Antiviral
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of raltegravir in human pregnancy have been located. Although the animal data suggest low risk, the absence of 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
Raltegravir is an HIV type 1 (HIV-1) integrase strand transfer inhibitor. There are no other antiviral agents in this class. Raltegravir, in combination with other antiretroviral agents, is indicated for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. The drug is partially metabolized by glucuronidation. Plasma protein binding is about 83% and the apparent terminal half-life is about 9 hours (1).
Reproduction studies have been conducted in rats and rabbits. In these species, at doses producing systemic exposures up to 3–4 times the human exposure at the recommended human dose (HERHD), no treatment-related effects on embryo–fetal survival or fetal weights were observed. In pregnant rats, an exposure 3 times the HERHD caused an increased incidence of supernumerary ribs. In pregnant rabbits receiving exposures that were 3–4 times the HERHD, no treatment-related external, visceral, or skeletal changes were observed (1).
Raltegravir crosses the placenta in rats and rabbits. In rats, doses producing systemic exposures that were 3–4 times the HERHD resulted in fetal plasma concentrations that were about 1.5–2.5 times the maternal plasma at 1 and 24 hours postdose, respectively. In rabbits, a similar maternal exposure produced mean drug concentrations in fetal plasma that were 2% of the mean maternal concentration at both 1 and 24 hours postdose (1).
It is not known if raltegravir crosses the human placenta. Although the molecular weight (about 483), moderate plasma protein binding, and terminal half-life suggest that exposure of the embryo–fetus will occur, the low lipid solubility might mitigate the amount of exposure.
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 (2). 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 raltegravir (8 in the 1st trimester and 10 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 in retrospective reports, there was no other pattern of anomalies (isolated or syndromic) (2). Health care professionals are encouraged to register patients exposed to raltegravir during pregnancy in the Antiviral Pregnancy Registry by calling the toll-free number 800-258-4263. (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 therapy during pregnancy and that treatment of the mother with monotherapy should be considered inadequate (3,4). 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 (5). 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 (6). If indicated, raltegravir should not be withheld in pregnancy since 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 (7). 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 (7).
BREASTFEEDING SUMMARY
No reports describing the use of raltegravir during lactation have been located. The molecular weight (about 483), moderate plasma protein binding (about 83%), and long terminal half-life (about 9 hours) suggest that the drug will be excreted into breast milk, but the low lipid solubility might mitigate the amount of exposure. The effect on a nursing infant is unknown.
Reports on the use of raltegravir during human lactation are unlikely, however, because the antiviral agent is used in the treatment of HIV infection. HIV-1 is transmitted in milk, and in developed countries, breastfeeding is not recommended (3,4,6,8–10). In developing countries, breastfeeding is undertaken, despite the risk, because there are no affordable milk substitutes 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. Isentress. Merck & Company, 2008.
2.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.
3.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.
4.Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:478–89.
5.Minkoff H. Human immunodeficiency virus infection in pregnancy. Obstet Gynecol 2003;101:797–810.
6.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.
7.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).
8.Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:276–89.
9.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.
10.Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast feeding dilemma. Am J Obstet Gynecol 1995;173:483–7.