the 1st trimester and 3 in the 2nd and/or 3rd trimesters) exposed to either efavirenz alone (2 in the 1st trimester) or in combination with other antiretroviral agents (2). No birth defects were observed in these pregnancies. In comparing the outcomes of prospective registered cases with 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 (2). (See Lamivudine for required statement.) In summary, the limited human data do not allow a prediction as to the safety of efavirenz during pregnancy. However, the teratogenicity observed in cynomolgus monkeys and the embryo toxicity in rats suggests that there is a potential for risk in the developing human. Moreover, exposure of the human embryo/fetus is likely to occur because the agent was found to easily cross the placenta of all animal species tested. Two reviews, one in 1996 and the other in 1997, concluded that all women receiving antiretroviral therapy should continue to receive therapy during pregnancy and that treatment of the mother with monotherapy should be considered inadequate (3,4). In 1998, the Centers for Disease Control and Prevention (CDC) made a similar recommendation that antiretroviral therapy 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 efavirenz, however, is unknown, especially in light of the data from a nonhuman primate. If possible, another agent should be substituted for efavirenz if pregnancy is planned or occurs while the mother is undergoing treatment with this agent. However, if combination therapy with efavirenz 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 potential 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 efavirenz during human lactation have been located. The molecular weight (about 316) is low enough that excretion into breast milk should be expected. In lactating rats, efavirenz is excreted into milk (1).

Reports on the use of efavirenz 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 (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 with controls see Zidovudine).

References

1. Product information. Sustiva. DuPont Pharma, 2000.
2. The Antiretroviral Pregnancy Registry for abacavir (Ziagen), amprenavir (Agenerase, APV), delavirdine meslyate (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-HGV), 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.
3. 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.
4. Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:478–89.
5. 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.
6. Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:276–89.
7. 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.
8. Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast feeding dilemma. Am J Obstet Gynecol 1995;173:483–7.