Chronic hepatitis B (CHB) was, and still is, a prevalent liver disease in the world, especially high in the Asia‐Pacific areas. With the advent of preventive vaccines and effective viral suppression ...drugs and active implementations, CHB has gradually become under control. The world‐wide prevalence reduces from 4.2% in 1980 to 3.2% in 2020 study. CHB patients receiving long‐term antiviral therapies significantly improve the clinical outcomes, saving from end‐stage liver diseases. Despite of these impressive progresses, to meet the WHO sustained development goals (SDG) for CHB control, a 90% reduction of incidence and a 65% reduction of mortality in year 2030, there is still a long way to go. In this review, four ongoing approaches have been proposed: (i) A continuous monitoring of long‐term vaccine efficacy in vaccinated populations; (ii) consolidating the hepatitis B virus vaccination program against vaccine hesitancy and limited resources; (iii) rolling‐out current oral antivirals to more CHB patients not only for diseases treatment but also for infection preventions; and (iv) development of curative therapies, both friendly‐to‐dispense and affordable. A coherent and persevere efforts by the society may succeed and achieve the SDG for CHB in the future.
Background & Aims
Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. The global HCC BRIDGE study was a multiregional, large‐scale, longitudinal cohort study ...undertaken to improve understanding of real‐life management of patients with HCC, from diagnosis to death.
Methods
Data were collected retrospectively from January 2005 to September 2012 by chart reviews of eligible patients newly diagnosed with HCC at participating institutions.
Results
Forty‐two sites in 14 countries contributed final data for 18 031 patients. Asia accounted for 67% of patients, Europe for 20% and North America for 13%. As expected, the most common risk factor was hepatitis C virus in North America, Europe and Japan, and hepatitis B virus in China, South Korea and Taiwan. The most common Barcelona Clinic Liver Cancer stage at diagnosis was C in North America, Europe, China and South Korea, and A in Taiwan and Japan. Across all stages, first HCC treatment was most frequently transarterial chemoembolization in North America, Europe, China and South Korea, percutaneous ethanol injection or radiofrequency ablation in Japan and resection in Taiwan. Survival from first HCC treatment varied significantly by region, with median overall survival not reached for Taiwan and 60, 33, 31, 24 and 23 months for Japan, North America, South Korea, Europe and China respectively (P < 0.0001).
Conclusions
Initial results from the BRIDGE study confirm previously reported regional trends in patient demographic characteristics and HCC risk factors, document the heterogeneity of treatment approaches across regions/countries and underscore the need for earlier HCC diagnosis worldwide.
Transmission of hepatitis B virus (HBV) and hepatitis C virus (HCV) is similar regarding the mode of transmission and related risk factors. Therefore, it is not rare to encounter dual HBV/HCV ...infection in populations at risk of parenteral exposure to hepatitis viruses. Besides, in HBV endemic countries before the era of global HBV vaccination, dual HBV/HCV infection was clinically significant likely because of HCV superinfection over pre‐existing HBsAg carriage. Universal childhood HBV vaccination was implemented worldwide since 1992. Public education programs for prevention of new hepatitis viral infections have been actively promoted recently by World Health Organization. Apart from preventive measures, potent anti‐HBV agents effective in the control of viral replication have been introduced gradually in the past three decades. Direct acting antiviral agents capable of curing HCV infection in more than 97% of patients with chronic hepatitis C have also been widely implemented in the past decade. These interventions will change the epidemiology of new HBV or HCV mono‐infection and dual HBV/HCV infection. Understanding the evolution in the epidemiology of dual HBV/HCV infection is important for evaluation of current public health policy towards infectious disease control in different countries. The changing prevalence of dual HBV/HCV infection in certain Asia‐Pacific countries will be re‐visited based on endemicity of HBV or HCV, as well as in populations at risk of parenteral viral infection.
Summary Background Therapy for chronic hepatitis B reduces the risk of progressing to hepatocellular carcinoma (HCC); however, there is no suitable and accurate means to assess risk. This study aimed ...to develop and validate a simple scoring system to predict HCC risk in patients with chronic hepatitis B. Methods The development cohort consisted of 3584 patients without cirrhosis from the community-based Taiwanese REVEAL-HBV study (of whom 131 developed HCC during follow-up), and a validation cohort of 1505 patients from three hospitals in Hong Kong and South Korea (of whom 111 developed HCC during follow-up). We used Cox multivariate proportional hazards model to predict risk of HCC at 3, 5, and 10 years. Variables included in the risk score were sex, age, serum alanine aminotransferase concentration, HBeAg status, and serum HBV DNA level. We calculated the area under receiver operating curve (AUROC) and calibration of predicted and observed HCC risk. Findings A 17-point risk score was developed, with HCC risk ranging from 0·0% to 23·6% at 3 years, 0·0% to 47·4% at 5 years, and 0·0% to 81·6% at 10 years for patients with the lowest and highest HCC risk, respectively. AUROCs to predict risk were 0·811 (95% CI 0·790–0·831) at 3 years, 0·796 (0·775–0·816) at 5 years, and 0·769 (0·747–0·790) at 10 years in the validation cohort, and 0·902 (0·884–0·918), 0·783 (0·759–0·806), and 0·806 (0·783–0·828), respectively, after exclusion of 277 patients in the validation cohort with cirrhosis. Predicted risk was well calibrated with Kaplan-Meier observed HCC risk. Interpretation A simple-to-use risk score that uses baseline clinical variables was developed and validated. The score accurately estimates the risk of developing HCC at 3, 5, and 10 years in patients with chronic hepatitis B. Clinicians can use this score to assess risk of HCC in patients with chronic hepatitis B and subsequently make evidence-based decisions about their clinical management. Funding The Academia Sinica; the National Health Research Institute, Taiwan; and Bristol-Myers Squibb.
Coronaviruses contain a positive-sense single-stranded genomic (g) RNA, which encodes nonstructural proteins. Several subgenomic mRNAs (sgmRNAs) encoding structural proteins are generated by template ...switching from the body transcription regulatory sequence (TRS) to the leader TRS. The process preferentially generates shorter sgmRNA. Appropriate readthrough of body TRSs is required to produce longer sgmRNAs and full-length gRNA. We find that phosphorylation of the viral nucleocapsid (N) by host glycogen synthase kinase-3 (GSK-3) is required for template switching. GSK-3 inhibition selectively reduces the generation of gRNA and longer sgmRNAs, but not shorter sgmRNAs. N phosphorylation allows recruitment of the RNA helicase DDX1 to the phosphorylated-N-containing complex, which facilitates template readthrough and enables longer sgmRNA synthesis. DDX1 knockdown or loss of helicase activity markedly reduces the levels of longer sgmRNAs. Thus, coronaviruses employ a unique strategy for the transition from discontinuous to continuous transcription to ensure balanced sgmRNAs and full-length gRNA synthesis.
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•GSK-3 inhibitor reduces coronavirus nucleocapsid phosphorylation (pN) and titer•pN recruits RNA helicase DDX1 and is crucial for long sgmRNA and gRNA synthesis•DDX1 knockdown or loss of helicase activity impairs longer sgmRNAs synthesis•pN/DDX1 bind to viral genome and assist template readthrough of viral body TRSs
To generate the full complement of genomic and subgenomic RNAs, coronaviruses transition from discontinuous to continuous transcription. Wu et al. find that phosphorylation of the viral nucleocapsid by glycogen synthase kinase-3 is required to recruit the cellular RNA helicase DDX1 and promote the switch to continuous transcription, suggesting therapeutic targets.
Many cell culture and animal models have been used to study hepatitis B virus (HBV) replication and its effects in the liver; these have facilitated development of strategies to control and clear ...chronic HBV infection. We discuss the advantages and limitations of systems for studying HBV and developing antiviral agents, along with recent advances. New and improved model systems are needed. Cell culture systems should be convenient, support efficient HBV infection, and reproduce responses of hepatocytes in the human body. We also need animals that are fully permissive to HBV infection, convenient for study, and recapitulate human immune responses to HBV and effects in the liver. High-throughput screening technologies could facilitate drug development based on findings from cell and animal models.
Background and Aims
Early recurrence of hepatocellular carcinoma (HCC) after surgical resection compromises patient survival. Timely detection of HCC recurrence and its clonality is required to ...implement salvage therapies appropriately. This study examined the feasibility of virus‐host chimera DNA (vh‐DNA), generated from junctions of hepatitis B virus (HBV) integration in the HCC chromosome, as a circulating biomarker for this clinical setting.
Approach and Results
HBV integration in 50 patients with HBV‐related HCC was determined by the Hybridization capture‐based next‐generation sequencing (NGS) platform. For individual HCC, the vh‐DNA was quantified by specific droplet digital PCR (ddPCR) assay in plasma samples collected before and 2 months after surgery. HBV integrations were identified in 44 out of 50 patients with HBV‐related HCC. Tumor‐specific ddPCR was developed to measure the corresponding vh‐DNA copy number in baseline plasma from each patient immediately before surgery. vh‐DNA was detected in 43 patients (97.7%), and the levels correlated with the tumor sizes (detection limit at 1.5 cm). Among the plasma collected at 2 months after surgery, 10 cases (23.3%) still contained the same signature vh‐DNA detected at baseline, indicating the presence of residual tumor cells. Nine of them (90%) experienced HCC recurrence within 1 year, supporting vh‐DNA as an independent risk factor in predicting early recurrence. Analysis of circulating vh‐DNA at recurrence further helped identify the clonal origin. A total of 81.8% of recurrences came from original HCC clones sharing the same plasma vh‐DNA, whereas 18.2% were from de novo HCC.
Conclusions
vh‐DNA was shown to be a circulating biomarker for detecting the tumor load in majority of patients with HBV‐related HCC and aided in monitoring residual tumor and recurrence clonality after tumor resection.
Background & Aims Patients with chronic hepatitis B virus (HBV) infection have a high risk for developing hepatocellular carcinoma (HCC). Patients with lower levels of hepatitis B surface antigen ...(HBsAg) have higher chances of losing HBsAg than those with high levels. However, little is known about whether higher levels of HBsAg increase risk for HCC. Methods We followed 2688 Taiwanese HBsAg-positive patients without evidence of cirrhosis for a mean time period of 14.7 years. In addition to the known risk factors of HCC, we investigated the association between levels of HBsAg and development of HCC. Results Of the patients followed, 191 developed HCC, with an average annual incidence rate of 0.5%. Baseline levels of HBsAg and HBV were associated with development of HCC, and risk increased with level. Compared to HBsAg level, by receiver operating characteristic curve analysis, HBV DNA level better predicted the development of HCC during 10-year and 15-year periods (both, P < .001). However, when we evaluated hepatitis B e antigen−negative patients with levels of HBV DNA <2000 IU/mL, factors that determined HCC risk included sex, age, and levels of alanine aminotransferase and HBsAg (≥1000 IU/mL), but not level of HBV DNA. Multivariate analysis showed that the adjusted hazard ratio for HCC in patients with levels of HBsAg ≥1000 IU/mL versus <1000 IU/mL was 13.7 (95% confidence interval: 4.8−39.3). Conclusions Among patients infected with HBV genotype B or C, determinants of HCC risk include their sex, age, hepatitis B e antigen status, HBV genotype, and levels of alanine aminotransferase and HBV DNA, but not level of HBsAg. Among hepatitis B e antigen−negative patients with low viral loads, HCC risk is determined by levels of HBsAg and alanine aminotransferase and age, but not HBV DNA.
The gender disparity of hepatocellular carcinoma (HCC) is most striking in hepatitis B virus (HBV)‐related cases. The majority of such HCC cases contain integrated HBV, and some hotspot integrations, ...such as those in the telomerase reverse transcriptase gene (TERT) promoter, activate gene expression to drive carcinogenesis. As the HBV genome contains both androgen‐responsive and estrogen‐responsive motifs, we hypothesized that the integrated HBV DNA renders a similar regulation for downstream gene expression and thus contributes to male susceptibility to HCC. To test this hypothesis, the HBV integration sites and the common mutations in the TERT promoter and tumor protein P53 (TP53) coding region were analyzed in 101 HBV‐related HCC cases using a capture‐next‐generation sequencing platform. The results showed that both HBV integration and –124G>A mutation in the TERT promoter region, occurring in a mutually exclusive manner, were more frequent in male than in female patients with HCC (integration: 22/58 male patients with HCC, 6/36 female patients with HCC, P = 0.0285; –124G>A: 17/62 male patients with HCC, 3/39 female patients with HCC, P = 0.0201; in combination, 39/62 male patients with HCC, 9/39 female patients with HCC, P < 0.0001). The effects of sex hormone pathways on the expression of TERT with both genetic changes were investigated using a reporter assay. HBV integration in the TERT promoter rendered the TERT transcription responsive to sex hormones, with enhancement by androgen receptor (AR) but suppression by estrogen receptor, both of which were dependent on hepatocyte nuclear factor 4 alpha. Besides, AR also increased TERT expression by targeting TERT promoter mutations in a GA binding protein transcription factor subunit alpha–dependent manner. Conclusion: TERT elevation by AR through integrated HBV and point mutation at the TERT promoter region was identified as a mechanism for the male dominance of HBV‐related HCCs; telomerase and AR thus may be targets for intervention of HCC.
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