The proposed study is a phase III, multicenter, controlled, double blind, randomized clinical trial in Thailand to compare the efficacy, safety and tolerance of each of two drugs, tenofovir and lamivudine, versus placebo, given to hepatitis B (HB) chronically infected pregnant women with a positive HBeAg test and normal liver function tests, from 28 weeks' gestation until two months postpartum to prevent perinatal transmission of hepatitis B virus (HBV). Chronic HBV, complicated by cirrhosis and hepatocellular carcinoma (HCC), is the 10th leading cause of death worldwide. About 7% of Thai adults are HBsAg carriers. Universal immunization programs have dramatically reduced the prevalence of infection wherever they have been implemented. Infant HBV immunization and HB immunoglobulin administered at birth effectively prevent most transmission from HBV infected mothers but, despite this active and passive immunization, about 12% of HBV highly viremic mothers transmit the virus to their infants. The antigen HBe (HBeAg) is a marker of high replication. Studies have suggested that antiviral treatment at the end of pregnancy and in the postpartum can reduce the risk of transmission to the child. A potential limitation to this approach is the risk of hepatic disease exacerbation (flare) following discontinuation of antiviral treatment, which has not been properly evaluated. No randomized clinical trials have adequately demonstrated the efficacy and safety of antiviral treatment and this approach is not recommended by the Associations for the Study of Liver Diseases. We hypothesize that tenofovir or lamivudine can decrease HBV viral load in HBV infected pregnant women and therefore the risk of in utero, intrapartum and postpartum transmission before infants are protected by passive-active immunization. We also hypothesize that only moderate flares will be observed after discontinuation of a short antiviral course (5 months). While the primary objective of the study is to assess the efficacy of tenofovir or lamivudine versus placebo for the prevention of perinatal transmission, an important secondary objective is the assessment of the risk of postpartum hepatic disease exacerbation. HBsAg positive women will be enrolled if they have an HBeAg positive test and ALT 30 U/L. They will be randomized to receive tenofovir or lamivudine or placebo from 28 weeks of pregnancy until 2 months postpartum. Within 2 years, 588 women and their infants will be enrolled in 8 sites of the PHPT network in Thailand, where the teams have gained considerable experience in conducting trials for the prevention of mother to child transmission of HIV over the past 15 years. Mothers and infants will be followed until one year postpartum. The primary endpoint will be the detection of HBsAg and HBV DNA at six months of life. An interim analysis will be conducted when half of the outcomes are available. The results of the study will help define policy to manage HBV infected pregnant women to prevent perinatal transmission. PUBLIC HEALTH RELEVANCE: Infants infected at birth with the hepatitis B virus are at risk of both liver damage (cirrhosis) and liver cancer during adulthood. Despite the administration of vaccination and immunoglobulin after birth, about 12% of infants born to mothers with high virus levels become infected. The proposed study will assess the efficacy and safety of giving pregnant women an anti-HBV drug, tenofovir or lamivudine, to prevent the transmission of this virus to their infants.