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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: March 28, 2014; last reviewed: March 28, 2014)
Efavirenz 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 60 mg/kg/day (resulting in plasma concentrations 1.3 times that of systemic human therapeutic exposure, with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values).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 readily crosses the placenta in rats, rabbits, and primates, producing cord blood concentrations similar to concentrations in maternal plasma. Maternal and fetal blood concentrations in pregnant rabbits and cynomolgus monkeys are equivalent, while fetal concentrations in rats exceeded maternal concentrations. In a study of 25 mother-infant pairs, median efavirenz cord blood/maternal blood concentration was 0.49 (range 0.37–0.74).2 In a study of 13 women in Rwanda, efavirenz was given during the last trimester of pregnancy and for 6 months after delivery.3 Efavirenz concentrations were measured in maternal plasma, breast milk, and infant plasma. Efavirenz concentration was significantly higher in maternal plasma than skim breast milk (mean breast milk to mean maternal plasma concentration ratio 0.54) and higher in skim breast milk than in infant plasma (mean skim breast milk to mean newborn plasma concentration ratio 4.08). Mean infant plasma efavirenz concentrations were 13.1% of maternal plasma levels. In a study of plasma and hair drug concentration in 56 mother-infant pairs receiving efavirenz-based therapy during pregnancy and breastfeeding, infant plasma levels at delivery and hair levels at age 12 weeks suggested moderate in utero transfer during pregnancy and breastfeeding, with approximately one-third of transfer occurring postpartum (40% cumulative with 15% during breastfeeding).4 All mothers and infants had detectable efavirenz plasma levels at 0, 8, and 12 weeks and mean infant to maternal hair concentration at 12 weeks postpartum was 0.40 for efavirenz.
No data currently are available about the safety and pharmacokinetics of efavirenz in neonates.
Human Studies in Pregnancy
In a study of 25 pregnant women receiving efavirenz during the third trimester as part of clinical care, efavirenz clearance was slightly increased and trough levels were decreased compared with levels measured postpartum.2 These differences are not of sufficient magnitude to warrant dose adjustment during pregnancy.
In a pharmacogenomics study, non-pregnant individuals with the CYP2B6 516 TT genotype had more than 3-fold increases in both short-term and long-term efavirenz exposure, as measured by plasma and hair drug levels, suggesting there could be significant variation in drug levels with CYP2B6 polymorphisms.5 The frequency of this allele varies between different ethnic populations, ranging from 3.4% in white, 6.7% in Hispanic and 20% in African Americans.2
In pregnancies with prospectively reported exposure to efavirenz-based regimens in the Antiretroviral Pregnancy Registry (APR) through July 2013, birth defects were observed in 18 of 766 live births with first-trimester exposure (2.3%, 95% confidence interval [CI], 1.4%–3.7%).6 Although these data provide sufficient numbers of first-trimester exposures to rule out a two-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 APR of defects after first-trimester efavirenz exposure have documented one neural tube defect case (sacral aplasia, myelomeningocele, and hydrocephalus with fetal alcohol syndrome) and one case of bilateral facial clefts, anophthalmia, and amniotic band.6 Among retrospective cases, there are six reports of CNS defects, including three cases of meningomyelocele in infants born to mothers receiving efavirenz during the first trimester.7 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%).8 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%).
Although two small studies (Pediatric AIDS Clinical Trials Group [PACTG] protocol 219/219C and PACTG protocol P1025) reported a higher rate of birth defects among infants with first-trimester exposure to efavirenz compared with those without exposure, the number of exposures was small (35 exposures in PACTG 219/219C and 42 in P1025) and there is overlap in defect cases between the 2 studies.9-11 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 to a rate of 1%) 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 8 weeks of pregnancy (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,12 efavirenz can be continued in pregnant women receiving efavirenz-based antiretroviral therapy who present for antenatal care in the first trimester, provided that the regimen produces virologic suppression. In such situations, additional fetal monitoring (e.g., second-trimester ultrasound) should be considered to evaluate fetal anatomy.
Pharmacokinetic (PK) interactions of efavirenz with some hormonal contraceptives have been reported, with the potential for failure of the progesterone component, particularly when used for emergency contraception.13-16 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 medroxyprogesterone acetate (DMPA) in 17 women found no change in the PK profile of either efavirenz or DMPA with concomitant use.17 DMPA levels remained above the level needed for inhibition of ovulation throughout the dosing interval.
Nightingale SL. From the Food and Drug Administration. JAMA. 1998;280(17):1472. Available at http://www.ncbi.nlm.nih.gov/pubmed/9809716.
Cressey TR, Stek A, Capparelli E, et al. Efavirenz pharmacokinetics during the third trimester of pregnancy and postpartum. J Acquir Immune Defic Syndr. 2012;59(3):245-252. Available at http://www.ncbi.nlm.nih.gov/pubmed/22083071.
Schneider S, Peltier A, Gras A, et al. Efavirenz in human breast milk, mothers', and newborns' plasma. J Acquir Immune Defic Syndr. 2008;48(4):450-454. Available at http://www.ncbi.nlm.nih.gov/pubmed/18614925.
Gandhi M, Mwesigwa J, Aweeka F, et al. Hair and plasma data show that lopinavir, ritonavir, and efavirenz all transfer from mother to infant in utero, but only efavirenz transfers via breastfeeding. J Acquir Immune Defic Syndr. 2013;63(5):578-584. Available at http://www.ncbi.nlm.nih.gov/pubmed/24135775.
Gandhi M, Greenblatt RM, Bacchetti P, et al. A single-nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in plasma and hair among HIV-infected women. J Infect Dis. 2012;206(9):1453-1461. Available at http://www.ncbi.nlm.nih.gov/pubmed/22927450.
Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 Jan 1989–31 July 2013. 2013. Available at http://www.APRegistry.com. Accessed March 5, 2014.
Food and Drug Administration. Efavirenz drug label. 2011. Accessed on February 14, 2014. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020972s038lbl.pdf.
Ford N, Calmy A, Mofenson L. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS. 2011;25(18):2301-2304. Available at http://www.ncbi.nlm.nih.gov/pubmed/21918421.
Knapp KM, Brogly SB, Muenz DG, et al. Prevalence of congenital anomalies in infants with in utero exposure to antiretrovirals. Pediatr Infect Dis J. 2012;31(2):164-170. Available at http://www.ncbi.nlm.nih.gov/pubmed/21983213.
Brogly SB, Abzug MJ, Watts DH, et al. Birth defects among children born to human immunodeficiency virus-infected women: pediatric AIDS clinical trials protocols 219 and 219C. Pediatr Infect Dis J. 2010;29(8):721-727. Available at http://www.ncbi.nlm.nih.gov/pubmed/20539252.
Ford N, Calmy A. Efavirenz is not a known teratogen. Pediatr Infect Dis J. Sep 2012;31(9):999; author reply 1000. Available at http://www.ncbi.nlm.nih.gov/pubmed/22609611.
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. 2010;11(6):303-311. Available at http://www.ncbi.nlm.nih.gov/pubmed/21239358.
Tseng A, Hills-Nieminen C. Drug interactions between antiretrovirals and hormonal contraceptives. Expert Opin Drug Metab Toxicol. 2013. Available at http://www.ncbi.nlm.nih.gov/pubmed/23425052.
Landolt NK, Phanuphak N, Ubolyam S, et al. Efavirenz, in contrast to nevirapine, is associated with unfavorable progesterone and antiretroviral levels when co-administered with combined oral contraceptives. J Acquir Immune Defic Syndr. 2012;62(5):534-539. Available at http://www.ncbi.nlm.nih.gov/pubmed/23187949.
Leticee N, Viard JP, Yamgnane A, Karmochkine M, Benachi A. Contraceptive failure of etonogestrel implant in patients treated with antiretrovirals including efavirenz. Contraception. Apr 2012;85(4):425-427. Available at http://www.ncbi.nlm.nih.gov/pubmed/22036046.
Carten ML, Kiser JJ, Kwara A, Mawhinney S, Cu-Uvin S. Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel (Plan B), and Efavirenz. Infect Dis Obstet Gynecol. 2012;2012:137192. Available at http://www.ncbi.nlm.nih.gov/pubmed/22536010.
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.