Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

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Non-Nucleoside Reverse Transcriptase Inhibitors

Etravirine (Intelence, ETR)

Last Updated: December 7, 2018; Last Reviewed: December 7, 2018

Etravirine is classified as Food and Drug Administration Pregnancy Category B.

Animal Studies

Carcinogenicity
Etravirine was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests.1 Etravirine was evaluated for carcinogenic potential in mice and rats for up to approximately 104 weeks. Due to intolerance of the formulation, areas under the concentration-time curve (AUC) for etravirine were 0.6-fold (in mice) and 0.2-fold to 0.7-fold (in rats) compared to the typical AUC in humans receiving standard dosing. In rats and male mice, no significant findings were noted. In female mice, increased incidences of hepatocellular carcinoma and hepatocellular adenomas or carcinomas combined were seen. It is unclear whether these liver tumor findings in mice are relevant to humans.1

Reproduction/Fertility
Etravirine had no effect on fertility and early embryonic development when tested in pregnant rats at doses that resulted in systemic drug exposures equivalent to those observed in humans who received the recommended dose (400 mg/day).1

Teratogenicity/Adverse Pregnancy Outcomes
Animal reproduction studies in rats and rabbits revealed no evidence of fetal toxicity or altered development at systemic exposures equivalent to those seen in humans who received the recommended dose of etravirine 400 mg/day.1

Human Studies in Pregnancy

Pharmacokinetics
Etravirine pharmacokinetics (PKs) in pregnant women have been reported in two studies. Ramgopal et al. found that total etravirine AUC, Cmin, and Cmax were increased approximately 1.1-fold to 1.4-fold in the second trimester (n = 13) and third trimester (n = 10) compared with levels in the same women postpartum (n = 10). Differences in unbound etravirine concentrations were less pronounced, with least-squares mean ratios of approximately 0.9 to 1.2.2 Similarly, Mulligan et al. found 1.3-fold to 1.9-fold increases in total etravirine AUC, Cmin, and Cmax during the third trimester (n = 13) compared with levels in the same women postpartum (n = 8).3 Etravirine was well tolerated in both of these studies.

Placental and Breast Milk Passage
In seven mother-infant pairs, the median ratio of cord blood to maternal plasma etravirine concentration at delivery was 0.52 (with a range of 0.19–4.25).3 In another study, the median ratio of cord blood to maternal plasma concentration in 10 mother-infant pairs was 0.32 (with a range of 0.19–0.63).2 Placental passage of etravirine was described in a report on the use of etravirine, darunavir/ritonavir, and enfuvirtide in a woman who gave birth to twins. Cord blood etravirine levels were 414 ng/mL in Twin 1 and 345 ng/mL in Twin 2 (no maternal plasma etravirine concentration at delivery was reported).4

Plasma and breast milk concentrations were measured on postpartum days 5 and 14 in eight women who began taking etravirine on postpartum day 1.5 Plasma PKs were similar between days 5 and 14 and were similar to published PK parameters of etravirine in nonpregnant adults. Etravirine AUC0-12h in breast milk was higher in mature milk (Day 14) than in colostrum/transitional milk (Day 5): 12,954 ± 10,200 ng*h/mL versus 4,372 ± 3,016 ng*h/mL (P = 0.046). Median etravirine concentrations in plasma and breast milk on Day 5 were 300 ng/mL and 241 ng/mL, respectively (within-subject breast milk/plasma ratio of 109%). Median plasma and breast milk concentrations on day 14 were 197 ng/mL and 798 ng/mL (within-subject breast milk/plasma ratio of 327%). The maximum etravirine concentration in breast milk was significantly higher than in plasma (1,245 ± 1,159 ng/mL vs. 531 ± 336 ng/mL, P = 0.04). Two women had detectable HIV RNA in breast milk on Day 14 despite suppressed plasma viral loads. Etravirine concentrations in the plasma and breast milk of these women were similar to those observed in women with undetectable HIV RNA in breast milk. Etravirine penetrates well and may accumulate in breast milk.

Teratogenicity/Adverse Pregnancy Outcomes
In eight reported cases of etravirine use in pregnancy, no maternal, fetal, or neonatal toxicity was noted.4,6 One infant was born with a small accessory auricle on the right ear but no other malformations, and no birth defects were noted in the other children.4 Among cases of first-trimester etravirine exposure reported to the Antiretroviral Pregnancy Registry, one defect has been noted out of 66 live births; due to this low number of cases to date, no conclusions can be made about risk of birth defects.7

Excerpt from Table 10a
Generic Name
(Abbreviation)
Trade Name
Formulation Dosing Recommendations Use in Pregnancy
Etravirine
(ETR)
Intelence
Tablets:
  • 25 mg
  • 100 mg
  • 200 mg
For patients unable to swallow tablets whole, the tablets may be dispersed in a glass of water.
Standard Adult Dose:
  • 200 mg twice daily with food

PK in Pregnancy:
  • PK data in pregnancy (n = 26) suggest that etravirine exposure during pregnancy increases 1.2-fold to 1.6-fold.

Dosing in Pregnancy:
  • No change in dose indicated.
Variable placental transfer, usually in the moderate to high categories, ranging from 0.19–4.25 (data from 19 mother-infant pairs).b

Insufficient data to assess for teratogenicity in humans. No evidence of teratogenicity in rats or rabbits.
a Individual ARV drug dosages may need to be adjusted in patients with renal or hepatic insufficiency (for details, see the Adult and Adolescent Guidelines Appendix B, Table 8).
b Placental transfer categories are determined by mean or median cord blood/maternal delivery plasma drug ratio:
          High: >0.6
          Moderate: 0.3–0.6
          Low: <0.3
Key to Acronyms: ARV = antiretroviral; ETR= etravirine; PK = pharmacokinetic

 

References

  1. Etravirine [package insert]. Food and Drug Administration. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022187s024lbl.pdf.
  2. Ramgopal M, Osiyemi O, Zorrilla C, et al. Pharmacokinetics of total and unbound etravirine in HIV-1-infected pregnant women. J Acquir Immune Defic Syndr. 2016;73(3):268-274. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27159225.
  3. Mulligan N, Schalkwijk S, Best BM, et al. Etravirine pharmacokinetics in HIV-infected pregnant women. Front Pharmacol. 2016;7:239. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27540363.
  4. 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. 2009;23(3):434-435. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19188762.
  5. Spencer L, Liu S, Wang C, Neely M, Louie S, Kovacs A. Intensive etravirine PK and HIV-1 viral load in breast milk and plasma in HIV+ women receiving HAART. Poster 891. Presented at: Conference on Retroviruses and Opportunistic Infections. 2014. Boston, MA.
  6. Calcagno A, Trentini L, Marinaro L, et al. Transplacental passage of etravirine and maraviroc in a multidrug-experienced HIV-infected woman failing on darunavir-based HAART in late pregnancy. J Antimicrob Chemother. 2013;68(8):1938-1939. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23535879.
  7. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report 1 January 1989–31 January 2018. Wilmington, NC. 2018. Available at: www.APRegistry.com.

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