The stages of chronic hepatitis B infection has been given a makeover. Is it time for Hep B Bear to move aside?
The latest clinical practice guidelines for hepatitis B published by the European Association for the Study of the Liver (EASL) not only set out recommended treatment protocols but also re-framed and re-named the phases of chronic hepatitis B virus (HBV) infection.
For a start, it was made clear that the phases are not necessarily sequential and there are five phases, not four as often presented.
Rather than describing the natural history of chronic hepatitis B infection through the lens of immune response*, the new naming system re-frames it in terms of the liver health and the presence or absence of the hepatitis B e antigen, clearly differentiating chronic hepatitis B virus (HBV) infection and chronic hepatitis B (CHB).
In this new description, chronic hepatitis B viral infection is broadly divided into two states: infection only versus infection plus hepatitis. In other words, disease development is separated into the states where:
- the person is infected with the virus but has no liver inflammation, (referred to as chronic infection) and
- where the person has the virus as well as the accompanying liver inflammation – hepatitis (referred to as chronic hepatitis).
These two broad states can further be refined into phases marked by the level of activity of the virus as indicated by the presence of hepatitis B e antigens. These resulting four phases correspond more or less to the old descriptions “immune tolerance”, “immune clearance”, “immune control” and “immune escape” as shown in the table below:
NATURAL HISTORY OF CHRONIC HEPATITIS B INFECTION
| New naming system | Old naming system |
| e antigen positive, chronic infection (no liver disease – normal ALT, high hepatitis B virus DNA) | immune tolerant |
| e antigen positive, chronic hepatitis B (liver damage – high ALT, high hepatitis B virus DNA) | immune clearance (also known as “immune reactive”) |
| e antigen negative, chronic infection (minimal liver damage – normal ALT, undetectable/low hepatitis B virus DNA) | immune control (also known as “inactive carrier”) |
| e antigen negative, chronic hepatitis B (liver damage – high ALT, high hepatitis B virus DNA) | immune escape (sometimes known as “mutant escape”) |
| Occult infection (surface antigen undetectable, core antibodies present) |
The occult HBV infection phase (often omitted in the old description), where hepatitis B surface antigen is not detected and hepatitis B core antibodies are present indicates suppression of the hepatitis B virus. If this phase occurs before the onset of cirrhosis, the risk of serious liver disease and cancer is minimised. In the old naming system, this phase was sometimes referred to as the Clear stage.
While it provides clarity for clinicians, the lack of a focus that provides a simple naming pattern means it is harder for the lay person to grasp and remember.
Phase 1 of chronic hepatitis B viral infection is prolonged in people who acquired the disease in childhood. In this phase the virus is replicating actively but the liver remains undamaged.
Phase 2 of chronic hepatitis B sees liver damage occurring together with active replication of the hepatitis B virus. People who acquire hepatitis B infection as adults get to this stage quicker than those who acquire it in childhood. Phase 2 may progress to either Phase 3 or Phase 4.
Phase 3 is where the hepatitis B virus is not replicating and liver function is normal even though the hepatitis B DNA, usually at low or undetectable levels in this Phase, may still be detected in some cases. There is low risk of cirrhosis or liver cancer in this phase but it can progress to 4 which is not as benign. A small percentage of people (1 to 3 %) in Phase 3 go on to spontaneous remission (Phase 5).
Phase 4 of chronic hepatitis B viral infection is characterised by moderate to severe liver disease with high hepatitis B DNA levels but undetectable e antigens. Variants, sometimes referred to as “mutants” can be found in virus core. Chances of spontaneous remission from this phase are low.
Phase 5 of chronic hepatitis B viral infection is where the virus, although still present, is suppressed and the HBV surface antigen cannot be detected. If cirrhosis has developed before reaching this point, liver cancer remains a risk. The virus may also be reactivated by immunosuppression.
So that, in a nutshell, is the new nomenclature for the chronic states of hepatitis B viral infection. While it provides clarity for clinicians, the new system’s lack of a focus that provides a simple naming pattern means it is harder for the lay person to grasp and remember.
With a bit of tweaking, Hep B Bear* could be around for a while yet.
Read the EASL hepatitis B clinical practice guidelines
* In the Hep B Bear analogy, the bear represents the hepatitis B virus and the bear’s changing states of freedom represents the immune system’s reaction to and control of the virus.