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Surgical resection is a curative therapy for early-stage hepatocellular carcinoma (HCC); however, HCC recurrence is not uncommon. Identifying outcome predictors helps to manage the disease. Gamma-glutamyl transferase (GGT) may predict the development of HCC, but its role to predict the outcomes after surgical resection of HCC was unclear. This study aimed to investigate pre-operative GGT levels for outcome prediction in patients with hepatitis B virus (HBV)-related HCC. We conducted a retrospective cohort study to include patients with HBV-related HCC receiving surgical resection. Clinical information, HCC characteristics and usage of antiviral therapy were collected. A time-dependent Cox proportional hazard regression analysis were used to predict HCC recurrence and survival. A total of 699 consecutive patients with HBV-related HCC who received surgical resection with curative intent between 2004 and 2013 were included. After a median of 4.4 years, 266 (38%) patients had HCC recurrence. Pre-operative GGT positively correlated with cirrhosis, tumor burden and significantly increased in patients to develop HCC recurrence. Multivariable analysis demonstrated that pre-operative GGT ≥38 U/L increased 57% risk (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.20–2.06) of recurrent HCC after adjustment for confounding factors. Specifically, pre-operative GGT ≥38 U/L predicted early (<2 years) HCC recurrence (HR: 1.94, 95% CI: 1.30–2.89). Moreover, pre-operative GGT ≥38 U/L predicted all-cause mortality (HR: 1.73, 95% CI: 1.06–2.84) after surgery. Pre-operative GGT levels ≥38 U/L independently predict high risks of HCC recurrence and all-cause mortality in HBV-related HCC patients receiving surgical resection. [ABSTRACT FROM AUTHOR]

Background and Aims: Patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are at risk of developing adverse outcomes. Coinfection with both viruses may further increase the risk. Currently, little is known about the role of fibrosis‐4 (FIB‐4) index, a simple liver fibrosis stage biomarker, in predicting the clinical outcomes. Methods: We retrospectively enrolled 152 non‐cirrhotic patients with dual chronic HCV and HBV infection: 56 patients received pegylated interferon/ribavirin therapy, while 96 patients remained untreated. The association between the FIB‐4 index and the incidence of liver cirrhosis and hepatocellular carcinoma (HCC) was explored. Results: After a 9.88‐year follow‐up, the incidence of hepatitis B surface antigen seroclearance was 4.97 (95% confidence interval: 3.13–7.89) per 100 person‐years in the treated group and was 1.77 (1.10–2.85) in the untreated group. Of the treated group, only three and six patients developed HCC and liver cirrhosis, respectively, while 17 and 23 patients developed HCC and liver cirrhosis, respectively, in untreated group. Baseline FIB‐4 index correlated with the development of liver cirrhosis in multivariable analysis of all subjects. High baseline FIB‐4 index (per 1 point increase) in the treated groups was associated with a higher risk of developing liver cirrhosis (P = 0.001) and HCC (P = 0.038) in univariable analysis. FIB‐4 index decreased only in the treated group who achieved sustained virological response (n = 34, FIB‐4 index decreasing from 1.84 to 1.55). Conclusions: In Taiwanese patients coinfected with HCV and HBV, FIB‐4 index helps identify patients at risk of developing adverse events, even in patients receiving pegylated interferon/ribavirin therapy. [ABSTRACT FROM AUTHOR]

Background Naturally occurring pre-S deletion mutants have been identified in hepatitis B virus ( HBV)-related hepatocellular carcinoma ( HCC). Aims This study investigated whether specific deletions within the pre- S region were associated with HCC development. Methods The virologic characteristics of 56 HBV chronic carriers and 112 age-matched patients with HBV-related HCC were examined. Results The HCC patients had a significantly higher frequency of high viral load, basal core promoter mutation and pre-S deletion than chronic carriers. Sequencing analysis showed that the deleted regions were clustered mainly in the C terminus of pre-S1 (70.5%) and the N terminus of pre-S2 (72.7%) in HCC patients. Immuno-epitope mapping of these pre-S deletion sequences showed that all the deletion regions encompassed T- and B- cell epitopes and the B-cell epitope at amino acid 1-6 of pre-S2 was significantly deleted in HCC patients (60.0% vs. 0.0%; P = 0.036). Functional mapping of these deletion mutants showed that most of HCC patients lost one or more functional sites and the deletion of site for viral secretion (aa 1-5 of pre-S2 domain) was significantly detected in HCC patients than chronic carriers (62.5% vs. 0.0%; P = 0.029). Computational protein function prediction indicated that these mutants may have different molecular functions and participate in other biological processes compared with wild-type pre-S. Conclusions Deletion of B-cell epitope at amino acid 1-6 of pre-S2 region and the site for virion secretion are significantly associated with the development of HCC in HBV carriers. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a worldwide health issue that has started receiving attention but is still poorly understood. However, the hepatitis B virus (HBV) and the hepatitis C virus (HCV) are known to be two major causative agents of HCC. They differ in their modes of infection, their treatment options, their genomes and their carcinogenic abilities. However, both share a link with HCC through alterations of the host genome. In order to continue in our search for the mechanisms behind viral hepatocarcinogenesis, the individual entities (HBV, HCV, HCC and host), their natural history, treatment options and genomic properties must be further understood. Additionally, an understanding of the genomics, the link between the entities, is crucial for the success of the ongoing search for therapeutic options for HCC. Similar to most types of cancer, hepatocarcinogenesis is a multistep process involving different genetic alterations that ultimately lead to malignant transformation of the hepatocyte. As technology advances and research continues, the genetic changes and influences among these entities will prove essential to improved diagnostic and therapeutic options. It remains a challenge to provide a clear picture of the connection between virus and cancer. We review (i) the epidemiological link between HBV/HCV infection to HCC; (ii) prevention and control of chronic hepatitis B or C in reducing HCC risk; and (iii) genetic characters of viruses and hosts and the mechanisms associated with HCC susceptibilities, with the intention of providing a direction for future research and treatment. [ABSTRACT FROM AUTHOR]

HBV expresses more than 10 spliced RNAs from the viral pregenomic RNA, but their functions remain elusive and controversial. To address the function of HBV spliced RNAs, we generated splicing-deficient HBV mutants and conducted experiments to assess the impact of these mutants on HBV infection. HepG2-NTCP cells, human hepatocyte chimeric FRG mice (hu-FRG mice), and serum from patients with chronic hepatitis B were used for experiments on HBV infection. Additionally, SHifter assays and cryo-electron microscopy were performed. We found the infectivity of splicing-deficient HBV was decreased 100-1,000-fold compared with that of wild-type HBV in hu-FRG mice. Another mutant, A487C, which loses the most abundant spliced RNA (SP1), also exhibits severely impaired infectivity. SP1 hypothetically encodes a novel protein HBcSP1 (HBc-Cys) that lacks the C-terminal cysteine from full-length HBc. In the SHifter assay, HBcSP1 was detected in wild-type viral particles at a ratio of about 20-100% vs. conventional HBc, as well as in the serum of patients with chronic hepatitis B, but not in A487C particles. When infection was conducted with a shorter incubation time of 4-8 h at lower PEG concentrations in HepG2-NTCP cells, the entry of the A487C mutant was significantly slower. SP1 cDNA complementation of the A487C mutant succeeded in rescuing its infectivity in hu-FRG mice and HepG2-NTCP cells. Moreover, cryo-electron microscopy revealed a disulfide bond between HBc cysteine 183 and 48 in the HBc intradimer of the A487C capsid, leading to a locked conformation that disfavored viral entry in contrast to the wild-type capsid. Prior studies unveiled the potential integration of the HBc-Cys protein into the HBV capsid. We confirmed the proposal and validated its identity and function during infection. HBV SP1 RNA encodes a novel HBc protein (HBcSP1) that lacks the C-terminal cysteine from conventional HBc (HBc-Cys). HBcSP1 was detected in cell culture-derived HBV and confirmed in patients with chronic infection by both immunological and chemical modification assays at 10-50% of capsid. The splicing-deficient mutant HBV (A487C) impaired infectivity in human hepatocyte chimeric mice and viral entry in the HepG2-NTCP cell line. Furthermore, these deficiencies of the splicing-deficient mutant could be rescued by complementation with the SP1-encoded protein HBcSP1. We confirmed and validated the identity and function of HBcSP1 during infection, building on the current model of HBV particles. [Display omitted] • The infectivity of splicing-deficient HBV was significantly decreased compared to WT HBV in hu-FRG mice. • SP1 RNA encodes HBcSP1, which is found in 10 to 50% of nucleocapsids in patients with CHB and cell line-derived WT HBV. • The splicing-deficient mutant A487C, lacking HBcSP1, reduces the efficiency of viral entry kinetics. • Disulfide bonds between Cys48 and Cys183 in the A487C capsid led to a locked conformation that disfavored viral entry. [ABSTRACT FROM AUTHOR]