Role of silent hepatitis B virus in chronic hepatitis B surface antigen(-) liver disease

Despite a number of studies documenting hepatitis B virus (HBV) infection in the absence of hepatitis B surface antigen (HBsAg) a causal relationship between silent HBV infection and liver disease remain difficult to establish. In particular, both the prevalence and clinical significance of this observation are poorly understood. Why is HBV replication apparently so low in these patients? A number of studies have tried to elucidate the mechanism of HBsAg negative infections, and considerable data documenting HBV infectivity or reinfection in the absence of detectable HBsAg support the hypothesis that in some of these cases, HBV is undergoing low-level replication in the liver and this, in several situations including: (1) chronic liver disease, alcoholic liver disease, hepatocellular carcinoma; (2) viral reactivation following cancer chemotherapy or immunosuppression and (3) transmission via transfusion or from human serum to chimpanzees. In a recent study including 50 patients with chronic liver disease of unknown etiology we could detect serum HBV DNA by nested polymerase chain reaction (PCR) in 15/50 patients (50% at the cirrhosis stage) in the absence of HBsAg; in the liver of the 15 patients both HBcAg and/or HBsAg can be detected at very low-level. Viral host factors allowing HBV persistence in the absence of HBsAg can depend on several mechanisms. Coinfections with HCV can explain only a proportion of HBsAg(-) HBV infections. Secondly, HBV mutations in the core promotor region leading to a minimal viral replication, or mutations in the HBsAg-encoding region might explain the absence of serological recognition. Finally, it is possible that in some cases host immune mechanisms can maintain HBV infection in a latent state until transmission to another individual who subsequently develops a more active infection especially when immunosuppressive therapy is employed. Existence of HBsAg(-) HBV infections should be taken into account by the use of sensitive PCR tests for prevention of viral transmission in the settings of blood donations and organ transplants.