Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States
Non-Nucleoside Reverse Transcriptase Inhibitors
Efavirenz (Sustiva, EFV)
(Last updated:9/14/2011)
Efavirenz (Sustiva, EFV) is classified as Food and Drug Administration (FDA pregnancy category D.
Animal carcinogenicity studies
Efavirenz was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. Long-term animal carcinogenicity studies with efavirenz have been completed in mice and rats. At systemic drug exposures approximately 1.7-fold higher than in humans receiving standard therapeutic doses, no increase in tumor incidence above background was observed in male mice, but in female mice, an increase above background was seen in hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas. No increase in tumor incidence above background was observed in male and female rats with systemic drug exposures lower than that in humans receiving therapeutic doses.
Reproduction/fertility animal studies
No effect of efavirenz on reproduction or fertility in rodents has been seen.
Teratogenicity/developmental toxicity
An increase in fetal resorption was observed in rats at efavirenz doses that produced peak plasma concentrations and area under the curve (AUC) values in female rats equivalent to or lower than those achieved in humans at the recommended human dose (600 mg once daily). Efavirenz produced no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma concentrations similar to and AUC values approximately half of those achieved in humans administered efavirenz (600 mg once daily). Central nervous system (CNS) malformations were observed in 3 of 20 infants born to pregnant cynomolgus monkeys receiving efavirenz from gestational Days 20–150 at a dose of 30 mg/kg twice daily (resulting in plasma concentrations comparable to systemic human therapeutic exposure) [1]. The malformations included anencephaly and unilateral anophthalmia in 1 fetus, microphthalmia in another fetus, and cleft palate in a third fetus.
In pregnancies with prospectively reported exposure to efavirenz-based regimens in the Antiretroviral Pregnancy Registry through January 2011, birth defects were observed in 17 of 623 live births with first-trimester exposure (2.7%, 95% confidence interval [CI], 1.6%–4.3%). Although these data provide sufficient numbers of first-trimester exposures to rule out a 2-fold or greater increase in the risk of overall birth defects, the low incidence of neural tube defects in the general population means that a larger number of exposures are still needed to be able to definitively rule out an increased risk of this specific defect. Prospective reports to the Antiretroviral Pregnancy Registry of defects after first-trimester efavirenz exposure have documented 1 neural tube defect case (sacral aplasia, myelomeningocele, and hydrocephalus with fetal alcohol syndrome) and 1 case of bilateral facial clefts, anophthalmia, and amniotic band [2]. Among retrospective cases, there are 6 reports of CNS defects, including 3 cases of meningomyelocele in infants born to mothers receiving efavirenz during the first trimester [3]. Although a causal relationship has not been established between these events and the use of efavirenz, similar defects have been observed in preclinical studies of the drug.
Placental and breast milk passage
Efavirenz crosses the placenta in rats, rabbits, and primates, producing cord blood concentrations similar to concentrations in maternal plasma. In a study of 13 women in Rwanda, efavirenz was given during the last trimester of pregnancy and for 6 months after delivery [4]. Efavirenz concentrations were measured in maternal plasma, breast milk, and infant plasma. Efavirenz passed into breast milk with a ratio of 0.54 (mean breast milk to mean maternal plasma concentration) and 4.08 (mean skim milk to mean newborn plasma concentration). Mean infant plasma efavirenz concentrations were 13.1% of maternal plasma levels. No data currently are available about efavirenz in neonates.
Human studies in pregnancy
In a meta-analysis of 16 observational cohorts reporting birth outcomes among women exposed to efavirenz during the first trimester, the rate of overall birth defects was similar among women exposed to efavirenz-containing regimens (1,132 live births) and non-efavirenz containing regimens (7,163 births) during the first trimester (pooled relative risk [RR] 0.87, 95% CI, 0.61–1.24, P = 0.45) [5]. Across all studies (1,256 live births with first-trimester efavirenz exposure), 1 neural tube defect (myelomeningocele) was observed, giving a point prevalence of 0.08% (95% CI, 0.002–0.44), within the range reported in the general population. In a separate study from the Ivory Coast, no congenital malformations were observed in 344 HIV-infected pregnant women who conceived while receiving NNRTI-based antiretroviral therapy (ART) (213 on efavirenz and 131 on nevirapine) [6]. In a South African study, the prevalence of overall birth defects was not significantly different between 184 women receiving efavirenz-based ART at conception and 623 receiving efavirenz-based ART in the second or third trimester (3.3% vs. 2.6%, respectively, prevalence ratio 1.27, 95% CI, 0.5–3.2) [7]. However, the number of reported first-trimester efavirenz exposures still remains insufficient to rule out a significant increase in low-incidence birth defects (0.1–0.4% incidence of neural tube defect in the general population).
Efavirenz is classified as FDA Pregnancy Category D and may cause fetal harm when administered to a pregnant woman during the first trimester. Because of the potential for teratogenicity, pregnancy should be avoided in women receiving efavirenz, and treatment with efavirenz should be avoided during the first trimester, which is the primary period of fetal organogenesis. Women of childbearing age should undergo pregnancy testing prior to initiation of efavirenz and should be counseled about the potential risk to the fetus and the need to avoid pregnancy. Higher rates of failure for hormonal contraceptives containing estrogen and progesterone may be associated with antiretroviral (ARV) drugs such as efavirenz. Alternate ARV regimens that do not include efavirenz should be strongly considered in women who are planning to become pregnant or who are sexually active and not using effective contraception. Barrier contraception should always be used in combination with other methods of contraception such as hormonal contraceptives and intrauterine devices. A study evaluating the interaction between efavirenz and depot medroxyprogesetrone (DMPA) in 17 women found no change in the pharmacokinetic (PK) profile of either efavirenz or DMPA with concomitant use [8]. DMPA levels remained above the level needed for inhibition of ovulation throughout the dosing interval.
Limited PK data exist for efavirenz in pregnancy. In a study of 25 pregnant women receiving efavirenz during the third trimester as part of clinical care, efavirenz clearance was increased and C24h was decreased compared with postpartum. These differences are not of sufficient magnitude to warrant dose adjustment during pregnancy [9].
References
1. Nightingale SL. From the Food and Drug Administration. JAMA. 1998 Nov 4;280(17):1472.
2. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 Jan 1989 - 31 January 2011. Wilmington, NC: Registry Coordinating Center; 2010. Available from URL: http://www.APRegistry.com. 2011.
3. Bristol-Myers Squibb Company. Efavirenz drug label. Revised August 2008.
4. Schneider S, Peltier A, Gras A, et al. Efavirenz in human breast milk, mothers', and newborns' plasma. J Acquir Immune Defic Syndr. 2008 Aug 1;48(4):450-454.
5. Ford N, Mofenson L, Kranzer K, et al. Safety of efavirenz in first-trimester of pregnancy: a systematic review and meta-analysis of outcomes from observational cohorts. AIDS. 2010 Jun 19;24(10):1461-1470.
6. Ekouevi DK, Coffie PA, Ouattara E, et al. Pregnancy outcomes in women exposed to efavirenz and nevirapine: an appraisal of the IeDEA West Africa and ANRS Databases, Abidjan, Cote d'Ivoire. J Acquir Immune Defic Syndr. 2011 Feb 1;56(2):183-187.
7. Bera E, McCausland K, Nonkwelo R, Mgudlwa B, Chacko S, Majeke B. Birth defects following exposure to efavirenz-based antiretroviral therapy during pregnancy: a study at a regional South African hospital. AIDS. 2010 Jan 16;24(2):283-289.
8. Cohn SE, Park JG, Watts DH, et al. Depo-medroxyprogesterone in women on antiretroviral therapy: effective contraception and lack of clinically significant interactions. Clin Pharmacol Ther. 2007 Feb;81(2):222-227.
9. Cressey T, Stek A, Capparelli E, et al. EFV Pharmacokinetics during the Third Trimester of Pregnancy and Postpartum. Paper presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI); Feb. 27- Mar 3, 2011; Boston, MA.