The Correlation Between Hepatitis B Virus Precore/Core Mutations and the Progression of Severe Liver Disease

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.

Conservation and variability of hepatitis B core at different chronic hepatitis stages

“…A number of studies have focused on detecting aa changes possibly related to different clinical stages. The mutations T1753C and A1762T/G1764A (K130M/V131I in HBx) of basal core promoter, for example, were identified as possible prognostic markers for HCC [38,39] , while HBc aa mutations F24Y, E64D, E77Q, A80I/T/V, L116I, and E180A were linked to the development of cirrhosis and HCC [40] . In our study, one of the aa changes detected, P79Q, was exclusively observed in the HCC group.…”

Association of Hepatitis B Virus DNA Level and Follow-up Interval With Hepatocellular Carcinoma Recurrence

“…16 Hepatitis B virus precure and core region mutations might be associated with HCC tumorigenesis. 17 In this study, when patients received a diagnosis, the BCLC stage was associated with antiviral treatment and baseline HBV DNA level.…”

Comparison of the Characteristics of Hepatitis B Virus Whole Genomes Derived From Patients With Hepatocellular Carcinoma and Chronic Hepatitis B Infection

“…Most pre-C/C mutations are generated during HBeAg seroconversion. Several types of HBV pre-C/C mutations, such as G1896A, A1762T, and G1764A, were reportedly related to disease severity [9,19,29]. Also, the HBeAg positive rate was signi cantly lower in the HCC group than the CHB group.…”

“…Various types of mutations to the HBV genome have been reported, resulting amino acid substitutions during long-term infection, some of which could serve as markers to predict the development of HBV-associated HCC [6,7], such as mutations in the pre-surface antigen (pre-S) (i.e., deletion to the preS1 [W4P/R] and pre-S2 start codon deletion, pre-core (i.e., nucleotide 1896(G1896A), or a double mutation to the basal core promoter (BCP) and X regions (V5M) [8][9][10].…”