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Diagnosis and management of pre-core mutant chronic hepatitis B
G V Papatheodoridis1, S J Hadziyannis
1Academic Department of Medicine, Hippokration General Hospital, Athens, Greece.
Insights
Pre-core hepatitis B virus (HBV) mutants cause HBeAg-negative chronic hepatitis B (CHB). While interferon-alpha shows some long-term benefit, lamivudine is largely ineffective due to resistance mutations.
Area of Science:
- Hepatology
- Virology
- Molecular Biology
Background:
- Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) arises from pre-core HBV mutants.
- These mutants, including stop codon mutations and core promoter variations, are prevalent in late-stage HBV infection and inactive carriers.
- Diagnosis relies on HBsAg positivity, HBeAg negativity, elevated ALT and HBV DNA, with differential diagnosis from inactive carriers requiring monitoring.
Purpose of the Study:
- To review the characteristics and management of HBeAg-negative CHB caused by pre-core HBV mutants.
- To evaluate the efficacy of current treatment options, including interferon-alpha and lamivudine.
- To discuss diagnostic challenges and future therapeutic directions.
Main Methods:
- Literature review of studies on pre-core HBV mutants and HBeAg-negative CHB.
- Analysis of diagnostic criteria including serological markers (HBsAg, HBeAg, anti-HBe, IgM anti-HBc) and viral load (HBV DNA).
- Evaluation of treatment outcomes for interferon-alpha and lamivudine, including sustained remission and resistance mutations.
Main Results:
- Interferon-alpha (IFN-alpha) achieved sustained remission in approximately 20% of patients after a 12-month course.
- Lamivudine demonstrated limited efficacy, with less than 15% remission post-therapy and increasing resistance (YMDD mutants) over time.
- Liver biopsy is crucial for assessing disease severity, and IgM anti-HBc may aid in diagnosing flares.
Conclusions:
- HBeAg-negative CHB due to pre-core mutants presents diagnostic and therapeutic challenges.
- Interferon-alpha offers modest long-term benefits, whereas lamivudine is largely ineffective due to rapid resistance development.
- Further research into novel antiviral agents and combination therapies is warranted for improved patient outcomes.
Abstract:
Chronic hepatitis due to pre-core hepatitis B virus (HBV) mutants presents as hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). HBeAg-negative CHB represents a late phase in the natural course of chronic HBV infection that develops after HBeAg loss and seroconversion to anti-HBe. It is usually associated with pre-core stop codon mutation at nucleotide 1896 (mainly selected in non-A HBV genotypes), but also with other pre-core changes or with mutations in the basic core promoter region (mainly in HBV genotype A). In chronic HBV infections, pre-core mutants can be detected both in patients with HBeAg-negative CHB and in inactive hepatitis B surface antigen (HBsAg) carriers. The diagnosis of HBeAg-negative CHB is based on HBsAg positivity, HBeAg negativity, and mainly on increased alanine aminotransferase (ALT) and serum HBV-DNA levels and exclusion of other causes of liver disease. The differential diagnosis between patients with CHB and inactive HBsAg carriers can be made only by close follow-up of aminotransferase activity and viraemia levels, although the cut-off level of serum HBV DNA has not been definitely determined. IgM anti-HBc levels have also been suggested as an index that increases the diagnostic accuracy for transient hepatitis flares, while liver biopsy confirms the diagnosis and evaluates the severity of the liver disease. Interferon-alpha (IFN-alpha) and lamivudine are the two drugs that have been tried, mainly in the management of HBeAg-negative CHB. A 12-month course of IFN-alpha achieves sustained biochemical remission in about 20% of patients, which has been associated with improvement in the long-term outcome of this subset. A 12-month course of lamivudine is rather ineffective, maintaining remission in less than 15% of patients after cessation of therapy. Long-term lamivudine is associated with progressively increasing rate of virological and subsequent biochemical breakthroughs due to YMDD mutants, with approximately 30% of patients remaining in remission in the third year of therapy. Several other antiviral agents are currently being evaluated in this setting with combined regimens being the most reasonable step for the near future.