Antiviral
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity (Hepatitis B) Contraindicated (HIV)
PREGNANCY SUMMARY
The animal data suggest low risk, but the human data are limited and prevent an assessment of the embryo–fetal risk. If indicated, the drug should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Adefovir, an acyclic nucleotide analog of adenosine monophosphate, is used for the treatment of chronic hepatitis B, especially in patients with clinical evidence of lamivudine-resistant hepatitis B virus. The mechanism involves the inhibition of hepatitis B virus DNA polymerase (reverse transcriptase) (1). It has also been used in patients infected with HIV (1,2). The antiviral agent is available as a prodrug, adefovir dipivoxil, which is rapidly converted to adefovir after oral administration (1). Adefovir is then phosphorylated to the active metabolite, adefovir diphosphate, by cellular kinases. Serum protein binding is very low (≤4%) and the terminal elimination half-life is about 7.5 hours (1).
Reproduction studies have been conducted in rats and rabbits. No evidence of embryotoxicity or teratogenicity was observed in rats after oral dosing that produced systemic exposures up to 23 times the human exposure achieved with the therapeutic dose of 10 mg/day (HE) or in rabbits at 40 times the HE. In rats given maternal toxic IV doses (systemic exposures 38 times the HE), embryotoxicity and an increase in the incidence of fetal malformations (anasarca, depressed eye bulge, umbilical hernia, and kinked tail) were observed. The no-effect exposure from IV doses in pregnant rats was 12 times the HE (1). Intraperitoneal doses of adefovir in mice resulted in dose-related resorptions, low birth weight, neonatal death, and severe lymphoid depletion of the thymus (3).
It is not known if adefovir crosses the human placenta. The molecular weight (about 501) of the prodrug, adefovir dipivoxil, the relative lack of protein binding, and the moderately long terminal elimination half-life suggest that adefovir will cross to the fetal compartment.
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 (4). 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 37 outcomes exposed to adefovir all in the 1st trimester 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) (4). (See Lamivudine for required statement.)
For HIV infection, 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 (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 type 1 (HIV-1)-infected patients continued the recommendation that therapy, with the exception of efavirenz, should be continued during pregnancy (8). If indicated, adefovir 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-1 transmission also were released in 2010 (9). Women receiving antiretroviral therapy during pregnancy should continue the therapy; however, regardless of the regimen, zidovudine administration is recommended during the intrapartum period to prevent vertical transmission of HIV to the newborn (9).
BREASTFEEDING SUMMARY
No reports describing the use of adefovir during lactation have been located. The molecular weight (about 501) of the prodrug, adefovir dipivoxil, the relative lack of protein binding, and the moderately long terminal elimination half-life suggest that the adefovir will be excreted into breast milk. Women infected with hepatitis B can breastfeed without additional risk for the transmission of hepatitis B. However, if adefovir is used during nursing for the treatment of the maternal infection, there is a potential risk of serious toxicity for the nursing infant, such as the nephrotoxicity seen in adults.
Reports on the use of adefovir during human lactation in women infected with HIV are unlikely because HIV-1 is transmitted in milk, and in developed countries, breastfeeding is not recommended (5,6,8,10–12). 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 in spite of breastfeeding when compared with controls (see Zidovudine).
References
1.Product information. Hepsera. Gilead Sciences, 2004.
2.Horowitz HW, Telzak EE, Sepkowitz KA, Wormser GP. Human immunodeficiency virus infection, part II. Dis Mon 1998;44:677–716.
3.Lee JS, Mullaney S, Bronson R, Sharpe AH, Jaenisch R, Balzarini J, De Clercq E, Ruprecht RM. Transplacental antiretroviral therapy with 9-(2-phosphonylmethoxyethyl)adenine is embryotoxic in transgenic mice. J Acquir Immune Defic Syndr 1991;4:833–8.
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, 39–44 (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.