Antiviral
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >>Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
There is limited human pregnancy experience with etravirine. No structural defects have been reported. The animal data suggest low risk. If indicated, the drug should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Etravirine is a specific, non-nucleoside reverse transcriptase inhibitor (NNRTI). It is in the same antiviral class as delavirdine, efavirenz, and nevirapine. Etravirine is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in antiretroviral treatment–experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to an NNRTI and other antiretroviral agents. The drug is metabolized by the liver to metabolites that are at least 90% less active than etravirine. Plasma protein binding of etravirine is 99.6% to albumin and about the same to alpha 1-acid glycoprotein. The elimination half-life is prolonged (41 ± 20 hours) (1).
Animal reproduction studies have been conducted in rats and rabbits. In pregnant rats and rabbits, no evidence of fetal harm was observed at exposures equivalent to the exposure from the recommended human dose of 400 mg/day (1).
Etravirine crosses the human placenta at 34 weeks (2). The etravirine umbilical cord blood concentrations in twins from a mother taking 200 mg twice daily were 577 and 1020 ng/mL. The presence of the drug in fetal blood is consistent with the molecular weight (about 435), prolonged elimination half-life, and lipid solubility.
The Antiretroviral Pregnancy Registry reported, for the period January 1989 through July 2009, prospective data (reported before the outcomes were known) involving 4702 live births that had been exposed during the 1st trimester to one or more antiretroviral agents (3). Congenital defects were noted in 134, a prevalence of 2.8% (95% confidence interval [CI] 2.4–3.4). In the 6100 live births with earliest exposure in the 2nd/3rd trimesters, there were 153 infants with defects (2.5%, 95% CI 2.1–2.9). The prevalence rates for the two periods did not differ significantly. There were 288 infants with birth defects among 10,803 live births with exposure anytime during pregnancy (2.7%, 95% CI 2.4–3.0). The prevalence rate did not differ significantly from the rate expected in a nonexposed population. There were 18 outcomes exposed to etravirine (9 in the 1st trimester and 9 in the 2nd/3rd trimesters) in combination with other antiretroviral agents. There were no birth defects. In reviewing the birth defects of prospective and retrospective (pregnancies reported after the outcomes were known) registered cases, the Registry concluded that, except for isolated cases of neural tube defects with efavirenz exposure, there was no other pattern of anomalies (isolated or syndromic). (See Lamivudine for required statement.)
Two reviews, one in 1996 and the other in 1997, concluded that all women currently receiving antiretroviral therapy should continue to receive the therapy during pregnancy and that treatment of the mother with monotherapy should be considered inadequate (4,5). The same conclusion was reached in a 2003 review with the added admonishment that therapy must be continuous to prevent emergence of resistant viral strains (6). In 2009, the updated U.S. Department of Health and Human Services guidelines for the use of antiretroviral agents in patients infected with HIV-1 continued the recommendation that therapy, with the exception of efavirenz, should be continued during pregnancy (7). If indicated, etravirine should not be withheld in pregnancy because the expected benefit to the HIV-positive mother outweighs the unknown risk to the fetus. Updated guidelines for the use of antiretroviral drugs to reduce perinatal HIV-1 transmission also were released in 2010 (8). Women receiving antiretroviral therapy during pregnancy should continue the therapy but, regardless of the regimen, zidovudine administration is recommended during the intrapartum period to prevent vertical transmission of HIV to the newborn (8). Health care professionals are encouraged to register patients exposed to etravirine during pregnancy in the Antiviral Pregnancy Registry by calling 1-800-258-4263.
BREASTFEEDING SUMMARY
No reports describing the use of etravirine during lactation have been located. The molecular weight (about 435), long elimination half-life (41 ± 20 hours), and lipid solubility suggest that the drug will be excreted into breast milk. However, the high (up to 99.6%) protein binding might limit the amount of exposure. The effect of exposure on a nursing infant is unknown.
Reports on the use of etravirine during human lactation are unlikely, however, because the antiviral agent is used in the treatment of HIV-1 infection. HIV-1 is transmitted in milk, and in developed countries, breastfeeding is not recommended (4,5,7,9–11). In developing countries, breastfeeding is undertaken, despite the risk because no affordable milk substitutes are 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 breastfeeding when compared with controls (see Zidovudine).
References
1.Product information. Intelence. Tibotec Therapeutics, 2008.
2.Furco A, Gosrani B, Nicholas S, Williams A, Braithwaite W, Pozniak A, Taylor G, Asboe D, Lyall H, Shaw A, Kapembwa M. Successful use of darunavir, etravirine, enfuvirtide and tenofovir/emtricitabine in pregnant woman with multiclass HIV resistance. AIDS 2009;23:434–5.
3.Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 July 2009. Wilmington, NC: Registry Coordinating Center; 2009. Available at www.apregistry.com. Accessed May 29, 2010.
4.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.
5.Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:478–89.
6.Minkoff H. Human immunodeficiency virus infection in pregnancy. Obstet Gynecol 2003;101:797–810.
7.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services. December 1, 2009:1–161. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed September 17, 2010:60, 96–8.
8.Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. 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. May 24, 2010:1–117. Available at http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf. Accessed September 17, 2010:30 (Table 5).
9.Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:276–89.
10.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.
11.Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast feeding dilemma. Am J Obstet Gynecol 1995;173:483–7.