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Natural history of chronic hepatitis B virus infection

Last reviewed dd mmm yyyy. Last edited dd mmm yyyy

Authoring team

The natural history of CHB is dynamic and complex, and progresses nonlinearly through several recognizable phases. The phases are of variable duration, are not necessarily sequential, and do not always relate directly to criteria and indications for antiviral therapy (1,2).


HBeAg serological status


indications for treatment

1. “Immune tolerant”

HBeAg positive

  • stage seen in many HBeAg-positive children and young adults, particularly among those infected at birth
  • high levels of HBV replication (HBV DNA levels >200 000 IU/mL))
  • persistently normal ALT
  • minimal histological disease

treatment not generally indicated, but monitoring required

2. “Immune active” (HBeAg-positive chronic hepatitis)

HBeAg positive; may develop anti-HBe

  • abnormal or intermittently abnormal ALT
  • high or fluctuating levels of HBV replication (HBV DNA levels >2000 IU/mL)
  • histological necroinflammatory activity present
  • HBeAg to anti-HBeseroconversion possible, with normalisation of ALT leading to “immune-control” phase

treatment may be indicated

3. Inactive chronic hepatitis “Immune control” (previously called inactive carrier)

HBeAg negative, anti-HBe positive

  • persistently normal ALT
  • low or undetectable HBV DNA (HBV DNA levels >2000 IU/mL)
  • risk of cirrhosis and HCC reduced
  • may develop HBeAg-negative disease

treatment not generally indicated, but monitoring required for reactivation and HCC

4. “Immune escape” (HBeAg-negative chronic hepatitis)

HBeAg negative, with or without being anti-HBe positive

  • HBeAg negative and anti-HBe positive
  • abnormal ALT (persistent or intermittently abnormal)
  • moderate to high levels of HBV replication (HBV DNA levels >20,000 IU/mL)
  • older persons especially at risk for progressive disease (fibrosis/cirrhosis)


5.“Reactivation” or “acute-onchronic hepatitis”

HBeAg positive or negative

  • can occur spontaneously or be precipitated by immunosuppression from chemo- or immunosuppressive therapy, HIV infection or transplantation, development of antiviral resistance, or withdrawal of antiviral therapy
  • abnormal ALT
  • moderate to high levels of HBV replication
  • seroconversion to HBeAg positivity can occur if HBeAg negative
  • high risk of decompensation in presence of cirrhosis

treatment indicated


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