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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: August 6, 2015; last reviewed: August 6, 2015)

Regarding embryo-fetal toxicity, the Food and Drug Administration (FDA) advises women to avoid becoming pregnant while taking efavirenz and health care providers to avoid administration in the first trimester of pregnancy as fetal harm may occur.1

Animal Studies

Carcinogenicity
Efavirenz was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. A study evaluating genotoxicity of efavirenz in mice noted DNA damage in brain cells after daily dosing for 36 days; no damage was seen in liver, heart, or peripheral blood cells.2 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
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 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).3 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. 

Human Studies in Pregnancy

Pharmacokinetics/Pharmacogenomics
In an intensive sampling pharmacokinetic (PK) 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.4 These differences are not of sufficient magnitude to warrant dose adjustment during pregnancy. A recent review of this study plus four others that measured single efavirenz concentrations in pregnant women found that efavirenz concentrations were not significantly affected by pregnancy and that high rates of HIV RNA suppression at delivery were achieved with efavirenz regimens.5

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.6 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.4

PK interactions between efavirenz and some hormonal contraceptives have been reported, with the potential for failure of the progesterone component, potentially affecting efficacy of emergency contraception, combined oral contraceptive pills, progestin-only pills, and progestin implants.7-10 A retrospective chart review study suggests that efavirenz may decrease the efficacy of levonorgestrel implants (e.g., Jadelle).11 Pregnancy occurred among 15 (12.4%) of 115 women on efavirenz using Jadelle, compared to no pregnancies among 208 women on nevirapine-based regimens and no pregnancies among 13 women on lopinavir/ritonavir-based regimens (P < 0.001) (see Preconception Counseling and Care). Barrier contraception should always be used in combination with hormonal contraceptives. 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.12 DMPA levels remained above the level needed for inhibition of ovulation throughout the dosing interval. In addition intrauterine devices (IUDs), both copper-containing and levonorgestrel-containing, would be expected to maintain efficacy. 

Placental and Breast Milk Passage
In a study of 25 mother-infant pairs, median efavirenz cord blood/maternal blood concentration was 0.49 (range 0.37–0.74).4 In a study of 13 women in Rwanda, efavirenz was given during the last trimester of pregnancy and for 6 months after delivery.13 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 860 ng/mL and the mean infant plasma efavirenz concentration was 13.1% of maternal plasma concentrations. All infants had detectable plasma concentrations of efavirenz, and 8 of 13 newborns had plasma efavirenz concentrations below the minimum therapeutic concentration of 1,000 ng/mL recommended for treatment of HIV-infected adults. In a study of 51 women in Nigeria receiving efavirenz 600 mg daily, the median (range) milk/maternal plasma ratio was 0.82 (0.51–1.1) and the median (range) infant efavirenz concentration was 178 (88–340) ng/mL.14 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).15 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 PK of efavirenz in neonates.

Teratogenicity Data
In pregnancies with prospectively reported exposure to efavirenz-based regimens in the Antiretroviral Pregnancy Registry through January 2015, birth defects were observed in 20 of 852 live births with first-trimester exposure (2.3%, 95% confidence interval [CI], 1.4% to 3.6%).16 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 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.16 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.1 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 23 studies (including the Antiretroviral Pregnancy Registry data) reporting on birth outcomes among women exposed to efavirenz during the first trimester, there were 44 infants with birth defects among 2,026 live births to women receiving first-trimester efavirenz (rate of overall birth defects (1.63%, 95% CI, 0.78% to 2.48%).17 The rate of overall birth defects was similar among women exposed to efavirenz-containing regimens and non-efavirenz-containing regimens during the first trimester (pooled relative risk [RR] 0.78, 95% CI, 0.56–1.08). Across all births, one neural tube defect (myelomeningocele) was observed, giving a point prevalence of 0.05% (95% CI, <0.01 to 0.28), 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% to 0.2%).

A recent French study of 13,124 live births between 1994 and 2010, included an analysis of 372 infants born after first-trimester efavirenz exposure.18 In the primary analysis using the European Surveillance of Congenital Anomalies (EUROCAT) classification system, no increase in birth defects after first trimester efavirenz exposure was detected compared to those without efavirenz exposure in pregnancy (adjusted odds ratio 1.16, 95% CI, 0.73–1.85). In a secondary analysis using the modified Metropolitan Atlanta Congenital Defect Program classification used by the Antiretroviral Pregnancy Registery, an association was found between first-trimester efavirenz exposure and neurologic defects. However, none of the four defects (i.e., ventricular dilatation with anomalies of the white substance, partial agenesis of the corpus callosum, subependymal cyst, and pachygyria) were neural tube defects, and none of the defects had common embryology.19 First-trimester efavirenz exposure was not associated with an increased risk of defects in a Pediatric HIV/AIDS Cohort Study analysis that included 2,580 live births, 94 after first-trimester efavirenz exposure20 or an analysis of a national cohort in Italy that included 1,257 pregnancies, 80 after first-trimester efavirenz exposure.21

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.22-24 Thus, additional data are needed on first-trimester efavirenz exposures to more conclusively determine if risk of neural tube defects is elevated.

The FDA advises women to avoid becoming pregnant while taking efavirenz and health care providers to avoid administration in the first trimester of pregnancy as fetal harm may occur. 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 more than 2,000 births suggest that there is not a large increase (e.g., a 10-fold increase to a rate of 1%) in the risk of neural tube defects with first-trimester exposure. 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 because of the potential for teratogenicity. 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 to 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,25 efavirenz can be continued in pregnant women receiving efavirenz-based antiretroviral therapy who present for antenatal care in the first trimester. In such situations, additional fetal monitoring (e.g., second-trimester ultrasound) should be considered to evaluate fetal anatomy.

References 

  1. Efavirenz (Sustiva) [package insert]. Food and Drug Administration. 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021360s037,020972s048lbl.pdf. Accessed June 22, 2015.
  2. de Oliveira HM, Damiani AP, Dias Rde O, Romao PR, Andrade VM. Effect of antiretroviral drugs on the DNA damage in mice. Environ Toxicol Pharmacol. 2014;37(1):390-395. Available at http://www.ncbi.nlm.nih.gov/pubmed/24441026.
  3. Nightingale SL. From the Food and Drug Administration. JAMA. 1998;280(17):1472. Available at http://www.ncbi.nlm.nih.gov/pubmed/9809716.
  4. 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.
  5. Hill A, Ford N, Boffito M, Pozniak A, Cressey TR. Does pregnancy affect the pharmacokinetics of efavirenz? AIDS. 2014;28(10):1542-1543. Available at http://www.ncbi.nlm.nih.gov/pubmed/24896806.
  6. 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.
  7. 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.
  8. 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. Available at http://www.ncbi.nlm.nih.gov/pubmed/23187949.
  9. Leticee N, Viard JP, Yamgnane A, Karmochkine M, Benachi A. Contraceptive failure of etonogestrel implant in patients treated with antiretrovirals including efavirenz. Contraception. 2012;85(4):425-427. Available at http://www.ncbi.nlm.nih.gov/pubmed/22036046.
  10. 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.
  11. Perry SH, Swamy P, Preidis GA, Mwanyumba A, Motsa N, Sarero HN. Implementing the Jadelle implant for women living with HIV in a resource-limited setting in sub-Saharan Africa: concerns for drug interactions leading to unintended pregnancies. AIDS. 2014. Available at http://www.ncbi.nlm.nih.gov/pubmed/24401645.
  12. 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;81(2):222-227. Available at http://www.ncbi.nlm.nih.gov/pubmed/17192768.
  13. Schneider E, Whitmore S, Glynn KM, et al. Revised surveillance case definitions for HIV infection among adults, adolescents, and children aged <18 months and for HIV infection and AIDS among children aged 18 months to <13 years--United States, 2008. MMWR Recomm Rep. 2008;57(RR-10):1-12. Available at http://www.ncbi.nlm.nih.gov/pubmed/19052530.
  14. Olagunju A, Siccardi M, et al. Pharmacogenetics of efavirenz excretion into human breast milk and transfer to breastfed infants. Presented at: Conference on Retroviruses and Opportunistic Infections. 2014. Boston, MA.
  15. 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.
  16. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 Jan 1989–31 January 2015. Wilmington, NC: Registry Coordinating Center. 2015. Available at http://www.APRegistry.com.
  17. Ford N, Mofenson L, Shubber Z, et al. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS. 2014;28 Suppl 2:S123-131. Available at http://www.ncbi.nlm.nih.gov/pubmed/24849471.
  18. Sibiude J, Mandelbrot L, Blanche S, et al. Association between prenatal exposure to antiretroviral therapy and birth defects: an analysis of the French perinatal cohort study (ANRS CO1/CO11). PLoS Med. 2014;11(4):e1001635. Available at http://www.ncbi.nlm.nih.gov/pubmed/24781315.
  19. Mofenson LM, Watts DH. Safety of pediatric HIV elimination: the growing population of HIV- and antiretroviral-exposed but uninfected infants. PLoS Med. 2014;11(4):e1001636. Available at http://www.ncbi.nlm.nih.gov/pubmed/24781352.
  20. Williams PL, Crain MJ, Yildirim C, et al. Congenital anomalies and in utero antiretroviral exposure in human immunodeficiency virus-exposed uninfected infants. JAMA Pediatr. 2015;169(1):48-55. Available at http://www.ncbi.nlm.nih.gov/pubmed/25383770.
  21. Floridia M, Mastroiacovo P, Tamburrini E, et al. Birth defects in a national cohort of pregnant women with HIV infection in Italy, 2001-2011. BJOG. 2013;120(12):1466-1475. Available at http://www.ncbi.nlm.nih.gov/pubmed/23721372.
  22. 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.
  23. 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.
  24. Ford N, Calmy A. Efavirenz is not a known teratogen. Pediatr Infect Dis J. 2012;31(9):999; author reply 1000. Available at http://www.ncbi.nlm.nih.gov/pubmed/22609611.
  25. 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.

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