Abstract
Viral mutations acquired during the course of chronic hepatitis B virus (HBV) infection are known to be associated with the progression and severity of HBV-related liver disease. This study of HBV-infected Saudi Arabian patients aimed to identify amino acid substitutions within the precore/core (preC/C) region of HBV, and investigate their impact on disease progression toward hepatocellular carcinoma (HCC). Patients were categorized according to the severity of their disease, and were divided into the following groups: inactive HBV carriers, active HBV carriers, liver cirrhosis patients, and HCC patients. Two precore mutations, W28* and G29D, and six core mutations, F24Y, E64D, E77Q, A80I/T/V, L116I, and E180A were significantly associated with the development of cirrhosis and HCC. Six of the seven significant core mutations that were identified in this study were located within immuno-active epitopes; E77Q, A80I/T/V, and L116I were located within B-cell epitopes, and F24Y, E64D, and V91S/T were located within T-cell epitopes. Multivariate risk analysis confirmed that the core mutations A80V and L116I were both independent predictors of HBV-associated liver disease progression. In conclusion, our data show that mutations within the preC/C region, particularly within the immuno-active epitopes, may contribute to the severity of liver disease in patients with chronic hepatitis. Furthermore, we have identified several distinct preC/C mutations within the study population that affect the clinical manifestation and progression of HBV-related disease. The specific identity of HBV mutations that are associated with severe disease varies between different ethnic populations, and so the specific preC/C mutations identified here will be useful for predicting clinical outcomes and identifying the HBV-infected patients within the Saudi population that are at high risk of developing HCC.
Highlights
Despite improvements in the availability of effective vaccines and antiviral medications, hepatitis B virus (HBV) infection continues to be a significant global health problem
Patients were assigned to the following groups based on disease severity: Case I-inactive HBV carriers (IC), including patients testing positive for HBV surface antigen (HBsAg) and negative for HBV e antigen (HBeAg), with persistently normal serum alanine aminotransferase (ALT) levels (40 U/L); Case II-active HBV carriers (AC), including patients testing positive for HBsAg, with elevated serum ALT levels and no evidence of liver complications; Case III-patients with HBV infection and liver cirrhosis (LC), confirmed by liver biopsy, and clinical, biochemical, or radiological evidence of cirrhosis; Case IV-patients with hepatocellular carcinoma (HCC) diagnosed by computed tomography and/or magnetic resonance imaging of the liver, using previously published guidelines for the diagnosis and management of HCC (Abdo et al, 2006)
While serum ALT levels were normal in carriers of inactive HBV, they were elevated in all other patient groups, these differences were not statistically significant
Summary
Despite improvements in the availability of effective vaccines and antiviral medications, hepatitis B virus (HBV) infection continues to be a significant global health problem. Recent studies have focused on the relationship between HBV strain variants and the clinical severity of liver diseases, hepatocellular carcinoma (HCC) (Kim et al, 2012). HBV genomic mutations reportedly affect viral replication and disease progression, and can affect therapeutic outcomes (Malik et al, 2012). Several studies have reported that point mutations, those in the S gene “a” determinant region, can arise during the natural course of HBV infection, and result in immune escape, active viral replication, and liver disease progression (Mathet et al, 2003; Lada et al, 2006). The role of the precore mutation G1896A and the basal core promoter double mutation A1762T/G1764A in the progression of HBV-related liver diseases has been intensively studied (Kim et al, 2016)
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