Antiviral
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
Several reports have described the use of darunavir in human pregnancy. The animal data suggest low risk, but the obtainable systemic exposures were very low. If indicated, the drug should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Darunavir is an inhibitor of HIV type 1 (HIV-1) protease. Darunavir, coadministered with 100 mg ritonavir, as well as other antiretroviral agents, is indicated for the treatment of HIV infection in antiretroviral-experienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor. Darunavir and ritonavir are combined because darunavir is primarily metabolized by CYP3A and ritonavir inhibits CYP3A, thereby markedly increasing the plasma concentrations of darunavir (lopinavir and tipranavir are combined with ritonavir for the same reason). The metabolites of darunavir are basically inactive, only having about 10% of the activity of darunavir. Plasma protein binding of darunavir is 95%, mainly to α1-acid glycoprotein. The terminal elimination half-life is about 15 hours when combined with ritonavir (1).
Reproduction studies with darunavir have been conducted mice, rats, and rabbits. No embryotoxicity or teratogenicity was observed in these species with doses producing exposures (AUC) that were about 50%, 50%, and 5%, respectively, of the human exposure obtained with the recommended clinical dose boosted with ritonavir based on AUC. The low exposures in the animals resulted from the limited oral bioavailability of darunavir and/or dosing limitations. Long-term carcinogenicity studies in rodents have not been completed. Assays for mutagenicity and chromosomal damage were negative. There was no effect on fertility in rats (1).
Darunavir crosses the human placenta (2–4). The darunavir umbilical cord plasma:maternal plasma ratios at term in two women taking 600/100 mg (darunavir/ritonavir) twice daily during pregnancy were 0.154 and 0.315 (2). The drug also was detected in cord blood at birth in two other women (3,4). The presence of the drug in fetal blood is consistent with the molecular weight (about 594) and prolonged elimination half-life.
Two case reports described the use of darunavir in two pregnancies beginning at 28 and 30 weeks’ gestation (5,6). Both pregnancies ended with births of healthy infants.
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 (7). 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 51 outcomes exposed to darunavir (31 in the 1st trimester and 20 in the 2nd/3rd trimesters) in combination with other antiretroviral agents. There were two birth defects (two in the 1st trimester and none in the 2nd/3rd trimesters). 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) (7). (See Lamivudine for required statement.)
In 1998, a public health advisory was issued by the FDA on the association between protease inhibitors and diabetes mellitus (8). Because pregnancy is a risk factor for hyperglycemia, there was concern that these antiretroviral agents would exacerbate this risk. The manufacturer’s product information also notes the potential risk for new-onset diabetes, exacerbation of preexisting diabetes, and hyperglycemia in HIV-infected patients receiving protease inhibitor therapy (1). An abstract published in 2000 described the results of a study involving 34 pregnant women treated with protease inhibitors compared with 41 controls that evaluated the association with diabetes (9). No association between protease inhibitors and an increased incidence of gestational diabetes was found.
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 therapy (10,11). 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 (12). 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 (13). If indicated, therefore, protease inhibitors, including darunavir, should not be withheld in pregnancy because the expected benefit to the HIV-positive mother outweighs the unknown risk to the fetus. Pregnant women taking protease inhibitors should be monitored for hyperglycemia. Updated guidelines for the use of antiretroviral drugs to reduce perinatal HIV-1 transmission also were released in 2010 (14). 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 (14).
BREASTFEEDING SUMMARY
No reports describing the use of darunavir during lactation have been located. The molecular weight (about 594) and prolonged elimination half-life (about 15 hours) suggest that the drug will be excreted into breast milk. The effect on a nursing infant is unknown.
Reports on the use of darunavir during human lactation are unlikely because the antiviral agent is used in the treatment of HIV infections. HIV-1 is transmitted in milk, and in developed countries, breastfeeding is not recommended (10,11,13,15–17). 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. Prezista. Tibotec Therapeutics, 2007.
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3.Furco A, Gosrani B, Nicholas S, Williams A, Braithwaite W, Pozniak A, Taylor G, Asboe D, Lyall H, Shaw A, Kapembwa M. Successful use of darunavir, etravirine, enfuvirtide and tenofovir/emtricitabine in pregnant woman with multiclass HIV resistance. AIDS 2009;23:434–5.
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5.Sued O, Lattner J, Gun A, Patterson P, Abusamra L, Cesar C, Fink V, Krolewiecki A, Cahn P. Use of darunavir and enfuvirtide in a pregnant woman. Int J STD Aids 2008;19:866–7.
6.Pacanowski J, Bollens D, Poirier JM, Morand-Joubert L, Castaigne V, Girard PM, Meyohas MC. Efficacy of darunavir despite low plasma trough levels during late pregnancy in an HIV-hepatitis C virus-infected patient. AIDS 2009;23:1923–4.
7.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.
8.CDC. Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR 1998;47:No. RR-2.
9.Fassett M, Kramer F, Stek A. Treatment with protease inhibitors in pregnancy is not associated with an increased incidence of gestational diabetes (abstract). Am J Obstet Gynecol 2000;182:S97.
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12.Minkoff H. Human immunodeficiency virus infection in pregnancy. Obstet Gynecol 2003;101:797–810.
13.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.
14.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, 39–44 (Table 5).
15.Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:276–89.
16.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.
17.Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast feeding dilemma. Am J Obstet Gynecol 1995;173:483–7.