Occult hepatitis B virus infection

Occult hepatitis B virus (HBV) infection (OBI) is defined as the presence of replication-competent HBV DNA in the liver or blood of individuals who are seronegative for hepatitis B surface antigen. The prevalence of OBI varies hugely according to the local endemicity of chronic HBV infection and risk of HBV exposure, ranging from 0.8% in the general population to >10% in those with hepatitis C virus or HIV infection, and to >40% in individuals with isolated positive antibody to hepatitis B core antigen (anti-HBc). Diagnosing OBI remains challenging due to extremely low and fluctuating levels of HBV DNA in individuals over time. Positive serological markers, such as anti-HBc, only arouse clinician suspicion, with no diagnostic confidence, but can be used to identify people with previous exposure to HBV and for subclassification of OBI, which should be combined with serum HBV DNA testing. The consequences of OBI include transmission of HBV during the transfusion of blood products or solid organ transplantation, reactivation of HBV in patients undergoing immunosuppressive therapy, acceleration of disease progression in those with pre-existing chronic liver diseases, and an increased risk of hepatocellular carcinoma development. In this Review, we describe the core knowledge of OBI - epidemiology, diagnosis, mechanisms and virology, and clinical management - that clinicians should be aware of, and elaborate on challenges and future directions associated with OBI.