Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States

Archived Drugs

Enfuvirtide (Fuzeon, T-20)

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

Animal Studies

Carcinogenicity
Enfuvirtide was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. Long-term animal carcinogenicity studies of enfuvirtide have not been conducted.

Reproduction/Fertility
Reproductive toxicity has been evaluated in rats and rabbits. Enfuvirtide produced no adverse effects on the fertility of male or female rats at doses up to 30 mg/kg/day administered SQ (a dose that is 1.6 times the maximum recommended adult human daily dose on a body surface area basis).

Teratogenicity/Adverse Pregnancy Outcomes
Studies in rats and rabbits have shown no evidence of teratogenicity and no effect on reproductive function with enfuvirtide.¹

Placental and Breast Milk Passage
A study in rats revealed no evidence of harm to the fetus when enfuvirtide was administered in doses up to 27 times the adult human daily dose on a body surface area basis. A separate study in rabbits likewise revealed no harm to the fetus from enfuvirtide doses that were up to 3.2 times the adult human daily dose. Studies of radiolabeled enfuvirtide administered to lactating rats indicated radioactivity in the milk; however, it is not known if this reflected radiolabeled enfuvirtide or metabolites (amino acid and peptide fragments) of enfuvirtide.¹

Human Studies in Pregnancy

Pharmacokinetics
Data on the use of enfuvirtide during human pregnancy are limited to case reports of a small number of women treated with the drug.^2-9

Placental and Breast Milk Passage
In vitro and in vivo studies suggest that enfuvirtide does not readily cross the human placenta. Minimal placental passage of enfuvirtide was reported in published studies that included a total of eight peripartum patients and their neonates. These findings were supported by data from an ex vivo human placental cotyledon perfusion model.^2,5,10-12

Teratogenicity/Adverse Pregnancy Outcomes
In the Antiretroviral Pregnancy Registry and in a national cohort of pregnant women with HIV infection in Italy, insufficient numbers of first-trimester exposures to enfuvirtide in humans have been monitored to be able to make a risk determination.^13,14

References

1. Enfuvirtide [package insert]. Food and Drug Administration. 2015. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021481s030lbl.pdf.
2. Brennan-Benson P, Pakianathan M, Rice P, et al. Enfurvitide prevents vertical transmission of multidrug-resistant HIV-1 in pregnancy but does not cross the placenta. AIDS. 2006;20(2):297-299. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16511429.
3. Cohan D, Feakins C, Wara D, et al. Perinatal transmission of multidrug-resistant HIV-1 despite viral suppression on an enfuvirtide-based treatment regimen. AIDS. 2005;19(9):989-990. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15905684.
4. Meyohas MC, Lacombe K, Carbonne B, Morand-Joubert L, Girard PM. Enfuvirtide prescription at the end of pregnancy to a multi-treated HIV-infected woman with virological breakthrough. AIDS. 2004;18(14):1966-1968. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15353987.
5. Weizsaecker K, Kurowski M, Hoffmeister B, Schurmann D, Feiterna-Sperling C. Pharmacokinetic profile in late pregnancy and cord blood concentration of tipranavir and enfuvirtide. Int J STD AIDS. 2011;22(5):294-295. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21571982.
6. 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.
7. Sued O, Lattner J, Gun A, et al. Use of darunavir and enfuvirtide in a pregnant woman. Int J STD AIDS. 2008;19(12):866-867. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19050223.
8. Madeddu G, Calia GM, Campus ML, et al. Successful prevention of multidrug resistant HIV mother-to-child transmission with enfuvirtide use in late pregnancy. Int J STD AIDS. 2008;19(9):644-645. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18725561.
9. Shust GF, Jao J, Rodriguez-Caprio G, et al. Salvage regimens containing darunavir, etravirine, raltegravir, or enfuvirtide in highly treatment-experienced perinatally infected pregnant women. J Pediatric Infect Dis Soc. 2014;3(3):246-250. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25844164.
10. Ceccaldi PF, Ferreira C, Gavard L, Gil S, Peytavin G, Mandelbrot L. Placental transfer of enfuvirtide in the ex vivo human placenta perfusion model. Am J Obstet Gynecol. 2008;198(4):433 e431-432. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18241815.
11. Peters PJ, Polle N, Zeh C, et al. Nevirapine-associated hepatotoxicity and rash among HIV-infected pregnant women in Kenya. J Int Assoc Physicians AIDS Care (Chic). 2012;11(2):142-149. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22020069.
12. Moisan A, Desmoyer A, Bourgeois-Moine A, et al. Placental transfer of antiretroviral drugs in HIV-infected women: a retrospective study from 2002 to 2009. Abstract 1. Presented at: 11th International Workshop on Clinical Pharmacology of HIV Therapy. 2010. Sorrento, Italy.
13. 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.
14. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 January 1989–31 January 2018. Wilmington, NC: Registry Coordinating Center. 2018. Available at: http://www.apregistry.com/