HBeAg negative variants and their role in the natural history of chronic hepatitis B virus infection

Abstract

Molecular virology methods including polymerase chain reaction, cloning and sequencing have revolutionised our understanding of viral genome variation. In the case of hepatitis B virus (HBV), sequencing studies have identified a number of virus variants normally found during the natural course of chronic infection. The appearance of the precore stop codon (with G-for-A substitution at position 1896) and basal core promoter (BCP) (with A-for-T and G-for-A, at positions 1762 and 1764, respectively) variants which reduce or abrogate hepatitis B e antigen (HBeAg) production, heralds the initiation of the seroconversion phase from HBeAg to anti-HBe positivity. The gradual removal of the tolerogenic effect of HBeAg leads to the awakening of the immune response (immune clearance phase). Most patients after HBeAg seroconversion become “inactive HBsAg carriers”. However during the course of infection precore and/or BCP variants may emerge and be selected leading to HBeAg negative chronic hepatitis B (CHB) with high viremia levels (reactivation phase). The prevalence of HBeAg negative CHB has been increasing over the last few decades and has become the commonest type of HBV infection in many countries of the world. This probably reflects the aging of existing HBV carriers and the effective prevention measures restricting new HBV infections. Frequent acute exacerbations accompanied by high viral replication, elevated alanine aminotransferase levels and histological activity are a common feature of HBeAg negative CHB leading to cirrhosis much faster than in HBeAg positive CHB patients.

Keywords: Precore stop codon variants, basal core promoter variants; hepatitis B e antigen negative chronic hepatitis B; Re-activation; Hepatitis B virus-DNA replication

Core tip: Chronic hepatitis B virus infection can in turn go through the immune tolerant, the immune clearance, the inactive or low replicative and the reactivation phases. hepatitis B e antigen (HBeAg) positivity characterises the first two phases. Seroconversion from HBeAg to the corresponding antibody is the result of the appearance of the precore and basal core promoter variants, which either abrogate or lead to reduced HBeAg levels. The absence of HBeAg eliminates its tolerogenic effect on the immune system which thus becomes activated, leading to seroconversion. The reasons why some patients then enter into the reactivation phase during which the variants are the dominant virus present remain unexplained.