Hepatitis B Virus: Epidemiology, Prophylaxis, Therapy, Clinical Outcomes, and Novel Therapeutic Directions

Hepatitis B virus (HBV) infection is a worldwide health concern that infects nearly 254 million people globally and causes more than 1 million deaths annually. The highest prevalence is seen in sub-Saharan Africa and the Western Pacific region. Cirrhosis, liver failure, and hepatocellular carcinoma (HCC) are reported as leading complications of chronic HBV. The route of transmission of this infection is mainly by exposure to infected blood and bodily fluids. Transmission from mother-to-child remains the predominant route in highly endemic areas. Vaccination has significantly reduced HBV seroprevalence and complications. However, incomplete vaccination of newborns continues to be a major obstacle to elimination of the disease. Current prevention strategies include universal vaccination, perinatal prophylaxis with hepatitis B immune globulin, and maternal antiviral therapy in pregnant women with high viral load. The management of chronic hepatitis B virus infection predominantly depends on nucleoside analogs, including entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide, as well as pegylated interferon alfa. These therapies effectively suppress viral replication and reduce the risks of cirrhosis, HCC, and liver-related mortality, but they rarely achieve functional cure characterized by hepatitis B surface antigen loss. The persistence of covalently closed circular DNA (cccDNA) remains a major hindrance in HBV eradication. Therefore, novel therapeutic strategies targeting different stages of the viral life cycle, including capsid assembly modulators, small interfering RNAs, nucleic acid polymers, and cccDNA-directed approaches, are under active investigation. This review summarizes the epidemiology, prevention, current therapies, clinical outcomes, and emerging therapeutic advances in HBV infection, highlighting ongoing efforts toward achieving a functional cure and global HBV elimination.