How does the HBeAg (Hepatitis B e-antigen) stratify the activity of Hepatitis B infection?

From the Guidelines

The presence of HBeAg in the blood is a key marker for high viral replication and infectivity in hepatitis B infection, indicating active viral replication in the liver and greater infectivity compared to HBeAg-negative patients. When HBeAg is positive, it typically represents earlier stages of infection with more active viral replication and higher risk of liver damage, while HBeAg-negative status (with anti-HBe antibodies) often indicates a later phase with lower viral loads and potentially less liver inflammation 1. However, some patients with HBeAg-negative chronic hepatitis B may still have significant viral replication due to viral mutations.

Stratification of Hepatitis B Infection

The HBeAg status helps clinicians stratify patients into different phases of infection:

• HBeAg-positive chronic hepatitis B: earlier stages of infection with more active viral replication and higher risk of liver damage
• HBeAg-negative status (with anti-HBe antibodies): later phase with lower viral loads and potentially less liver inflammation The loss of HBeAg and development of anti-HBe antibodies (seroconversion) is generally considered a favorable prognostic sign, often associated with decreased viral replication, reduced infectivity, and lower risk of progression to cirrhosis and hepatocellular carcinoma 1.

Treatment Decisions

This stratification directly impacts treatment decisions, as HBeAg-positive patients with elevated ALT levels are typically prioritized for antiviral therapy, with HBeAg seroconversion representing an important treatment endpoint in these patients. The goal of antiviral treatment is to suppress viral replication, reduce liver inflammation, and prevent progression to cirrhosis and hepatocellular carcinoma. The clearance or seroconversion of HBeAg is an important goal of antiviral treatment in patients with HBeAg-positive active hepatitis 1.

Key Points

• HBeAg is a key marker for high viral replication and infectivity in hepatitis B infection
• HBeAg-positive status indicates active viral replication and greater infectivity
• HBeAg-negative status (with anti-HBe antibodies) often indicates a later phase with lower viral loads and potentially less liver inflammation
• The loss of HBeAg and development of anti-HBe antibodies (seroconversion) is a favorable prognostic sign
• HBeAg seroconversion is an important treatment endpoint in HBeAg-positive patients with elevated ALT levels 1.

From the Research

HBeAg and Hepatitis B Infection Activity

The presence of Hepatitis B e-antigen (HBeAg) is a key indicator of active Hepatitis B virus (HBV) replication and disease progression.

• HBeAg is a marker for active viral replication in hepatocytes, indicating the presence of HBV DNA 2.
• The presence of HBeAg is associated with highly replicative activity of the HBV, marking the first two phases of chronic HBV infection, namely the immune tolerant phase and the immune clearance phase 3.
• HBeAg positivity is linked to an increased risk of hepatocellular carcinoma (HCC), with a relative risk of 60.2 compared to those negative for both HBsAg and HBeAg 2.

HBeAg and Disease Progression

HBeAg plays a crucial role in the natural history of chronic HBV infection, influencing disease progression and treatment outcomes.

• HBeAg seropositivity is a marker for active viral replication, and its presence is associated with significant necroinflammation and fibrosis 3.
• The presence of HBeAg can affect treatment decisions, with antiviral therapy recommended for patients in the immune clearance phase with evidence of significant necroinflammation and fibrosis 3.
• HBeAg can also influence the risk of developing HCC, with positivity for HBeAg associated with an increased risk of HCC development 2.

HBeAg and Occult HBV Infection

HBeAg can also be present in cases of occult HBV infection (OBI), where HBV DNA is detectable in serum and/or liver without detectable HBsAg.

• The presence of HBeAg in OBI is unusual, but can occur in patients with negative HBsAg but positive HBV DNA 4.
• Patients with negative HBsAg but positive HBeAg may represent a unique type of OBI, highlighting the importance of testing for HBeAg in such cases 4.

HBeAg and Immune Response

HBeAg can also modulate the immune response, influencing the host's ability to control HBV infection.

• HBeAg can activate the suppressor of cytokine signaling 2 (SOCS2) to repress interferon action, facilitating HBV replication 5.
• HBeAg can impair IFN/JAK/STAT signaling, reducing the stability of tyrosine kinase 2 (TYK2) and downregulating the expression of type I and III IFN receptors 5.