Occult hepatitis B infection and hepatocellular carcinoma: Epidemiology, virology, hepatocarcinogenesis and clinical significance

Abstract

Occult hepatitis B infection (OBI) refers to a condition where replication-competent HBV DNA is present in the liver, with or without HBV DNA in the blood, in individuals with serum HBsAg negativity assessed by currently available assays. The episomal covalently closed circular DNA (cccDNA) in OBI is in a low replicative state. Viral gene expression is mediated by epigenetic control of HBV transcription, including the HBV CpG island methylation pathway and post-translational modification of cccDNA-bound histone, with a different pattern from patients with chronic HBV infection. The prevalence of OBI varies tremendously across patient populations owing to numerous factors, such as geographic location, assay characteristics, host immune response, coinfection with other viruses, and vaccination status. Apart from the risk of viral reactivation upon immunosuppression and the risk of transmission of HBV, OBI has been implicated in hepatocellular carcinoma (HCC) development in patients with chronic HCV infection, those with cryptogenic or known liver disease, and in patients with HBsAg seroclearance after chronic HBV infection. An increasing number of prospective studies and meta-analyses have reported a higher incidence of HCC in patients with HCV and OBI, as well as more advanced tumour histological grades and earlier age of HCC diagnosis, compared with patients without OBI. The proposed pathogenetic mechanisms of OBI-related HCC include the influence of HBV DNA integration on the hepatocyte cell cycle, the production of pro-oncogenic proteins (HBx protein and mutated surface proteins), and persistent lowgrade necroinflammation (contributing to the development of fibrosis and cirrhosis). There remain uncertainties about exactly how, and in what order, these mechanisms drive the development of tumours in patients with OBI.

Cryptic HBV Replicative Activity Is Frequently Revealed in Anti-HBc-Positive/HBsAg-Negative Patients with HIV Infection by Highly Sensitive Molecular Assays, and Can Be Predicted by Integrating Classical and Novel Serological HBV Markers

“…Finally, in line with previous studies, an association between cryptic serum HBV-DNA and chronic HCV infection was observed mainly attributable to the shared transmission route of these two viruses [10,15].…”

“…In this light, it is particularly relevant to apply highly sensitive molecular assays, capable of detecting few viral copies in the setting of anti-HBc/HBsAg-negative patients [12]. Understanding this issue is critical since cryptic HBV-replication may represent a factor fueling liver disease progression [13][14][15] and exposing patients to a higher risk of viral reactivation in the setting of an exacerbated immune-compromised status [16].…”

Impact of Hepatitis B Virus Genetic Variation, Integration, and Lymphotropism in Antiviral Treatment and Oncogenesis

“…Despite the HBsAg-negativity and low-level viremia, OBI remains clinically significant as HBV may reactivate with immunosuppression and individuals with OBI have increased risks of malignant disease relative to HBV-negative individuals [ 149 , 150 ]. A prior study following 1217 Alaskan Natives an average of 19.6 years revealed no differences amongst those who cleared HBsAg (OBI) and those who remained HBsAg positive [ 151 ].…”

<p>Development and Validation of a Novel 8 Immune Gene Prognostic Signature Based on the Immune Expression Profile for Hepatocellular Carcinoma</p>

“…2 The incidence of HCC varies by geographic region, gender, age, and risk factors associated with cancer development. 3 Despite advances in treatments such as liver transplantation, surgical resection, and radiofrequency ablation, the prognosis in patients with HCC is still very poor, with a 5-year survival rate of less than 30%. 4 In addition, tumor heterogeneity and immune microenvironment play key roles in the progression, treatment, and prognosis of HCC.…”