Hepatitis B virus kinetics under antiviral therapy sheds light on differences in hepatitis B e antigen positive and negative infections

Approximately 2 billion people have been infected with hepatitis B virus (HBV) in their lifetime [1, 2]. Since only a small percentage of infected adults develops chronic hepatitis B, global prevalence of this disease is estimated at 350 million people [1]. End-stage HBV infection can lead to cirrhosis and to hepatocellular carcinoma (HCC), and up to 1.2 million people die every year from the consequences of this infection [1]. Chronic HBV infection (CHB) is usually characterized by detectable HBV DNA in serum, as well as the presence of hepatitis B surface antigen (HBsAg). Hepatitis B e antigen (HBeAg) can also be present. However, a large proportion of infected individuals are HBeAg-negative [3], because they are infected with HBV variants that are unable to produce high amounts of the excreted protein that bears the HBe epitope. These HBV mutants are rather uncommon in North America and Northern Europe, but the vast majority of patients with CHB in Southern Europe and Africa is infected with variants that express little or no HBeAg, and prevalence of HBeAg-negative CHB seems to be increasing worldwide [3–5]. Infection with HBeAg-negative hepatitis B variants is associated with lower serum viral levels [6–8], higher intra-hepatic necroinflammatory lesions and more severe progression of disease, with frequent development of cirrhosis and/or HCC [9, 10], than infection with HBeAg-positive strains [6, 11]. Taken together these observations may indicate a stronger immune response against HBeAg-negative infection. Consistent with this, even though the function of the HBe protein is not clear, it has been suggested that it serves to down modulate the immune response [12, 13]. In addition, HBeAg-negative HBV patients represent a more difficult to treat patient pool, due to lower off-treatment sustained responses [7, 14, 15]. Modeling of different viral infections and their treatment has given insight into aspects of viral evolution, pathogenesis and the mechanisms of antiviral drug action [16–20]. Such analyses of HBeAg-positive HBV infection showed that this virus has a short half-life in plasma and rapid viral production. We and others have calculated that the daily production of HBV in HBeAg-positive infection is in excess of 1011 virions and that infected cell lifespan is very variable but can be as short as 2 days [21, 22]. A few studies have also analyzed the effect of drug therapy on the kinetics of HBeAg-negative viral infection [23, 24]. The results from these studies suggest that viral clearance may be even faster in the setting of HBeAg-negative infection. Here we analyze the dynamics of HBeAg-negative infection under a variety of drug treatments and conduct an exhaustive meta-analysis of published results concerning HBV viral dynamics. Our goal was to understand the respective roles of viral production and the immune response in HBeAg-negative infection and compare them with HBeAg-positive infection.