Antiviral
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
Although the animal data suggest low risk, the absence of detailed human pregnancy experience prevents an assessment of the embryo–fetal risk. If indicated, the drug should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Maraviroc, a cellular chemokine receptor (CCR5) antagonist, is in the same antiviral subclass of entry inhibitors as enfuvirtide. It is indicated for combination antiretroviral treatment of adults infected with only CCR5-tropic detectable HIV-1, who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. The drug is metabolized to inactive compounds by the cytochrome P450 system and is moderately (76%) bound to plasma proteins, including both albumin and α1-acid glycoprotein. The terminal half-life at steady state is 14–18 hours (1).
Reproduction studies have been conducted in rats and rabbits. No increase in the incidence of fetal variations and malformations was observed in these species at exposures (AUC) that were 20 and 5 times, respectively, the human exposure from the recommended daily dose (HE). No effects of the exposure were observed in the offspring during prenatal and postnatal development studies, including fertility and reproductive performance (1).
Carcinogenicity studies have been conducted in mice and rats and no drug-related increases in tumor incidence were observed. Maraviroc was not genotoxic in multiple assays and did not impair mating or fertility of male and female rats at exposures that were about 20 times the HE (1).
Consistent with the molecular weight (514), moderate protein binding, and long elimination half-life, maraviroc crosses the human placenta. A woman with HIV became pregnant and was treated with multiple antiviral agents (2). Maraviroc (150 mg twice daily) was started at 29 weeks’ gestation. At 38 weeks’, a cesarean section gave birth to a baby with no abnormalities. At birth, maraviroc concentrations in the maternal plasma and cord blood, 13 hours after a dose, were 186 and 69 ng/mL, respectively, a ratio of 0.37 (2). Another study using an ex vivo human cotyledon perfusion model also found that the drug crosses the human placenta (3).
The Antiretroviral Pregnancy Registry has reported one 2nd/3rd trimester exposure to maraviroc. An apparently normal outcome was observed (4).
Two reviews, one in 1996 and the other in 1997, concluded that all women receiving antiretroviral therapy should continue to receive the therapy during pregnancy and that treatment of the mother with monotherapy should be considered inadequate (5,6). 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 (7). In 2009, the updated U.S. Department of Health and Human Services guidelines for the use of antiretroviral agents in HIV-1 infected patients continued the recommendation that therapy, with the exception of efavirenz, should be continued during pregnancy (8). If indicated, maraviroc 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 transmission also were released in 2010 (9). 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 (9). Physicians are encouraged to register exposed patients in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263 (1).
BREASTFEEDING SUMMARY
No reports have been located that describe the use of maraviroc during human lactation. The molecular weight (about 514) and long elimination half-life (14–18 hours) suggest that the drug will be excreted into breast milk. The effect on a nursing infant is unknown.
Reports on the use of maraviroc during human lactation are unlikely because the drug is used in the treatment of HIV infections. HIV is transmitted in milk, and in developed countries, breastfeeding is not recommended (5,6,8–12). In developing countries, breastfeeding is undertaken, despite the risk, because milk substitutes are not affordable. Until 1999, no studies had been published that examined the effect of any antiretroviral therapy on HIV 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. Selzentry. Pfizer. 2007.
2.Calcagno A, Trentini L, Marinaro L, Montrucchio C, D’Avolio A, Ghisetti V, Di Perri G, Bonora S. 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;68:1938–9.
3.Vinot C, Gavard L, Treluyer JM, Manceau S, Courbon E, Scherrmann JM, Decleves X, Duro D, Peytavin G, Mandelbrot L, Giraud C. Placental transfer of maraviroc in an ex vivo human cotyledon perfusion model and influence of ABC transporter expression. Antimicrob Agents Chemother 2013;57:1415–20.
4.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.
5.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.
6.Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:478–89.
7.Minkoff H. Human immunodeficiency virus infection in pregnancy. Obstet Gynecol 2003;101:797–810.
8.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.
9.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.
10.Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:276–89.
11.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.
12.Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast-feeding dilemma. Am J Obstet Gynecol 1995;173:483–7.