Prevalence of hepatocarcinoma-related hepatitis B virus mutants in patients in grey zone of treatment

World J Gastroenterol. 2019 Oct 14;25(38):5883-5896. doi: 10.3748/wjg.v25.i38.5883.


Background: Antiviral treatment of patients with chronic hepatitis B (CHB) in the grey zone of treatment comands risk management in order to optimize the health outcome. In this sense, the identification of HBV mutants related with an increased risk of hepatocellular carcinoma (HCC) could be useful to identify subpopulations with potential indication of antiviral treatment.

Aim: To analyze the prevalence/persistence of hepatitis B virus (HBV) preS and basal core promoter (BCP)/precore/core variants associated to HCC development in CHB patients in the grey zone.

Methods: Work was designed as a longitudinal retrospective study, including 106 plasma samples from 31 patients with CHB in the grey zone of treatment: Hepatitis B e antigen negative, HBV-DNA levels between 12-20000 IU/mL, normal or discordant transaminase levels during follow up and mild/moderate necro-inflammatory activity in liver biopsy or Fibroscan (up to 9.5 kPa). Serum HBV-DNA was tested using the Abbott Real Time HBV Assay and the BCP/precore/core and the hepatitis B surface antigen (HBsAg) coding regions were analyzed in positive samples by PCR/bulk-sequencing to identify the HCC-related HBV mutants.

Results: High-risk HCC related mutants were detected in 24 (77%) patients: 19 (61%) in the BCP/precore/core, and 7 (23%) in the HBsAg coding region (2 preS1 and 5 preS2 deletions). The prevalence of preS deletions was genotype-dependent: 3/5 (60%) patients with preS2 deletions and 1/2 with preS1 deletions were infected with the HBV-E genotype. Since HBV-E was the most prevalent in sub-Saharan patients, a correlation between preS deletions and ethnicity was also found: 6/8 (75%) sub-Saharan vs 1/19 (5%) Caucasian patients had preS deletions (P = 0.00016). Remarkably, this correlation was maintained in those patients infected with HBV-A, a minor genotype in sub-Saharan patients: 2/2 patients infected with HBV-A from West Africa vs 0/6 of Caucasian origin had preS deletions. The HCC related variants were the major strains and persisted over time (up to 48 mo). Patients with preS deletions had a significant higher prevalence of F2 fibrosis stage than the negatives (57% vs 10%, P = 0.0078).

Conclusion: HBV genetic analysis of selected populations, like sub-Saharans infected with HBV-E/A genotypes, will allow identification of subpopulations with risk of HCC development due to accumulation of high-risk HBV variants, thus commanding their increased clinical surveillance.

Keywords: Grey zone; Hepatitis B virus; Hepatitis B virus treatment; Hepatocellular carcinoma; PreS deletions.

Publication types

  • Observational Study

MeSH terms

  • Adult
  • Antiviral Agents / therapeutic use*
  • Biopsy
  • Carcinoma, Hepatocellular / prevention & control*
  • Carcinoma, Hepatocellular / virology
  • DNA Mutational Analysis
  • DNA, Viral / genetics
  • DNA, Viral / isolation & purification
  • Female
  • Follow-Up Studies
  • Genotype
  • Hepatitis B Surface Antigens / genetics
  • Hepatitis B virus / genetics*
  • Hepatitis B virus / isolation & purification
  • Hepatitis B, Chronic / drug therapy*
  • Hepatitis B, Chronic / pathology
  • Hepatitis B, Chronic / virology
  • Humans
  • Liver / pathology
  • Liver / virology
  • Liver Neoplasms / prevention & control*
  • Liver Neoplasms / virology
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Mutation
  • Patient Selection
  • Promoter Regions, Genetic / genetics
  • Retrospective Studies


  • Antiviral Agents
  • DNA, Viral
  • Hepatitis B Surface Antigens