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
Etravirine (Intelence, ETR)
(Last updated:7/31/2012; last reviewed:7/31/2012)
Etravirine (Intelence, ETV) is classified as FDA Pregnancy Category B.
Animal carcinogenicity studies
Etravirine was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to approximately 104 weeks. Daily doses of 50, 200, and 400 mg/kg were administered to mice and doses of 70, 200, and 600 mg/kg were administered to rats in the initial period of approximately 41 to 52 weeks. The high and middle doses were subsequently adjusted because of tolerability and reduced by 50% in mice and by 50% to 66% in rats to allow for completion of the studies. In the mouse study, statistically significant increases in the incidences of hepatocellular carcinoma and incidences of hepatocellular adenomas or carcinomas combined were observed in treated females. In the rat study, no statistically significant increases in tumor findings were observed in either sex. The relevance to humans of these liver tumor findings in mice is unknown. Because of tolerability of the formulation in these rodent studies, maximum systemic drug exposures achieved at the doses tested were lower than those in humans at the clinical dose (400 mg/day), with animal versus human AUC ratios being 0.6-fold (mice) and 0.2 to 0.7-fold (rats).
Reproduction/fertility
No effect on fertility and early embryonic development was observed when etravirine was tested in rats at maternal doses up to 500 mg/kg/day, resulting in systemic drug exposure equivalent to the recommended human dose (400 mg/day).
Teratogenicity/developmental toxicity
Animal reproduction studies in rats and rabbits at systemic exposures equivalent to those at the recommended human dose of 400 mg/day revealed no evidence of fetal toxicity or altered development. Developmental toxicity studies were performed in rabbits (at oral doses up to 375 mg/kg/day) and rats (at oral doses up to 1000 mg/kg/day). In both species, no treatment-related embryo-fetal effects, including malformations, were observed. In addition, no treatment effects were observed in a separate pre- and postnatal study performed in rats at oral doses up to 500 mg/kg/day. The systemic exposures achieved in these animal studies were equivalent to those at the recommended human dose (400 mg/day).
Placental and breast milk passage
There are no data on whether etravirine crosses the placenta or is excreted in breast milk in humans.
Human studies in pregnancy
No adequate and well-controlled studies of etravirine use in pregnant women have been conducted and very limited case report data are available on etravirine use in pregnancy. One small study described use of etravirine in combination with darunavir/ritonavir and other ARV drugs in four pregnant women; PK sampling was done to determine etravirine plasma concentration during the third trimester.1 PK data from these women were similar to those in non-pregnant adults. Data on etravirine in postpartum cord blood and concurrent maternal plasma specimens were available for one patient with values of 112 ng/mL and 339 ng/mL (cord/maternal blood ratio 0.33). No maternal, fetal, or neonatal toxicity was reported; one infant was born with a small accessory auricle on the right ear with no other malformations; no birth defects were noted in the other children. Placental passage of etravirine was noted in another report of use of etravirine, darunavir/ritonavir, and enfuvirtide in a pregnant woman who gave birth to twins (cord blood levels 414 ng/mL in Twin 1 and 345 ng/mL in Twin 2).2 In a separate report on two women receiving etravirine, darunavir/ritonavir, and raltegravir during pregnancy, no perinatal transmission of HIV or congenital abnormalities were observed.3
References
- Izurieta P, Kakuda TN, Feys C, Witek J. Safety and pharmacokinetics of etravirine in pregnant HIV-1-infected women. HIV Med. Apr 2011;12(4):257-258. Available at http://www.ncbi.nlm.nih.gov/pubmed/21371239.
- Furco A, Gosrani B, Nicholas S, et al. Successful use of darunavir, etravirine, enfuvirtide and tenofovir/emtricitabine in pregnant woman with multiclass HIV resistance. AIDS. Jan 28 2009;23(3):434-435. Available at http://www.ncbi.nlm.nih.gov/pubmed/19188762.
- Jaworsky D, Thompson C, Yudin MH, et al. Use of newer antiretroviral agents, darunavir and etravirine with or without raltegravir, in pregnancy: a report of two cases. Antivir Ther. 2010;15(4):677-680. Available at http://www.ncbi.nlm.nih.gov/pubmed/20587860.