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
Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors
Lamivudine (Epivir, 3TC)
(Last updated:9/14/2011)
Lamivudine (Epivir, 3TC) is classified as FDA pregnancy category C.
Animal carcinogenicity studies
Lamivudine has weak mutagenic activity in one in vitro assay but no evidence of in vivo genotoxicity in rats at 35–45 times human exposure. Long-term animal carcinogenicity screening studies at 10 and 58 times human exposure have been negative in mice and rats, respectively.
Reproduction/fertility
Lamivudine administered to rats at doses up to 4,000 mg/kg/day, producing plasma levels 47–70 times those in humans, revealed no evidence of impaired fertility and no effect on the offsprings’ survival, growth, and development up to the time of weaning.
Teratogenicity/developmental toxicity studies
There is no evidence of lamivudine-induced teratogenicity at 35 times human plasma levels in rats and rabbits. Early embryolethality was seen in rabbits at doses similar to human therapeutic exposure but not in rats at 35 times the human exposure level.
In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to lamivudine in humans have been monitored to detect at least a 1.5-fold increase in risk of overall birth defects and a 2-fold increase in the most commonly occurring birth defects, such as defects of the cardiovascular and genitourinary systems. No such increase in birth defects has been observed with lamivudine. Among cases of first-trimester lamivudine exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 3.1% (118 of 3,864 births, 95% CI, 2.5%–3.7%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance [1].
Placental and breast milk passage
Lamivudine readily crosses the placenta in humans, achieving comparable cord blood and maternal concentrations [2]. Lamivudine is excreted into human breast milk. In a study in Kenya of 67 HIV-infected nursing mothers receiving a combination regimen of zidovudine, lamivudine, and nevirapine, the median breast milk lamivudine concentration was 1,214 ng/mL and the median ratio of lamivudine concentration in breast milk to that in plasma was 2.56 [3]. In infants who received lamivudine only via breast milk, median plasma lamivudine concentration was 23 ng/mL (half-maximal inhibitory concentration [IC50] of wild-type HIV against lamivudine = 0.6–21 ng/mL).
Human studies in pregnancy
A small Phase I study in South Africa evaluated the safety and PKs of lamivudine alone or in combination with zidovudine in 20 HIV-infected pregnant women; therapy was started at 38 weeks’ gestation, continued through labor, and given to the infants for 1 week following birth [2]. The drug was well tolerated in the women at the recommended adult dose of 150 mg orally twice daily; PKs were similar to those observed in nonpregnant adults, and no PK interaction with zidovudine was observed.
Intrapartum oral administration of combination zidovudine and lamivudine was well tolerated. Lamivudine was well tolerated in the neonates, but clearance was about 50% that of older children, requiring a reduced dosing regimen (4 mg/kg/day in neonates compared with 8 mg/kg/day for infants older than 3 months). No data currently exist on the PKs of lamivudine in infants 2–6 weeks of age, and the exact age at which lamivudine clearance begins to approximate that in older children is unknown.
References
1. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 Jan 1989 - 31 January 2011. Wilmington, NC: Registry Coordinating Center; 2010. Available from URL: http://www.APRegistry.com. 2011.
2. Moodley J, Moodley D, Pillay K, et al. Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. J Infect Dis. 1998 Nov;178(5):1327-1333.
3. Mirochnick M, Thomas T, Capparelli E, et al. Antiretroviral concentrations in breast-feeding infants of mothers receiving highly active antiretroviral therapy. Antimicrob Agents Chemother. 2009 Mar;53(3):1170-1176.