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:7/31/2012; last reviewed:7/31/2012)
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.
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 and cleft palate were observed in 3 of 20 infants born to pregnant cynomolgus monkeys receiving efavirenz from gestational Days 20 to 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 one fetus, microphthalmia in another fetus, and cleft palate in a third fetus.
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.2 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 pregnancies with prospectively reported exposure to efavirenz-based regimens in the Antiretroviral Pregnancy Registry through January 2012, birth defects were observed in 18 of 679 live births with first-trimester exposure (2.7%, 95% confidence interval [CI], 1.6%–4.2%).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.3 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.4 Retrospective reports can be biased toward reporting of more unusual and severe cases and are less likely to be representative of the general population experience.
In an updated meta-analysis of 19 studies (including the Antiretroviral Pregnancy Registry data) reporting on birth outcomes among women exposed to efavirenz during the first trimester, there were 39 infants with birth defects among live births in 1,437 women receiving first-trimester efavirenz (rate of overall birth defects, 2.0%, 95% CI, 0.8–3.2%).5 The rate of overall birth defects was similar among women exposed to efavirenz-containing regimens (1,290 live births) and non-efavirenz containing regimens (8,122 births) during the first trimester (pooled relative risk [RR] 0.85, 95% CI, 0.61–1.20). Across all births (1,437 live births with first-trimester efavirenz exposure), 1 neural tube defect (myelomeningocele) was observed, giving a point prevalence of 0.07% (95% CI, 0.002–0.39), within the range reported in the general population. However, the number of reported first-trimester efavirenz exposures still remains insufficient to rule out a significant increase in low-incidence birth defects (incidence of neural tube defects in the general U.S. population is 0.02%–0.2%).
In contrast to the meta-analysis, the Pediatric AIDS Clinical Trials Protocols (PACTG) 219 and 219C studies reported a higher defect rate among infants with first-trimester exposure to efavirenz compared with those without such exposure (adjusted odds ratio 4.31, 95% CI, 1.56–11.86). However, only 32 infants had efavirenz exposure. The PACTG protocol P1025 is a companion study of PACTG 219 with considerable overlap of the cases enrolled. Whereas the P1025 study reported a significant increased risk of congenital anomalies in infants born between 2002 and 2007 with first-trimester exposure to efavirenz, there is overlap in the defect cases between the two studies and only 42 infants are included in this analysis. Thus, additional data are needed on first-trimester efavirenz exposures to more conclusively determine if risk of neural tube defects is elevated.
Efavirenz is classified as FDA Pregnancy Category D, which means that there is positive evidence of human fetal risk based on studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Although the limited data on first-trimester efavirenz exposure cannot rule out a 2- or 3-fold increased incidence of a rare outcome, such as neural tube defects, the available data from the meta-analysis on >1,400 births suggest that there is not a large increase (such as a 10-fold increase) in the risk of neural tube defects with first-trimester exposure. 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 (the primary period of fetal organogenesis) whenever possible. Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz and should be counseled about the potential risk to the fetus and desirability of avoiding pregnancy. Alternate antiretroviral (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 if such alternative regimens are acceptable to provider and patient and will not compromise the woman’s health. However, given that the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy (the neural tube closes at 36–39 days after last menstrual period), pregnancy is rarely recognized before 4 to 6 weeks of pregnancy, and ARV drug changes in pregnancy may be associated with loss of viral control and thus increase risk of transmission to the infant,6 efavirenz can be continued in pregnant women receiving efavirenz-based antiretroviral therapy (ART) who present for antenatal care in the first trimester, provided that the regimen produces virologic suppression. In such situations, additional fetal monitoring (such as second-trimester ultrasound) should be considered to evaluate fetal anatomy.
Higher rates of failure for hormonal contraceptives containing estrogen and progesterone may be associated with 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 if such alternative regimens are acceptable to provider and patient and will not compromise the woman’s health. 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.7 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 clearance after 24 hours was decreased compared with postpartum. These differences are not of sufficient magnitude to warrant dose adjustment during pregnancy.8
- Nightingale SL. From the Food and Drug Administration. JAMA. Nov 4 1998;280(17):1472.Available at http://www.ncbi.nlm.nih.gov/pubmed/9809716.
- Schneider S, Peltier A, Gras A, et al. Efavirenz in human breast milk, mothers', and newborns' plasma. J Acquir Immune Defic Syndr. Aug 1 2008;48(4):450-454. Available at http://www.ncbi.nlm.nih.gov/pubmed/18614925.
- Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center. 2012. Available at http://www.APRegistry.com.
- Bristol-Myers Squibb Company. Efavirenz drug label. Revised June 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020972s041,021360s029lbl.pdf. Accessed on June 25, 2012.
- Ford N, Calmy A, Mofenson L. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS. Nov 28 2011;25(18):2301-2304. Available at http://www.ncbi.nlm.nih.gov/pubmed/21918421.
- Floridia M, Ravizza M, Pinnetti C, et al. Treatment change in pregnancy is a significant risk factor for detectable HIV-1 RNA in plasma at end of pregnancy. HIV Clin Trials. Nov-Dec 2010;11(6):303-311. Available at http://www.ncbi.nlm.nih.gov/pubmed/21239358.
- 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. Feb 2007;81(2):222-227. Available at http://www.ncbi.nlm.nih.gov/pubmed/17192768.
- Cressey TR, Stek A, Capparelli E, et al. Efavirenz pharmacokinetics during the third trimester of pregnancy and postpartum. J Acquir Immune Defic Syndr. Mar 1 2012;59(3):245-252. Available at http://www.ncbi.nlm.nih.gov/pubmed/22083071.