Antiviral
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: Contraindicated (HIV) No Human Data—Probably Compatible (Hepatitis B)
PREGNANCY SUMMARY
The human pregnancy experience with entecavir is limited. No structural anomalies have been reported. The animal data suggest low risk. If indicated, the drug should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Entecavir is a guanosine nucleoside analog with selective activity against hepatitis B virus (HBV). It is indicated for the treatment of chronic hepatitis B infection in adults with evidence of active viral replication and other evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. This indication is based on responses after 1-year of treatment in nucleoside-treatment-naïve and lamivudine-resistant adult patients with HBeAg-positive or HBeAg-negative chronic HBV infection with compensated liver disease and on more limited data in adult patients with HIV/HBV co-infection who have received prior lamivudine therapy. Binding to human serum proteins is low (about 13%) and only minor metabolites have been identified. The terminal elimination half-life is about 128–149 hours (1).
Reproduction studies have been conducted in rats and rabbits. Oral doses in these species resulting in systemic exposures up to about 28 and 212 times the human exposure achieved with the maximum recommended human dose of 1 mg/kg (MRHD), respectively, caused no embryo or maternal toxicity. In rats, doses 3100 times the MRHD caused maternal toxicity, embryo–fetal toxicity (resorptions), lower fetal body weights, tail and vertebral malformations, reduced ossification (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and ribs. In rabbits, exposures 883 times the MRHD caused embryo–fetal toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib. In a rat peri-postnatal study, systemic exposures greater than 94 times the MRHD revealed no evidence of adverse effects in offspring (1).
Long-term carcinogenicity studies in mice and rats were positive. In mice, exposures from 3 to 42 times the MRHD resulted in various tumors involving the lungs (may have been a species effect), hepatocellular carcinomas, hemangiomas of ovaries and uterus, and hemangiosarcomas of the spleen. In female rats, hepatocellular adenomas, and combined carcinomas and adenomas were observed at 24 times the MRHD, whereas skin fibromas were induced at 4 times the MRHD. In male and female rats, brain gliomas were induced at 35 and 24 times the MRHD, respectively. Entecavir was not mutagenic in various assays, but clastogenicity was observed in human lymphocyte culture (1).
No evidence of impaired fertility was observed in male and female rats given doses resulting in exposures greater than 90 times the MRHD. However, in other studies, exposures greater than 35 times the MRHD resulted in seminiferous tubular degeneration in rodents and dogs, but not in monkeys (1).
It is not known if entecavir crosses the human placenta. The molecular weight (about 277), minimal metabolism, and long elimination half-life suggest that the drug will cross to the embryo and fetus.
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 10 outcomes exposed to entecavir (9 in the 1st trimester and 1 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). (See Lamivudine for required statement.)
BREASTFEEDING SUMMARY
No reports describing the use of entecavir during human lactation have been located. The molecular weight (about 277), minimal metabolism, and long elimination half-life (128–149 hours) suggest that the drug will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown. Infants of HBsAg-positive or HBeAg-positive mothers should receive hepatitis B immune globulin at birth, followed by the start of the hepatitis B vaccine series soon after birth (3). After the infant receives the first dose of immune globulin, breastfeeding is then permitted (4). However, breastfeeding is contraindicated in women infected with HIV.
References
1.Product information. Baraclude. Bristol-Meyers Squibb, 2007.
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.Product information. HyperHeb B S/D. Talecris Biotherapeutics, 2007.
4.Lawrence RA, Lawrence RM. Breastfeeding. A Guide for the Medical Profession. 5th ed. St. Louis, MO: Mosby, 1999:225.