|
1
|
Guo H, Fang F, Lin L, Guo Z, Lai L, Shi Y, Chen T, Lai R, Ou Q, Fu Y. Novel prognostic scoring models for hepatitis B virus-related acute-on-chronic liver failure: A comparison with classical models. Virulence 2025; 16:2500490. [PMID: 40376958 PMCID: PMC12087482 DOI: 10.1080/21505594.2025.2500490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 04/21/2025] [Accepted: 04/23/2025] [Indexed: 05/18/2025] Open
Abstract
Early diagnosis and accurate prognostic evaluation are important for guiding clinical treatment and reducing mortality in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). The present study established novel prognostic scoring models to guide the clinical treatment of patients with HBV-ACLF. We performed a retrospective analysis of clinical data from two cohorts of patients diagnosed with HBV-ACLF. By comparing differences in baseline characteristics and clinical indicators between the survival (n = 102) and dead (n = 64) groups in the derivation cohort(n = 166), four laboratory indicators (age, INR, TBIL, and HBeAg status) and three clinical signs (extrahepatic infection, ascites, and hepatic encephalopathy) were identified as independent risk factors. Logistic regression and nomogram models were used to construct three novel predictive models. By comparing the death and survival groups, we found that the three new models had higher predictions for AUROC (average of 0.856) than the three old models (average of 0.773). Model 1 had the strongest predictive power for the short-term survival rate of HBV-ACLF patients. Finally, we verified the predictive value of the new models for HBV-ACLF in a validation cohort (n = 42), and the Model 2 demonstrated good predictive accuracy for the 30-day survival rate of patients. The novel model based on seven predictors could accurately predict short-term mortality in patients with HBV-ACLF, which is promising for guiding clinical management and addressing the aetiological differences in Asian populations.
Collapse
Affiliation(s)
- Hongyan Guo
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- The School of Public Health, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Fengling Fang
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Lin Lin
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Zhaopei Guo
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Lu Lai
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yue Shi
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Tianbin Chen
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Ruimin Lai
- Department of the Center of Liver Diseases, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Qishui Ou
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Ya Fu
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| |
Collapse
|
|
2
|
Sato K, Inoue J, Akahane T, Kobayashi T, Ninomiya M, Sano A, Tsuruoka M, Onuki M, Sawahashi S, Ouchi K, Doi K, Watanabe K, Niitsuma H, Masamune A. Comparison of hepatitis B virus genotype B and C patients in Japan in terms of family history and maternal age at birth. Hepatol Res 2025; 55:773-779. [PMID: 40317570 DOI: 10.1111/hepr.14169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 01/07/2025] [Accepted: 01/22/2025] [Indexed: 05/07/2025]
Abstract
AIM Hepatitis B virus of genotypes B (HBV/B) and C (HBV/C) prevails in Japan and patients with HBV/B have been known to be older than those with HBV/C, but the reason has remained unknown. We aimed to clarify the reason by focusing on the family history of HBV infection. METHODS In a total of 508 patients with chronic HBV infection, HBV genotype, patient age, and age of the mother at birth were compared. RESULTS Patient age was significantly older in HBV/B than in HBV/C, and the patient percentage with a family history of HBV infection was lower in HBV/B. When comparing maternal age at birth between the two genotypes, there was no significant difference in the overall patient population, but the proportion of older birth group (≥26 years old) was significantly lower in HBV/B (38.7% vs. 59.3%, p = 0.048) in patients with a family history of HBV infection in both mothers and siblings whose HBV were considered to be transmitted vertically. There was a negative correlation between maternal age at birth and patient age in this group, reflecting the fact that the age of childbearing is increasing recently in Japan. Because patients with HBV/B experience hepatitis B e antigen seroconversion at an earlier age, it was considered that HBV/B has become harder to transmit vertically in recent decades. CONCLUSION The recent decrease in vertical transmission of HBV/B associated with an older childbearing age in Japan might be one of the reasons for the finding that HBV/B patients were older than HBV/C patients.
Collapse
Affiliation(s)
- Kosuke Sato
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
- Institute for Excellence in Higher Education, Tohoku University, Sendai, Japan
| | - Takehiro Akahane
- Department of Gastroenterology, Japanese Red Cross Ishinomaki Hospital, Ishinomaki, Japan
| | - Tomoo Kobayashi
- Department of Gastroenterology, Tohoku Rosai Hospital, Sendai, Japan
| | - Masashi Ninomiya
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
- Institute for Excellence in Higher Education, Tohoku University, Sendai, Japan
| | - Akitoshi Sano
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mio Tsuruoka
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masazumi Onuki
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Satoko Sawahashi
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Keishi Ouchi
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kotaro Doi
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kengo Watanabe
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hirofumi Niitsuma
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| |
Collapse
|
|
3
|
Eilard A, Ringlander J, Andersson ME, Nilsson S, Norkrans G, Lindh M. Long-Term Outcome of Chronic Hepatitis B-Histological Score and Viral Genotype Are Important Predictors of Hepatocellular Carcinoma. J Viral Hepat 2025; 32:e70008. [PMID: 39878776 PMCID: PMC11777188 DOI: 10.1111/jvh.70008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 01/13/2025] [Accepted: 01/21/2025] [Indexed: 01/31/2025]
Abstract
Current guidelines to prevent hepatocellular carcinoma (HCC) by chronic hepatitis B virus (HBV) infection are based on risk assessments that include age, sex, and virological and biochemical parameters. The study aim was to investigate the impact of predictive markers on long-term outcomes. The clinical outcomes of 100 patients with chronic hepatitis B were investigated 30 years after a baseline assessment that included liver biopsy. A favourable outcome-HBsAg loss or HBeAg-negative infection (ENI; previously termed 'inactive carrier')-was observed in 74% of all patients, whereas 7% developed HCC. HBsAg loss was observed in 75% of patients with genotype A, compared with 42%, 33% and 0% with genotypes D, B and C, respectively (p < 0.0001). HCC developed in 3 patients (33%) with genotype C as compared with 3 (17%), 1 (2%) and 0 patients with genotypes B, D and A, respectively (p < 0.0001). In multiple logistic regression analysis, both HBsAg loss and HCC were associated with HBV genotype and baseline HBV DNA level, and HCC also with histological score. The results suggest that genotyping and histological assessment may improve outcome prediction and help decisions about HCC screening, particularly in populations with HBV-infected individuals of mixed geographic origin.
Collapse
Affiliation(s)
- Anders Eilard
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Department of Infectious DiseasesSahlgrenska University HospitalGothenburgSweden
| | - Johan Ringlander
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| | - Maria E. Andersson
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| | - Staffan Nilsson
- Department of Laboratory Medicine, Institute of BiomedicineUniversity of GothenburgSweden
| | - Gunnar Norkrans
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| | - Magnus Lindh
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| |
Collapse
|
|
4
|
Chen CL, Yang WS, Yang HI, Chen CF, Wang LY, Lu SN, Kao JH, Chen PJ, Chen CJ. Plasma Adiponectin Levels in Relation to Chronic Hepatitis B Infection Progression to Liver Cancer Milestones: A Prospective Study. Liver Cancer 2025; 14:19-35. [PMID: 40144469 PMCID: PMC11936446 DOI: 10.1159/000539909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 06/11/2024] [Indexed: 03/28/2025] Open
Abstract
Introduction Our previous nested-case-control study demonstrated elevated adiponectin increased liver cirrhosis and HCC risk in HBV carriers. We extended the analysis to the whole REVEAL-HBV cohort to prospectively evaluate whether adiponectin directly affected end-stage liver diseases, or through affecting HBV progression. Methods Baseline plasma adiponectin was determined to investigate the association between adiponectin and subsequent HBeAg, HBsAg, and HBV DNA seroclearance, and the development of cirrhosis, HCC and liver-related death. Whether HBV characteristics modify the adiponectin-milestones associations was also examined. Results Among 3,931 HBsAg(+)/anti-HCV(-) REVEAL-HBV participants, 3,684 had sufficient biosamples left for adiponectin assay. Elevated adiponectin was associated with a higher chance of HBeAg-seropositive, high HBV viral load (≥2 × 105 IU/mL) and high HBsAg titers (≥1,000 IU/mL) in a dose-response manner (OR = 2.25, 95% CI: 1.55-3.28; OR = 2.11, 95% CI: 1.47-3.04; and OR = 1.92, 95% CI: 1.47-2.52 for Q5 vs. Q1, respectively). Those with the highest quintile had a lower chance of achieving HBeAg (HR = 0.48, 95% CI: 0.27-0.85), HBsAg (HR = 0.69, 95% CI: 0.49-0.97), and HBV DNA seroclearance (HR = 0.63, 95% CI: 0.43-0.90) and a higher chance of developing liver cirrhosis (HR = 2.88, 95% CI: 1.98-4.20, HCC (HR = 2.38, 95% CI: 1.52-3.73), and died from liver-related causes (HR = 2.32, 95% CI: 1.51-3.54). HBV genotype significantly modified the adiponectin-HCC (Pinteraction = 0.005) and adiponectin-liver death associations (Pinteraction = 0.0157), with higher risk among genotype C. Conclusion Elevated adiponectin is consistently associated with all important chronic HBV infection milestones toward progression to liver cancer. The exact mechanism of how adiponectin mediates HBV infection toward carcinogenesis remains unclear and warrants further investigation. Disentangling this may help us in finding new HBV treatment target, biomarker in HBV surveillance to identify high-risk patients, or even cancer prevention.
Collapse
Affiliation(s)
- Chi-Ling Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei, Taiwan
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Wei-Shiung Yang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Hwai-I. Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan
- Doctoral Program of Clinical and Experimental Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Chuen-Fei Chen
- Department of Medicine, Mackay Medical College, Kaohsiung, Taiwan
| | - Li-Yu Wang
- Department of Medicine, Mackay Medical College, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Department of Gastroenterology, Kaohsiung Chang-Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chien-Jen Chen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| |
Collapse
|
|
5
|
Liu SJ, Zhang X, Yan LJ, Wang HC, Ding ZN, Liu H, Pan GQ, Han CL, Tian BW, Dong ZR, Wang DX, Yan YC, Li T. Comparison of tenofovir versus entecavir for preventing hepatocellular carcinoma in chronic hepatitis B patients: an umbrella review and meta-analysis. J Cancer Res Clin Oncol 2025; 151:77. [PMID: 39934513 PMCID: PMC11814049 DOI: 10.1007/s00432-025-06082-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 01/02/2025] [Indexed: 02/13/2025]
Abstract
There are several meta-analyses about the comparison of tenofovir disoproxil fumarate (TDF) versus entecavir (ETV) for preventing hepatocellular carcinoma in patients with chronic HBV infection published in recent years. However, the conclusions vary considerably. This umbrella review aims to consolidate evidence from various systematic reviews to evaluate differences in hepatocellular carcinoma prevention between two drugs. Systematic searches were conducted using PubMed, Embase, and Web of Science to identify original meta-analyses. Finally, twelve studies were included for quantitative analyses. We found that TDF treatment was associated with a significantly lower risk of HCC than ETV (hazard ratio, 0.80; 95% CI 0.75-0.86, p < 0.05). The lower risk of HCC in patients given TDF compared with ETV persisted in subgroup analyses performed with propensity score-matched cohorts, cirrhosis cohorts, nucleos(t)ide naïve cohorts and Asian cohorts. In the cohorts of non-Asia and patients without cirrhosis, there was no difference exhibited between these two drugs. Subsequent analyses showed TDF treatment was also associated with a lower incidence of death or transplantation than patients receiving ETV. Overall, the preventive effect of these two drugs on HCC has been studied in several published meta-analyses, but few were graded as high-quality evidence, meanwhile, most of which had high overlap. Thus, future researchers should include updated cohorts or conduct prospective RCTs to further explore this issue.
Collapse
Affiliation(s)
- Shi-Jia Liu
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Xiao Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Lun-Jie Yan
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Han-Chao Wang
- Institute for Financial Studies, Shandong University, Jinan, China
| | - Zi-Niu Ding
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Hui Liu
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Guo-Qiang Pan
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Cheng-Long Han
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Bao-Wen Tian
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Dong-Xu Wang
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wen Hua Road, Jinan, 250012, China
| | - Yu-Chuan Yan
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wen Hua Road, Jinan, 250012, China.
| | - Tao Li
- Department of General Surgery, Qilu Hospital of Shandong University, 107 West Wen Hua Road, Jinan, 250012, China.
| |
Collapse
|
|
6
|
Hwang SY, Danpanichkul P, Agopian V, Mehta N, Parikh ND, Abou-Alfa GK, Singal AG, Yang JD. Hepatocellular carcinoma: updates on epidemiology, surveillance, diagnosis and treatment. Clin Mol Hepatol 2025; 31:S228-S254. [PMID: 39722614 PMCID: PMC11925437 DOI: 10.3350/cmh.2024.0824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 11/08/2024] [Accepted: 12/20/2024] [Indexed: 12/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a major global burden, ranking as the third leading cause of cancer-related mortality. HCC due to chronic hepatitis B virus (HBV) or C virus (HCV) infection has decreased due to universal vaccination for HBV and effective antiviral therapy for both HBV and HCV, but HCC related to metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease is increasing. Biannual liver ultrasonography and serum α-fetoprotein are the primary surveillance tools for early HCC detection among high-risk patients (e.g., cirrhosis, chronic HBV). Alternative surveillance tools such as blood-based biomarker panels and abbreviated magnetic resonance imaging (MRI) are being investigated. Multiphasic computed tomography or MRI is the standard for HCC diagnosis, but histological confirmation should be considered, especially when inconclusive findings are seen on cross-sectional imaging. Staging and treatment decisions are complex and should be made in multidisciplinary settings, incorporating multiple factors including tumor burden, degree of liver dysfunction, patient performance status, available expertise, and patient preferences. Early-stage HCC is best treated with curative options such as resection, ablation, or transplantation. For intermediate-stage disease, locoregional therapies are primarily recommended although systemic therapies may be preferred for patients with large intrahepatic tumor burden. In advanced-stage disease, immune checkpoint inhibitor-based therapy is the preferred treatment regimen. In this review article, we discuss the recent global epidemiology, risk factors, and HCC care continuum encompassing surveillance, diagnosis, staging, and treatments.
Collapse
Affiliation(s)
- Soo Young Hwang
- Department of Internal Medicine, University of Maryland Medical Center, Midtown Campus, Baltimore, Maryland, USA
| | - Pojsakorn Danpanichkul
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Vatche Agopian
- Dumont-UCLA Transplant and Liver Cancer Centers, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Neil Mehta
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, California, USA
| | - Neehar D. Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Ghassan K. Abou-Alfa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
- Department of Medicine, Weill Medical College at Cornell University, New York, USA
- Trinity College Dublin, Dublin, Ireland
| | - Amit G. Singal
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| |
Collapse
|
|
7
|
Gavilán P, Gavilán JC, Arnedo R, Clavijo E, Viciana I, González-Correa JA. Prediction model of hepatocellular carcinoma development in chronic hepatitis B virus infection in a Spanish cohort. Med Clin (Barc) 2024; 163:609-616. [PMID: 39424472 DOI: 10.1016/j.medcli.2024.07.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 07/20/2024] [Accepted: 07/27/2024] [Indexed: 10/21/2024]
Abstract
INTRODUCTION AND OBJECTIVES To identify risk factors associated with the development of hepatocellular carcinoma (HCC) in an unselected cohort of patients with chronic B virus infection (CHB) in Spain. A predictive model was developed to assess the risk of HCC. MATERIAL AND METHODS A prospective open-cohort study recruited 446 unselected patients with chronic hepatitis B infection from two hospitals in Málaga (Spain). The follow-up time ranged from 0.5 to 31.5 years (mean: 13.8; SD: 9.5; median: 11.4 years). We used a Cox proportional hazard model to estimate the multivariable-adjusted hazard ratios of risk factors associated with the development of liver cancer and developed a clinical score, (HCCB score) to determine the risk of liver cancer, that categories patients into two risk levels for the development of HCC. We compared the diagnostic accuracy of our model with other previously published. RESULTS During the follow-up period, 4.80% of the patients developed liver cancer (21 out of 437), 0.33 cases per 100 patient-years. Multivariate Cox regression analysis revealed that age >45 years, male gender, hepatitis C coinfection, alkaline phosphatase >147IU/L, Child score >5 points, glucose >126mg/dL, and a viral load >4.3 log10 IU/mL were independent risk factors. A risk score has been developed with a high predictive capacity for identifying patients at high risk of developing hepatocellular carcinoma. AUROC 0.87 (95% CI: 0.79-0.95). CONCLUSIONS An HCCB score greater than 5.42 points identifies a subgroup of chronic hepatitis B patients at high risk of developing liver cancer, who could benefit from screening measures for the early diagnosis of HCC.
Collapse
Affiliation(s)
- Paula Gavilán
- Universidad de Málaga, IBIMA-Plataforma BIONAND, Departamento de Farmacología y Pediatría, Facultad de Medicina, Campus de Teatinos s/n, 29071 Málaga, Spain
| | - Juan-Carlos Gavilán
- Departamento de Medicina Interna, Hospital Universitario Virgen de la Victoria, Málaga, Spain; Hospital Internacional Vithas Xanit, Benalmádena, Spain.
| | - Rocío Arnedo
- Departamento de Medicina Interna, Hospital Universitario Virgen de la Victoria, Málaga, Spain; Hospital Internacional Vithas Xanit, Benalmádena, Spain
| | - Encarnación Clavijo
- Universidad de Málaga, IBIMA-Plataforma BIONAND, Departamento de Microbiología, Facultad de Medicina, Campus de Teatinos s/n, 29071 Málaga, Spain
| | - Isabel Viciana
- Departamento de Microbiología, Hospital Universitario Virgen de la Victoria, Málaga, Spain
| | - José-Antonio González-Correa
- Universidad de Málaga, IBIMA-Plataforma BIONAND, Departamento de Farmacología y Pediatría, Facultad de Medicina, Campus de Teatinos s/n, 29071 Málaga, Spain
| |
Collapse
|
|
8
|
Bruni A, Castellana C, Dajti E, Barbara G, Marasco G, Maida M, Serviddio G, Facciorusso A. Epidemiological, diagnostic, therapeutic and prognostic impact of hepatitis B and D virus infection on hepatocellular carcinoma: A review of the literature. Virology 2024; 600:110273. [PMID: 39454228 DOI: 10.1016/j.virol.2024.110273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 10/17/2024] [Accepted: 10/21/2024] [Indexed: 10/28/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) accounts for >90% of primary liver cancer cases, and chronic infections with hepatitis B virus (HBV) and hepatitis D virus (HDV) are major contributors. METHODS A comprehensive literature review was conducted using the MEDLINE (PubMed) database, focusing on studies related to HBV, HDV, and HCC. RESULTS HBV contributes to HCC through mechanisms like viral integration into the host genome, chronic inflammation, and immune modulation, leading to genomic instability and altered cell signaling. HDV exacerbates HBV-induced liver damage, accelerating fibrosis and cirrhosis, and significantly increasing HCC risk. Antiviral therapies and vaccinations have majorly reduced the burden of HBV-related HCC, but HDV remains challenging to treat due to limited therapeutic options. Emerging treatments like Bulevirtide showed promising results. CONCLUSION This review highlights the critical impact of HBV and HDV co-infections on HCC development, emphasizing the need for more effective therapeutic strategies. While advances in antiviral therapies have reduced the incidence of HBV-related HCC, the high burden of HDV-related complications persists. Future research should focus on improving treatments for HDV and understanding its unique contribution to HCC pathogenesis.
Collapse
Affiliation(s)
- Angelo Bruni
- Department of Medical and Surgical Sciences, Università di Bologna, Bologna, Italy
| | - Chiara Castellana
- Gastroenterology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Elton Dajti
- Department of Medical and Surgical Sciences, Università di Bologna, Bologna, Italy; Gastroenterology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giovanni Barbara
- Department of Medical and Surgical Sciences, Università di Bologna, Bologna, Italy; Gastroenterology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giovanni Marasco
- Department of Medical and Surgical Sciences, Università di Bologna, Bologna, Italy; Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Marcello Maida
- Department of Medicine and Surgery, University of Enna 'Kore', Enna, Italy; Gastroenterology Unit, Umberto I Hospital, Enna, Italy
| | - Gaetano Serviddio
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Antonio Facciorusso
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
| |
Collapse
|
|
9
|
Bucio-Ortiz L, Enriquez-Navarro K, Maldonado-Rodríguez A, Torres-Flores JM, Cevallos AM, Salcedo M, Lira R. Occult Hepatitis B Virus Infection in Hepatic Diseases and Its Significance for the WHO's Elimination Plan of Viral Hepatitis. Pathogens 2024; 13:662. [PMID: 39204261 PMCID: PMC11357063 DOI: 10.3390/pathogens13080662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 09/03/2024] Open
Abstract
Liver damage can progress through different stages, resulting in cirrhosis or hepatocellular carcinoma (HCC), conditions that are often associated with viral infections. Globally, 42% and 21% of cirrhosis cases correlate with HBV and HCV, respectively. In the Americas, the prevalence ranges from 1% to 44%. The WHO has the goal to eliminate viral hepatitis, but it is important to consider occult HBV infection (OBI), a clinical condition characterized by the presence of HBV genomes despite negative surface antigen tests. This review aims to provide an overview of recent data on OBI, focusing on its role in the development of hepatic diseases and its significance in the WHO Viral Hepatitis Elimination Plan. Specific HBV gene mutations have been linked to HCC and other liver diseases. Factors related to the interactions between OBI and mutated viral proteins, which induce endoplasmic reticulum stress and oxidative DNA damage, and the potential role of HBV integration sites (such as the TERT promoter) have been identified in HCC/OBI patients. Health initiatives for OBI research in Latin American countries are crucial to achieving the WHO's goal of eradicating viral hepatitis by 2030, given the difficulty in diagnosing OBI and its unclear association with hepatic diseases.
Collapse
Affiliation(s)
- Leticia Bucio-Ortiz
- Medicina y Carcinogénesis Experimental, Universidad Autónoma Metropolitana Iztapalapa, Ciudad de Mexico 09340, Mexico; (L.B.-O.); (K.E.-N.)
| | - Karina Enriquez-Navarro
- Medicina y Carcinogénesis Experimental, Universidad Autónoma Metropolitana Iztapalapa, Ciudad de Mexico 09340, Mexico; (L.B.-O.); (K.E.-N.)
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, UMAE Hospital de Pediatría, CMN Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Ciudad de Mexico 06720, Mexico;
| | - Angélica Maldonado-Rodríguez
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, UMAE Hospital de Pediatría, CMN Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Ciudad de Mexico 06720, Mexico;
| | - Jesús Miguel Torres-Flores
- Laboratorio Nacional de Vacunología y Virus Tropicales, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de Mexico 11350, Mexico;
| | - Ana María Cevallos
- Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de Mexico, Ciudad de Mexico 04510, Mexico;
| | - Mauricio Salcedo
- Unidad de Investigación Biomédica Oncológica Genómica, Hospital de Gineco Pediatría 3-A, Instituto Mexicano del Seguro Social, Órgano de Operación Administrativa Desconcentrada (OOAD) Cd Mx Norte, Ciudad de Mexico 07760, Mexico;
| | - Rosalia Lira
- Unidad de Investigación Biomédica Oncológica Genómica, Hospital de Gineco Pediatría 3-A, Instituto Mexicano del Seguro Social, Órgano de Operación Administrativa Desconcentrada (OOAD) Cd Mx Norte, Ciudad de Mexico 07760, Mexico;
| |
Collapse
|
|
10
|
Chen YC, Yang CC, Kuo HT, Sheu MJ, Feng IC, Liu CF, Sun CS, Wang SH, Lin CY, Chen CH, Lin SH. Risk Factors and Nomogram Model for Hepatocellular Carcinoma Development in Chronic Hepatitis B Patients with Low-Level Viremia. Int J Med Sci 2024; 21:1661-1671. [PMID: 39006848 PMCID: PMC11241087 DOI: 10.7150/ijms.95861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 06/04/2024] [Indexed: 07/16/2024] Open
Abstract
Background and aim: Patients with chronic hepatitis B patients (CHB) with low-level viremia (LLV) are not necessarily at low risk of developing hepatocellular carcinoma (HCC). The question of whether CHB patients with LLV require immediate antiviral agent (AVT) or long-term AVT remains controversial. The study aims to investigate the risk of HCC development and the risk factors in CHB patients with LLV and construct a nomogram model predicting the risk of HCC. Methods: We conducted a retrospective cohort study that enrolled 16,895 CHB patients from January 2008 to December 2020. The patients were divided into three groups for comparison: the LLV group, maintained virological response (MVR) group and HBV-DNA>2000 group. The cumulative incidence of progression to HCC was assessed. Cox regression analysis was performed to determine the final risk factors, and a nomogram model was constructed. The 10-fold Cross-Validation method was utilized for internal validation. Results: A total of 408 new cases of HCC occurred during the average follow-up period of 5.78 years. The 3, 5, and 10-year cumulative HCC risks in the LLV group were 3.56%, 4.96%, and 9.51%, respectively. There was a significant difference in the cumulative risk of HCC between the HBV-DNA level > 2000 IU/mL and LLV groups (p = 0.049). Independent risk factors for HCC development in LLV group included male gender, age, presence of cirrhosis, and platelets count. The Area Under the Curve (AUC) values for the 3-year and 5-year prediction from our HCC risk prediction model were 0.75 and 0.76, respectively. Conclusion: Patients with LLV and MVR are still at risk for developing HCC. The nomogram established for CHB patient with LLV, incorporating identified significant risk factors, serves as an effective tool for predicting HCC-free outcomes. This nomogram model provides valuable information for determining appropriate surveillance strategies and prescribing AVT.
Collapse
Affiliation(s)
- Yu-Ching Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Yongkang District, Tainan, Taiwan
- Department of Internal Medicine, Chi Mei Medical Center, Yongkang District, Tainan, Taiwan
| | - Chun-Chi Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Yongkang District, Tainan, Taiwan
| | - Hsing-Tao Kuo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Yongkang District, Tainan, Taiwan
| | - Ming-Jen Sheu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Yongkang District, Tainan, Taiwan
| | - I-Che Feng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Yongkang District, Tainan, Taiwan
| | - Chung-Feng Liu
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
| | - Chi-Shu Sun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Yongkang District, Tainan, Taiwan
| | - Su-Hung Wang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Yongkang District, Tainan, Taiwan
| | - Cheng-Yi Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Yongkang District, Tainan, Taiwan
| | - Chi-Hsing Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Yongkang District, Tainan, Taiwan
| | - Sheng-Hsiang Lin
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Biostatistics Consulting Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| |
Collapse
|
|
11
|
Lin HC, Jeng WJ, Liu J, Pan MH, Lee MH, Batrla-Utermann R, Lu SN, Chen CF, Yang HI, Chen CJ. Persistently high HBsAg levels during HBeAg-seropositive stage predict lower risk of hepatocellular carcinoma in chronic hepatitis B patients. Aliment Pharmacol Ther 2024; 59:993-1002. [PMID: 38410882 DOI: 10.1111/apt.17915] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 11/15/2023] [Accepted: 02/11/2024] [Indexed: 02/28/2024]
Abstract
BACKGROUND High hepatitis B surface antigen (HBsAg) level predicts hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with low viral load. The role of longitudinal HBsAg levels in predicting HCC in HBeAg-positive CHB patients remains unknown. METHOD HBeAg-positive CHB participants from the REVEAL-HBV cohort with ≥2 HBsAg measurements before HBeAg seroclearance were enrolled. Group-based trajectory modelling identified distinct HBsAg trajectory groups during a median of 11 years of HBeAg-positive status. Cox regression models were applied for investigating independent predictors of HCC and estimating adjusted hazard ratio (HRadj) with a 95% confidence interval (CI). A p-value less than 0.05 was considered statistically significant. RESULTS A total of 319 patients were enrolled and classified by HBsAg trajectory patterns as (A) persistently high group (n = 72): HBsAg persistently ≥104 IU/mL, and (B) non-stationary group (n = 233): low HBsAg at baseline or declining to <104 IU/mL during the follow-up. Group B had higher proportions of abnormal ALT levels, HBV genotype C and basal core mutation than group A (p < 0.05); age at entry and gender were comparable. The annual incidence of HCC in group A and group B were 0.37% and 1.16%, respectively (p = 0.03). In multivariate analysis, age >40 years (HRadj [95% CI] = 4.11 [2.26-7.48]), genotype C (HRadj [95% CI] = 4.39 [1.96-9.81]) and the non-stationary group (HRadj [95% CI] = 3.50 [1.49-8.21]) were independent predictors of HCC. Basal core promoter mutation was the only risk factor of HCC in the persistently high HBsAg group (HRadj [95% CI] = 32.75 [5.41-198.42]). CONCLUSION Patients with persistently high HBsAg levels during HBeAg-seropositive stage represent a unique population with low risk of HCC development.
Collapse
Affiliation(s)
- Hsin-Che Lin
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan
- Chang Gung University College of Medicine, Taoyuan City, Taiwan
| | - Jessica Liu
- Perinatal Epidemiology and Health Outcomes Research Unit, Division of Neonatology, Department of Pediatrics, School of Medicine, Stanford University and Lucile Packard Children's Hospital, Palo Alto, California, USA
| | - Mei-Hung Pan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
| | | | - Sheng-Nan Lu
- Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chuen-Fei Chen
- Mackay Medical College Department of Medicine, Taipei, Taiwan
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan
- Doctoral Program of Clinical and Experimental Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Chien-Jen Chen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| |
Collapse
|
|
12
|
Jeng WJ, Chien RN, Chen YC, Lin CL, Wu CY, Liu YC, Peng CW, Su CW, Hsu CE, Liaw YF. Hepatocellular carcinoma reduced, HBsAg loss increased, and survival improved after finite therapy in hepatitis B patients with cirrhosis. Hepatology 2024; 79:690-703. [PMID: 37625144 DOI: 10.1097/hep.0000000000000575] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 07/31/2023] [Indexed: 08/27/2023]
Abstract
BACKGROUND AND AIMS Long-term nucleos(t)ide analog (Nuc) treatment can reduce HCC in patients with HBV-related liver cirrhosis (HBV-LC). Earlier small cohort studies showed a comparable 5-year incidence of HCC in HBeAg-negative patients with HBV-LC who stopped and those continued Nuc therapy. This study aimed to validate these findings using a large cohort with 10-year follow-up. APPROACH AND RESULTS From 2 centers, 494 HBeAg-negative patients with HBV-LC who stopped (finite group) and 593 who continued (continuous group) Nuc therapy were recruited. HCC, HBsAg loss, liver-related mortality/transplantation, and overall survival rates were compared between 2 groups with 1:1 propensity score matching of sex, treatment history, types of Nuc, age, transaminases, platelet count, and HBsAg levels at end of therapy in finite group or 3-year on-therapy in continuous groups. During a median follow-up of 6.2 (3.4-8.9) years, the annual and 10-year HCC incidence were lower in finite group (1.6 vs. 3.3%/y and 10-y 15.7% vs. 26.8%, respectively; log-rank test, p <0.0001). The finite group showed greater HBsAg decline/year (-0.116 vs. -0.095 log 10 IU/mL, p =0.0026) and 7.6 times higher 10-year incidence of HBsAg loss (22.7% vs. 3%, p <0.0001). Multivariate Cox regression showed finite therapy an independent factor for HBsAg loss (adjusted HR: 11.79) but protective against HCC (adjusted HR: 0.593), liver-related mortality/transplantation (adjusted HR: 0.312), and overall mortality (adjusted HR: 0.382). CONCLUSIONS Finite Nuc therapy in HBeAg-negative HBV-LC may reduce HCC incidence, increase HBsAg loss, and improve survival. Greater HBsAg decline/loss may reflect enhanced immunity and contribute to the reduction of hepatic carcinogenesis.
Collapse
Affiliation(s)
- Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Yi-Cheng Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Chih-Lang Lin
- College of Medicine, Chang Gung University, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Keelung Branch, Taiwan
| | - Chia-Ying Wu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Yen-Chun Liu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Chien-Wei Peng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Chung-Wei Su
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Cheng-Er Hsu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
- College of Medicine, Chang Gung University, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| |
Collapse
|
|
13
|
Varghese N, Majeed A, Nyalakonda S, Boortalary T, Halegoua-DeMarzio D, Hann HW. Review of Related Factors for Persistent Risk of Hepatitis B Virus-Associated Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:777. [PMID: 38398168 PMCID: PMC10887172 DOI: 10.3390/cancers16040777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 01/30/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Chronic hepatitis B virus (HBV) infection is the largest global cause of hepatocellular carcinoma (HCC). Current HBV treatment options include pegylated interferon-alpha and nucleos(t)ide analogues (NAs), which have been shown to be effective in reducing HBV DNA levels to become undetectable. However, the literature has shown that some patients have persistent risk of developing HCC. The mechanism in which this occurs has not been fully elucidated. However, it has been discovered that HBV's covalently closed circular DNA (cccDNA) integrates into the critical HCC driver genes in hepatocytes upon initial infection; additionally, these are not targets of current NA therapies. Some studies suggest that HBV undergoes compartmentalization in peripheral blood mononuclear cells that serve as a sanctuary for replication during antiviral therapy. The aim of this review is to expand on how patients with HBV may develop HCC despite years of HBV viral suppression and carry worse prognosis than treatment-naive HBV patients who develop HCC. Furthermore, HCC recurrence after initial surgical or locoregional treatment in this setting may cause carcinogenic cells to behave more aggressively during treatment. Curative novel therapies which target the life cycle of HBV, modulate host immune response, and inhibit HBV RNA translation are being investigated.
Collapse
Affiliation(s)
- Nevin Varghese
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Amry Majeed
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Suraj Nyalakonda
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Tina Boortalary
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Hie-Won Hann
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| |
Collapse
|
|
14
|
Lin W. Disparities in Healthcare and HBV Vaccination by Smoking Status: Findings from the National Health and Nutrition Examination Survey (NHANES) 2017-2018. Healthcare (Basel) 2023; 12:41. [PMID: 38200947 PMCID: PMC10779267 DOI: 10.3390/healthcare12010041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 12/12/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Cigarette smokers face greater challenges in accessing healthcare compared with non-smokers. In the US, approximately 2.2 million individuals are chronically infected with hepatitis B virus (HBV). I used data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 to investigate the association between smoking status (current, former, and never smoker) and different health outcomes, including healthcare accessibility, HBV vaccination, general health condition, and health insurance. Multivariable logistic regressions were used to analyze healthcare disparity by smoking status. I found that current smokers had 40% higher odds (AOR = 1.4, 95% CI: 1.1, 1.8) of lacking routine healthcare access compared with non-smokers. Regardless of smoking status, I observed a high rate of HBV non-vaccination among all participants. Specifically, 64% of current smokers, 67% of former smokers, and 57% of non-smokers had not received a single dose of HBV immunization. My study sheds light on the persisting gaps in healthcare access, particularly for smokers, and the urgent need to promote awareness and vaccination against hepatitis B.
Collapse
Affiliation(s)
- Wenxue Lin
- Department of Epidemiology and Biostatistics, College of Public Health, Temple University, Philadelphia, PA 19122, USA
| |
Collapse
|
|
15
|
Abubakar A, Yusuf F, Firdausa S, Maghfirah D, Gunawan A, Yeni CM, Sari F. Co-incidence of COVID-19 and hepatocellular carcinoma during pregnancy: Double punches to disease severity and mortality? NARRA J 2023; 3:e264. [PMID: 38455627 PMCID: PMC10919738 DOI: 10.52225/narra.v3i3.264] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 09/26/2023] [Indexed: 03/09/2024]
Abstract
Hepatocellular carcinoma (HCC), a considerable leading cause of cancer-related deaths worldwide, is the most common primary liver cancer with poor prognosis and outcome. Many advances in prevention, screening, and new technologies in diagnostics and therapy have been achieved, but its incidence and mortality remain increasing. Co-infection of another viral disease in HCC patients with pregnancy might exacerbate the condition and double the mortality rate. The aim of this case report was to describe the co-infection of coronavirus disease 2019 (COVID-19) in an HCC patient during pregnancy. A 26-year-old woman with 16-17 weeks of gestation was admitted to Dr. Zainoel Abidin Hospital, Banda Aceh, Indonesia with shortness of breath. The patient also reported that the abdomen expanded rapidly in the last three weeks, followed by severe pain and collateral vein appearance. Laboratory findings revealed anemia, leukocytosis, HBsAg reactive, hypoalbuminemia, hyperbilirubinemia, elevated liver enzymes, increased alpha-fetoprotein (AFP), and cancer antigen 125 (CA-125). Ultrasonography indicated gestation with a single fetus, an enlarged liver with a 9.9 × 9.4 cm nodule, and massive ascites. The patient was also RT-PCR-confirmed COVID-19. On day 8 of hospitalization, the patient suddenly reported severe abdominal pain. Ultrasonography revealed fetal distress immediately followed by fetal death. Adequate management of cancer pain, continuous evacuation of ascites, and other supportive care could not save the patient who died on the day 17 of hospitalization. In this case, we found no proof that the patient experienced cirrhosis prior to HCC. Pregnancy through hormonal alteration is thought to be the aggravating factor that accelerates the progression of pre-existing liver disease into carcinoma and infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worsened the outcome in this patient.
Collapse
Affiliation(s)
- Azzaki Abubakar
- Division of Gastroenterohepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia
- Division of Gastroenterohepatology, Department of Internal Medicine, Dr. Zainoel Abidin Hospital, Banda Aceh, Indonesia
| | - Fauzi Yusuf
- Division of Gastroenterohepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia
- Division of Gastroenterohepatology, Department of Internal Medicine, Dr. Zainoel Abidin Hospital, Banda Aceh, Indonesia
| | - Sarah Firdausa
- Division of Endocrine, Metabolic, and Diabetes, Department of Internal Medicine, Faculty of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia
- Division of Endocrine, Metabolic, and Diabetes, Department of Internal Medicine, Dr. Zainoel Abidin Hospital, Banda Aceh, Indonesia
| | - Desi Maghfirah
- Division of Gastroenterohepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia
- Division of Gastroenterohepatology, Department of Internal Medicine, Dr. Zainoel Abidin Hospital, Banda Aceh, Indonesia
| | - Andrie Gunawan
- Division of Gastroenterohepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia
- Division of Gastroenterohepatology, Department of Internal Medicine, Dr. Zainoel Abidin Hospital, Banda Aceh, Indonesia
| | - Cut M. Yeni
- Division of Feto-Maternal, Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia
- Division of Feto-Maternal, Department of Obstetrics and Gynecology, Dr. Zainoel Abidin Hospital, Banda Aceh, Indonesia
| | - Fitrah Sari
- Department of Internal Medicine, Faculty of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia
- Department of Internal Medicine, Dr. Zainoel Abidin Hospital, Banda Aceh, Indonesia
| |
Collapse
|
|
16
|
Hur MH, Park MK, Yip TCF, Chen CH, Lee HC, Choi WM, Kim SU, Lim YS, Park SY, Wong GLH, Sinn DH, Jin YJ, Kim SE, Peng CY, Shin HP, Chen CY, Kim HY, Lee HA, Seo YS, Jun DW, Yoon EL, Sohn JH, Ahn SB, Shim JJ, Jeong SW, Cho YK, Kim HS, Jang MJ, Kim YJ, Yoon JH, Lee JH. Personalized Antiviral Drug Selection in Patients With Chronic Hepatitis B Using a Machine Learning Model: A Multinational Study. Am J Gastroenterol 2023; 118:1963-1972. [PMID: 36881437 DOI: 10.14309/ajg.0000000000002234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 03/01/2023] [Indexed: 03/08/2023]
Abstract
INTRODUCTION Tenofovir disoproxil fumarate (TDF) is reportedly superior or at least comparable to entecavir (ETV) for the prevention of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B; however, it has distinct long-term renal and bone toxicities. This study aimed to develop and validate a machine learning model (designated as Prediction of Liver cancer using Artificial intelligence-driven model for Network-antiviral Selection for hepatitis B [PLAN-S]) to predict an individualized risk of HCC during ETV or TDF therapy. METHODS This multinational study included 13,970 patients with chronic hepatitis B. The derivation (n = 6,790), Korean validation (n = 4,543), and Hong Kong-Taiwan validation cohorts (n = 2,637) were established. Patients were classified as the TDF-superior group when a PLAN-S-predicted HCC risk under ETV treatment is greater than under TDF treatment, and the others were defined as the TDF-nonsuperior group. RESULTS The PLAN-S model was derived using 8 variables and generated a c-index between 0.67 and 0.78 for each cohort. The TDF-superior group included a higher proportion of male patients and patients with cirrhosis than the TDF-nonsuperior group. In the derivation, Korean validation, and Hong Kong-Taiwan validation cohorts, 65.3%, 63.5%, and 76.4% of patients were classified as the TDF-superior group, respectively. In the TDF-superior group of each cohort, TDF was associated with a significantly lower risk of HCC than ETV (hazard ratio = 0.60-0.73, all P < 0.05). In the TDF-nonsuperior group, however, there was no significant difference between the 2 drugs (hazard ratio = 1.16-1.29, all P > 0.1). DISCUSSION Considering the individual HCC risk predicted by PLAN-S and the potential TDF-related toxicities, TDF and ETV treatment may be recommended for the TDF-superior and TDF-nonsuperior groups, respectively.
Collapse
Affiliation(s)
- Moon Haeng Hur
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Min Kyung Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Terry Cheuk-Fung Yip
- Medical Data Analytics Centre (MDAC), Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hyung-Chul Lee
- Department of Anesthesiology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Won-Mook Choi
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine and Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young-Suk Lim
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Soo Young Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Grace Lai-Hung Wong
- Medical Data Analytics Centre (MDAC), Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Dong Hyun Sinn
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Young-Joo Jin
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Republic of Korea
| | - Sung Eun Kim
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Hyun Phil Shin
- Department of Gastroenterology and Hepatology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Republic of Korea
| | - Chi-Yi Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan
| | - Hwi Young Kim
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Han Ah Lee
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Yeon Seok Seo
- Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Republic of Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Eileen L Yoon
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Republic of Korea
- Department of Internal Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Republic of Korea
| | - Joo Hyun Sohn
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Republic of Korea
| | - Sang Bong Ahn
- Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University College of Medicine, Seoul, Republic of Korea
| | - Jae-Jun Shim
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Republic of Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Yong Kyun Cho
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hyoung Su Kim
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea
| | - Myoung-Jin Jang
- Medical Research Collaboration Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| |
Collapse
|
|
17
|
Fernandes da Silva C, Keeshan A, Cooper C. Hepatitis B virus genotypes influence clinical outcomes: A review. CANADIAN LIVER JOURNAL 2023; 6:347-352. [PMID: 38020195 PMCID: PMC10652982 DOI: 10.3138/canlivj-2023-0003] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/28/2023] [Indexed: 12/01/2023]
Abstract
Hepatitis B virus (HBV) is a hepatotropic virus that affects approximately 296 million people worldwide. A crucial step to HBV replication is the transcription of its infectious DNA from its viral RNA intermediate. The production of the RNA intermediate hinges on reverse transcription, and therefore the lack of proofreading in that process commonly yields mutants and has led to nine well-described genotypes (A-I) and over 30 known sub-genotypes of the virus. The influence of genotype on HBV infection outcomes, which include fibrosis progression, cirrhosis, and hepatocellular carcinoma (HCC), remain uncertain. This review aims to analyze the influence of HBV genotype on the risk of development of these outcomes. The response to current and future HBV therapies is considered. Further study of larger and more diverse samples will hopefully resolve outstanding uncertainties.
Collapse
Affiliation(s)
| | - Alexa Keeshan
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
| | - Curtis Cooper
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
| |
Collapse
|
|
18
|
Yang D, Zou J, Guan G, Feng X, Zhang T, Li G, Liu H, Zheng H, Xi J, Yu G, Dai L, Lu F, Chen X. The A1762T/G1764A mutations enhance HBV replication by alternating viral transcriptome. J Med Virol 2023; 95:e29129. [PMID: 37772469 DOI: 10.1002/jmv.29129] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 09/13/2023] [Accepted: 09/19/2023] [Indexed: 09/30/2023]
Abstract
The A1762T/G1764A mutations, one of the most common mutations in the hepatitis B virus basal core promoter, are associated with the progression of chronic HBV infection. However, effects of these mutations on HBV replication remains controversial. This study aimed to systematically investigate the effect of the mutations on HBV replication and its underlying mechanisms. Using the prcccDNA/pCMV-Cre recombinant plasmid system, a prcccDNA-A1762T/G1764A mutant plasmid was constructed. Compared with wild-type HBV, A1762T/G1764A mutant HBV showed enhanced replication ability with higher secreted HBV DNA and RNA levels, while Southern and Northern blot indicated higher intracellular levels of relaxed circular DNA, single-stranded DNA, and 3.5 kb RNA. Meanwhile, the mutations increased expression of intracellular core protein and decreased the production of HBeAg and HBsAg. In vitro infection based on HepG2-NTCP cells and mice hydrodynamic injection experiment also proved that these mutations promote HBV replication. 5'-RACE assays showed that these mutations upregulated transcription of pregenomic RNA (pgRNA) while downregulating that of preC RNA, which was further confirmed by full-length transcriptome sequencing. Moreover, a proportion of sub-pgRNAs with the potential to express polymerase were also upregulated by these mutations. The ChIP-qPCR assay showed that A1762T/G1764A mutations created a functional HNF1α binding site in the BCP region, and its overexpression enhanced the effect of A1762T/G1764A mutations on HBV. Our findings revealed the mechanism and importance of A1762T/G1764A mutations as an indicator for management of CHB patients, and provided HNF1α as a new target for curing HBV-infected patients.
Collapse
Affiliation(s)
- Danli Yang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Jun Zou
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China
- Research and Development Center, Shenzhen Sanyuansheng Biotechnology Co., Ltd, Shenzhen, China
| | - Guiwen Guan
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Xiaoyu Feng
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ting Zhang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Guixin Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Hui Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Huiling Zheng
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Jingyuan Xi
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China
- Department of Clinical Laboratory Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| | - Guangxin Yu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Lizhong Dai
- Peking University-Sansure Biotech Joint Laboratory of Molecular Medicine, Sansure Biotech Co., LTD, Changsha, China
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China
- Hepatology Institute, Peking University People's Hospital, Beijing, China
| | - Xiangmei Chen
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China
| |
Collapse
|
|
19
|
Thiyagarajah K, Basic M, Hildt E. Cellular Factors Involved in the Hepatitis D Virus Life Cycle. Viruses 2023; 15:1687. [PMID: 37632029 PMCID: PMC10459925 DOI: 10.3390/v15081687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/30/2023] [Accepted: 08/01/2023] [Indexed: 08/27/2023] Open
Abstract
Hepatitis D virus (HDV) is a defective RNA virus with a negative-strand RNA genome encompassing less than 1700 nucleotides. The HDV genome encodes only for one protein, the hepatitis delta antigen (HDAg), which exists in two forms acting as nucleoproteins. HDV depends on the envelope proteins of the hepatitis B virus as a helper virus for packaging its ribonucleoprotein complex (RNP). HDV is considered the causative agent for the most severe form of viral hepatitis leading to liver fibrosis/cirrhosis and hepatocellular carcinoma. Many steps of the life cycle of HDV are still enigmatic. This review gives an overview of the complete life cycle of HDV and identifies gaps in knowledge. The focus is on the description of cellular factors being involved in the life cycle of HDV and the deregulation of cellular pathways by HDV with respect to their relevance for viral replication, morphogenesis and HDV-associated pathogenesis. Moreover, recent progress in antiviral strategies targeting cellular structures is summarized in this article.
Collapse
Affiliation(s)
| | | | - Eberhard Hildt
- Paul-Ehrlich-Institute, Department of Virology, D-63225 Langen, Germany; (K.T.); (M.B.)
| |
Collapse
|
|
20
|
Raihan R, Akbar SMF. A Narrative Review on the Specific Pattern of HBV Genotype in Bangladesh: Clinical Implications for Management. Euroasian J Hepatogastroenterol 2023; 13:152-158. [PMID: 38222956 PMCID: PMC10785131 DOI: 10.5005/jp-journals-10018-1412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 11/21/2023] [Indexed: 01/16/2024] Open
Abstract
Background and aims Bangladesh's unique epidemiological landscape presents an intriguing puzzle. This South Asian nation, with its complex sociodemographic and environmental factors, is home to a diverse array of hepatitis-B virus (HBV) genotypes, identified as Genotype C, with Genotypes D and A also making a significant contribution to the viral landscape. Reviewing such insights is necessary not only to underscore the country's regional diversity in HBV strains but also to bring into focus the clinical implications these genetic variations may have on disease progression and management. Methods A thorough database search covered various sources using relevant keywords like "Hepatitis B virus genotypes", "HBV genotypes in Bangladesh", and "HBV clinical implications". The review synthesized findings and analyzed HBV genotype prevalence and clinical implications in Bangladesh. Results Genotypes C and D collectively represent 82% of chronic hepatitis-B infection (CHB) cases in Bangladesh, underscoring their regional prevalence. The geographic context is pivotal in understanding HBV infection dynamics and disease progression in this area. Notably, genotype C and the presence of A1762T/G1764A mutations appear to have a distinct impact on disease development, potentially affecting the immune response in CHB patients. This highlights the need for tailored management approaches in this specific region. Further research is vital to confirm and elaborate on these findings, particularly in relation to how these mutations influence the host's immune response. Conclusion and clinical significance In summary, studies on HBV genotypes in Bangladesh stress the need for genotype-specific clinical considerations and more research to improve diagnostics and therapies. How to cite this article Raihan R, Akbar SMF. A Narrative Review on the Specific Pattern of HBV Genotype in Bangladesh: Clinical Implications for Management. Euroasian J Hepato-Gastroenterol 2023;13(2):152-158.
Collapse
Affiliation(s)
- Ruksana Raihan
- Department of Microbiology, US Bangla Medical College and Hospital, University of Malaya, Dhaka, Bangladesh
| | - Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine; Research Center for Global and Local Infectious Diseases, Faculty of Medicine, Oita University, Oita; Miyakawa Memorial Research Foundation, Tokyo, Japan
| |
Collapse
|
|
21
|
Kim NJ, Cravero A, VoPham T, Vutien P, Carr R, Issaka RB, Johnston J, McMahon B, Mera J, Ioannou GN. Addressing racial and ethnic disparities in US liver cancer care. Hepatol Commun 2023; 7:e00190. [PMID: 37347221 PMCID: PMC10289716 DOI: 10.1097/hc9.0000000000000190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 05/09/2023] [Indexed: 06/23/2023] Open
Abstract
HCC, the most common form of primary liver cancer, is the fastest rising cause of cancer-related death in the United States. HCC disproportionately affects racial and ethnic minorities in the United States. A practical framework is needed to organize the complex patient, provider, health system, and societal factors that drive these racial and ethnic disparities. In this narrative review, we adapted and applied the National Institute on Minority Health and Health Disparities (NIMHD) Research Framework to the HCC care continuum, as a step toward better understanding and addressing existing HCC-related disparities. We first summarize the literature on HCC-related disparities by race and ethnicity organized by the framework's 5 domains (biological, behavioral, physical/built environment, sociocultural environment, and health care system) and 4 levels (individual, interpersonal, community, and societal) of influence. We then offer strategies to guide future research initiatives toward promotion of health equity in HCC care. Clinicians and researchers may help mitigate further inequities and better address racial and ethnic disparities in HCC care by prioritizing the following in HCC research: (1) increasing racial and ethnic minority representation, (2) collecting and reporting HCC-related data by racial and ethnic subgroups, (3) assessing the patient experience of HCC care by race and ethnicity, and (4) evaluating HCC-specific social determinants of health by race and ethnicity. These 4 priorities will help inform the development of future programs and interventions that are tailored to the unique experiences of each racial and ethnic group.
Collapse
Affiliation(s)
- Nicole J. Kim
- Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Anne Cravero
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Trang VoPham
- Epidemiology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA
| | - Philip Vutien
- Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Rotonya Carr
- Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Rachel B. Issaka
- Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, USA
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Janet Johnston
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, Alaska
| | - Brian McMahon
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, Alaska
| | - Jorge Mera
- Cherokee Nation Health Services, Tahlequah, Oklahoma
| | - George N. Ioannou
- Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, USA
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
| |
Collapse
|
|
22
|
Abstract
Hepatitis B virus (HBV) infection is a major public health problem, with an estimated 296 million people chronically infected and 820 000 deaths worldwide in 2019. Diagnosis of HBV infection requires serological testing for HBsAg and for acute infection additional testing for IgM hepatitis B core antibody (IgM anti-HBc, for the window period when neither HBsAg nor anti-HBs is detected). Assessment of HBV replication status to guide treatment decisions involves testing for HBV DNA, whereas assessment of liver disease activity and staging is mainly based on aminotransferases, platelet count, and elastography. Universal infant immunisation, including birth dose vaccination is the most effective means to prevent chronic HBV infection. Two vaccines with improved immunogenicity have recently been approved for adults in the USA and EU, with availability expected to expand. Current therapies, pegylated interferon, and nucleos(t)ide analogues can prevent development of cirrhosis and hepatocellular carcinoma, but do not eradicate the virus and rarely clear HBsAg. Treatment is recommended for patients with cirrhosis or with high HBV DNA levels and active or advanced liver disease. New antiviral and immunomodulatory therapies aiming to achieve functional cure (ie, clearance of HBsAg) are in clinical development. Improved vaccination coverage, increased screening, diagnosis and linkage to care, development of curative therapies, and removal of stigma are important in achieving WHO's goal of eliminating HBV infection by 2030.
Collapse
Affiliation(s)
- Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - George V Papatheodoridis
- Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Anna S F Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
| |
Collapse
|
|
23
|
Relevance of HBx for Hepatitis B Virus-Associated Pathogenesis. Int J Mol Sci 2023; 24:ijms24054964. [PMID: 36902395 PMCID: PMC10003785 DOI: 10.3390/ijms24054964] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/20/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
The hepatitis B virus (HBV) counts as a major global health problem, as it presents a significant causative factor for liver-related morbidity and mortality. The development of hepatocellular carcinomas (HCC) as a characteristic of a persistent, chronic infection could be caused, among others, by the pleiotropic function of the viral regulatory protein HBx. The latter is known to modulate an onset of cellular and viral signaling processes with emerging influence in liver pathogenesis. However, the flexible and multifunctional nature of HBx impedes the fundamental understanding of related mechanisms and the development of associated diseases, and has even led to partial controversial results in the past. Based on the cellular distribution of HBx-nuclear-, cytoplasmic- or mitochondria-associated-this review encompasses the current knowledge and previous investigations of HBx in context of cellular signaling pathways and HBV-associated pathogenesis. In addition, particular focus is set on the clinical relevance and potential novel therapeutic applications in the context of HBx.
Collapse
|
|
24
|
Genetic Susceptibility to Hepatocellular Carcinoma in Patients with Chronic Hepatitis Virus Infection. Viruses 2023; 15:v15020559. [PMID: 36851773 PMCID: PMC9964813 DOI: 10.3390/v15020559] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/13/2023] [Accepted: 02/14/2023] [Indexed: 02/22/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. The risk factors for HCC include chronic hepatitis B and C virus infections, excessive alcohol consumption, obesity, metabolic disease, and aflatoxin exposure. In addition to these viral and environmental risk factors, individual genetic predisposition is a major determinant of HCC risk. Familial clustering of HCC has been observed, and a hereditary factor likely contributes to the risk of HCC development. The familial aggregation may depend on a shared environment and genetic background as well as the interactions of environmental and genetic factors. Genome-wide association studies (GWASs) are one of the most practical tools for mapping the patterns of inheritance for the most common form of genomic variation, single nucleotide polymorphisms. This approach is practical for investigating genetic variants across the human genome, which is affected by thousands of common genetic variants that do not follow Mendelian inheritance. This review article summarizes the academic knowledge of GWAS-identified genetic loci and their association with HCC. We summarize the GWASs in accordance with various chronic hepatitis virus infection statuses. This genetic profiling could be used to identify candidate biomarkers to refine HCC screening and management by enabling individual risk-based personalization and stratification. A more comprehensive understanding of the genetic mechanisms underlying individual predisposition to HCC may lead to improvements in the prevention and early diagnosis of HCC and the development of effective treatment strategies.
Collapse
|
|
25
|
Ward JW, Wanlapakorn N, Poovorawan Y, Shouval D. Hepatitis B Vaccines. PLOTKIN'S VACCINES 2023:389-432.e21. [DOI: 10.1016/b978-0-323-79058-1.00027-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
26
|
Yeh SH, Li CL, Lin YY, Ho MC, Wang YC, Tseng ST, Chen PJ. Hepatitis B Virus DNA Integration Drives Carcinogenesis and Provides a New Biomarker for HBV-related HCC. Cell Mol Gastroenterol Hepatol 2023; 15:921-929. [PMID: 36690297 PMCID: PMC9972564 DOI: 10.1016/j.jcmgh.2023.01.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 12/24/2022] [Accepted: 01/02/2023] [Indexed: 01/25/2023]
Abstract
Hepatitis B virus (HBV) DNA integration is an incidental event in the virus replication cycle and occurs in less than 1% of infected hepatocytes during viral infection. However, HBV DNA is present in the genome of approximately 90% of HBV-related HCCs and is the most common somatic mutation. Whole genome sequencing of liver tissues from chronic hepatitis B patients showed integration occurring at random positions in human chromosomes; however, in the genomes of HBV-related HCC patients, there are integration hotspots. Both the enrichment of the HBV-integration proportion in HCC and the emergence of integration hotspots suggested a strong positive selection of HBV-integrated hepatocytes to progress to HCC. The activation of HBV integration hotspot genes, such as telomerase (TERT) or histone methyltransferase (MLL4/KMT2B), resembles insertional mutagenesis by oncogenic animal retroviruses. These candidate oncogenic genes might shed new light on HBV-related HCC biology and become targets for new cancer therapies. Finally, the HBV integrations in individual HCC contain unique sequences at the junctions, such as virus-host chimera DNA (vh-DNA) presumably being a signature molecule for individual HCC. HBV integration may thus provide a new cell-free tumor DNA biomarker to monitor residual HCC after curative therapies or to track the development of de novo HCC.
Collapse
Affiliation(s)
- Shiou-Hwei Yeh
- Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan; National Taiwan University Center for Genomic Medicine, National Taiwan University, Taipei, Taiwan
| | - Chiao-Ling Li
- Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - You-Yu Lin
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Genome and Systems Biology Degree Program, National Taiwan University College of Life Science, Taipei, Taiwan
| | - Ming-Chih Ho
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | | | | | - Pei-Jer Chen
- National Taiwan University Center for Genomic Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
| |
Collapse
|
|
27
|
Xu Y, Xiong H, Zhang B, Lee I, Xie J, Li M, Zhang H, Seung Kim J. Photodynamic Alzheimer’s disease therapy: From molecular catalysis to photo-nanomedicine. Coord Chem Rev 2022. [DOI: 10.1016/j.ccr.2022.214726] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
|
|
28
|
Yang C, Chen H, Zhou B, Yin J, Cao G, Hou J, Jiang D. The effects of the interactions of STAT4 rs7574865 with HBV mutations on the risk of hepatocellular carcinoma. Mol Carcinog 2022; 61:933-940. [PMID: 35880842 DOI: 10.1002/mc.23449] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 06/13/2022] [Accepted: 07/02/2022] [Indexed: 11/11/2022]
Abstract
Signal transducer and activator of transcription 4 (STAT4) is closely related to liver diseases and affects the processes of inflammation and carcinogenesis by regulating immune responses. A single-nucleotide polymorphism rs7574865 (T > G) in STAT4 has been reported to be associated with the risk of hepatocellular carcinoma (HCC). In addition, hepatitis B virus (HBV) mutations are crucial risk factors for HBV-induced HCC. However, the effects of the interactions of STAT4 rs7574865 with HBV mutations on the risk of HCC remain unknown. Rs7574865 was genotyped in 846 healthy controls (HCs), 968 chronic hepatitis B (CHB) subjects, 316 liver cirrhosis (LC) subjects and 1021 HCC subjects using Sequenom MassArray. HBV mutations were detected via direct sequencing. Multivariate logistic regression analysis was used to evaluate the effects of the interactions of STAT4 rs7574865 with HBV mutations on the risk of HCC. We found that the rs7574865 TT genotype was significantly associated with HBeAg seroconversion (TT vs. GG, p = 0.012; TT vs. GT, p = 0.033). The rs7574865 GG genotype was significantly associated with increased risks of CHB (p = 0.048), LC (p = 0.005) and HCC (p < 0.001). The interaction term between rs7574865 and HBV C1913A significantly increased the risk of progression from CHB to HCC (p = 0.038), while the interaction term between rs7574865 and HBV T1674C significantly increased the risk of progression from LC to HCC (p = 0.023). STAT4 rs7574865 is significantly associated with the risks of CHB, LC and HCC. The interactions of rs7574865 with HBV C1913A and T1674C mutations significantly increase the risk of HCC, which have the potential to identify HBV-infected individuals who tend to progress from CHB or LC to HCC.
Collapse
Affiliation(s)
- Chou Yang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Haitao Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jianhua Yin
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Guangwen Cao
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Deke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| |
Collapse
|
|
29
|
Zhu M, Wang H, Lou T, Xiong P, Zhang J, Li L, Sun Y, Wu Y. Current treatment of chronic hepatitis B: Clinical aspects and future directions. Front Microbiol 2022; 13:975584. [PMID: 36160238 PMCID: PMC9493448 DOI: 10.3389/fmicb.2022.975584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 07/26/2022] [Indexed: 11/23/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a public health threat worldwide, and there is no direct treatment yet available. In the event of infection, patients may present liver cirrhosis and cancer, which threaten the patients’ health globally, especially in the Asia-Pacific region and China. In 2019, Chinese hepatopathologists updated the 2015 Guidelines for the Prevention and Treatment of Chronic Hepatitis B as the clinical reference. The other versions formulated by the American Association for the Study of Liver Diseases (2018 AASLD guidelines) (AASLD, 2018), European Association for the Study of the Liver (2017 EASL guidelines) (EASL, 2017), and Asian-Pacific Association for the Study of the Liver (2015 APASL guidelines) (APASL, 2015) also provide clinical guidance. However, there are still some issues that need to be addressed. In the present study, the following aspects will be introduced successively: (1) Who should be treated in the general population according to the guidelines; (2) Treatment of specific populations infected with HBV; (3) Controversial issues in clinical practice; (4) Perspective.
Collapse
Affiliation(s)
- Minmin Zhu
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Hui Wang
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Tao Lou
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Pian Xiong
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Jiebing Zhang
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Lele Li
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Yuchao Sun
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
- International Institutes of Medicine, Zhejiang University, Jinhua, China
| | - Yingping Wu
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
- International Institutes of Medicine, Zhejiang University, Jinhua, China
- *Correspondence: Yingping Wu,
| |
Collapse
|
|
30
|
Huang J, Su M, Chen H, Wu S, Chen Z. The S267F variant of sodium taurocholate co-transporting polypeptide is strongly associated with resistance to chronic hepatitis B and high level of serum total bile acids. LIVER RESEARCH 2022; 6:186-190. [PMID: 39958196 PMCID: PMC11791793 DOI: 10.1016/j.livres.2022.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 07/11/2022] [Accepted: 08/29/2022] [Indexed: 11/30/2022]
Abstract
Background and aims The sodium taurocholate co-transporting polypeptide (NTCP) is a functional receptor for the hepatitis B virus (HBV), and it is critical for bile acid homeostasis. Previous studies of the association between the S267F variant and chronic hepatitis B (CHB) have generated conflicting results. This study analyzed the correlation between the NTCP S267F variant and CHB susceptibility by using a large sample of participants classified by gender and age, and this study also analyzed the relationship between this variant and the level of serum total bile acids. Methods In total, 543 patients with CHB and 429 control subjects underwent S267F variant genotyping using SNaPshot technology. Logistic regression was utilized to evaluate any association of the NTCP S267F variant with CHB susceptibility. Results The S267F variant was inversely correlated with the risk of chronic HBV infection in both the dominant model (GG genotype vs. AG genotype: odds ratio (OR) = 0.46, 95% confidence interval (CI) 0.30-0.71, P < 0.001) and the allele model (G allele vs. A allele: OR = 0.50, 95% CI 0.33-0.76, P = 0.001), and this correlation was not affected by gender and age stratification. The carriers of the heterozygous NTCP variant exhibited higher total bile acids levels than the carriers of wild-type NTCP, regardless of whether they were control subjects or patients with CHB. Heterozygous carriers exhibited reduced hepatitis B e antigen (HBeAg)-positivity rates and had lower ALT, AST, and lg DNA concentrations compared with wild-type carriers in patients with CHB. Conclusions The S267F variant of NTCP is a protective factor that reduces the risk of chronic HBV infection and exhibits a higher total bile acids level. Patients with CHB who carry this variant may have a better prognosis than those carrying wild-type NTCP.
Collapse
Affiliation(s)
- Jiancheng Huang
- Department of Laboratory Medicine, Mindong Hospital Affiliated to Fujian Medical University, Fuan, Fujian, China
| | - Mingkuan Su
- Department of Laboratory Medicine, Mindong Hospital Affiliated to Fujian Medical University, Fuan, Fujian, China
| | - Hongbin Chen
- Department of Laboratory Medicine, Mindong Hospital Affiliated to Fujian Medical University, Fuan, Fujian, China
| | - Shuiqing Wu
- Department of Gastroenterology, Mindong Hospital Affiliated to Fujian Medical University, Fuan, Fujian, China
| | - Zongyun Chen
- Department of Laboratory Medicine, Mindong Hospital Affiliated to Fujian Medical University, Fuan, Fujian, China
| |
Collapse
|
|
31
|
Martin P, Nguyen MH, Dieterich DT, Lau DTY, Janssen HLA, Peters MG, Jacobson IM. Treatment Algorithm for Managing Chronic Hepatitis B Virus Infection in the United States: 2021 Update. Clin Gastroenterol Hepatol 2022; 20:1766-1775. [PMID: 34329775 DOI: 10.1016/j.cgh.2021.07.036] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 07/15/2021] [Accepted: 07/21/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Chronic hepatitis B (CHB) infection remains the most frequent etiology of hepatocellular carcinoma globally as well as a major cause of cirrhosis. Despite vaccination, substantial numbers of persons have already been infected with hepatitis B virus and remain at risk of progressive liver disease. METHODS In 2004, a CHB management algorithm was developed by a panel of North American hepatologists, which was subsequently updated in 2006, 2008, and 2015. Since the most recent version, several developments have altered the management of CHB. Tenofovir alafenamide, with a more favorable safety profile than tenofovir disoproxil fumarate, has been introduced as an initial antiviral choice as well as an alternative for long-term therapy. Quantitation of hepatitis B surface antigen is becoming more widely available in clinical practice, with implications for monitoring response to treatment. Additionally, there has been a shift in how the natural history of CHB is perceived, as newer evidence has challenged the concept that during the immunotolerant phase of infection disease progression is not a concern. Finally, recent analyses indicate that in the United States, the average age of patients with CHB has increased, implying that the presence of comorbidities, including metabolic liver disease, increasing use of biologics associated with aging will increasingly affect disease management. RESULTS This updated algorithm is intended to serve as a guide to manage CHB while new antiviral strategies are developed. CONCLUSIONS Recommendations have been based on evidence from the scientific literature, when possible, as well as clinical experience and consensus expert opinion. Points of continued debate and areas of research need are also described.
Collapse
Affiliation(s)
- Paul Martin
- Division of Digestive Health and Liver Diseases, University of Miami School of Medicine, Miami, Florida.
| | - Mindie H Nguyen
- Department of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California; Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, California
| | | | - Daryl T-Y Lau
- Liver Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Harry L A Janssen
- Toronto Centre for Liver Diseases, University Health Network, Toronto, Canada
| | - Marion G Peters
- Division of Gastroenterology, University of California, San Francisco, San Francisco, California
| | - Ira M Jacobson
- Division of Gastroenterology, NYU Langone Health, New York, New York
| |
Collapse
|
|
32
|
Stella L, Santopaolo F, Gasbarrini A, Pompili M, Ponziani FR. Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment. World J Gastroenterol 2022; 28:2251-2281. [PMID: 35800182 PMCID: PMC9185215 DOI: 10.3748/wjg.v28.i21.2251] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/08/2021] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a global health challenge. Due to the high prevalence in low-income countries, hepatitis B virus (HBV) and hepatitis C virus infections remain the main risk factors for HCC occurrence, despite the increasing frequencies of non-viral etiologies. In addition, hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection. The molecular processes underlying HCC development are complex and various, either independent from liver disease etiology or etiology-related. The reciprocal interlinkage among non-viral and viral risk factors, the damaged cellular microenvironment, the dysregulation of the immune system and the alteration of gut-liver-axis are known to participate in liver cancer induction and progression. Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis. The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance, both through clinical-biochemical scores and periodic ultrasound assessment. This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC.
Collapse
Affiliation(s)
- Leonardo Stella
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| |
Collapse
|
|
33
|
Zhang C, Xie Y, Lai R, Wu J, Guo Z. Nonsynonymous C1653T Mutation of Hepatitis B Virus X Gene Enhances Malignancy of Hepatocellular Carcinoma Cells. J Hepatocell Carcinoma 2022; 9:367-377. [PMID: 35535232 PMCID: PMC9078866 DOI: 10.2147/jhc.s348690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 04/26/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose Methods Results Conclusion
Collapse
Affiliation(s)
- Cuifang Zhang
- Department of Rheumatology and Immunology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
- Department of Oncology, The Pingshan County People’s Hospital, Shijiazhuang, People’s Republic of China
| | - Ying Xie
- Hebei Key Laboratory of Laboratory Animal Science, Hebei Medical University, Shijiazhuang, People’s Republic of China
| | - Ruixue Lai
- Department of Rheumatology and Immunology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
| | - Jianhua Wu
- Animal Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
| | - Zhanjun Guo
- Department of Rheumatology and Immunology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
- Correspondence: Zhanjun Guo, Department of Rheumatology and Immunology, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, 050011, People’s Republic of China, Tel + 86 311 8609 5734, Fax + 86 311 8609 5237, Email
| |
Collapse
|
|
34
|
Kumar R. Review on hepatitis B virus precore/core promoter mutations and their correlation with genotypes and liver disease severity. World J Hepatol 2022; 14:708-718. [PMID: 35646275 PMCID: PMC9099108 DOI: 10.4254/wjh.v14.i4.708] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/04/2021] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
Of 350 million people worldwide are chronically infected with hepatitis B virus (HBV) and are at risk of developing cirrhosis and hepatocellular carcinoma (HCC) later in life. HBV is the most diverse DNA virus, and its genome is composed of four open reading frames: Presurface antigen/surface antigen gene (preS/S), precore/core gene (preC/C), polymerase gene (P), and the X gene (X). HBV produces quasispecies naturally or in response to antiviral agents because of the absence of proofreading activity amid reverse transcription and a high replication rate. The virus has 10 genotypes (A to J) with different geographical distributions. There are various HBV mutations in the HBV genome, including preC/C mutations, preS/S mutations, P gene mutations, and X gene mutations. The core promoter region plays a vital part in the replication, morphogenesis and pathogenesis of the virus. The precore region also plays a crucial role in viral replication. Both core promoter and precore mutations rescue the virus from host immune surveillance and result in the formation of mutated strains that may have altered pathogenicity. preC/C mutations are associated with liver disease progression. Precore mutations stop hepatitis B e antigen (HBeAg) production and basal core promoter mutations downregulate HBeAg production. Mutations in the basal core promoter are also associated with increased HBV replication and an increased incidence of advanced liver diseases such as cirrhosis and HCC. The emergence of antiviral-resistant mutations is the main reason for treatment failure. This review focuses mainly on preC/C promoter mutations and their correlation with genotypes and liver disease severity. Thorough perception and knowledge of HBV genetic variety and mutants could be vital to discover techniques for the prognosis and control of HBV infection.
Collapse
Affiliation(s)
- Rajesh Kumar
- Department of School Education, Haryana Government, Panchkula 134109, Haryana, India
| |
Collapse
|
|
35
|
The Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2022; 28:276-331. [PMID: 35430783 PMCID: PMC9013624 DOI: 10.3350/cmh.2022.0084] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 01/10/2023] Open
|
|
36
|
Liu T, Liu A, Liu Y, Cen S, Zhang Q. In vitro investigation of HBV clinical isolates from Chinese patients reveals that genotype C isolates possess higher infectivity than genotype B isolates. Virol Sin 2022; 37:398-407. [PMID: 35314401 PMCID: PMC9243618 DOI: 10.1016/j.virs.2022.03.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 03/15/2022] [Indexed: 10/26/2022] Open
|
|
37
|
Jiang S, Wang X, Chen K, Yang P. Establishment of an inducible cell line for Hepatitis B virus genotype C2 and its pharmacological responses to interferons. Pharmacol Res 2022; 178:106142. [PMID: 35218895 DOI: 10.1016/j.phrs.2022.106142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/17/2022] [Accepted: 02/22/2022] [Indexed: 11/16/2022]
Abstract
Hepatitis B virus (HBV) genotype C is closely associated with poor prognosis, contributing greatly to heavy chronic hepatitis B (CHB)-related liver disease burden in China and worldwide. However, the mechanistic studies on genotype C of HBV remain largely limited, partially because of a long-term lack of genotype C HBV-based stable cell tools. According to a bioinformatic analysis on the sub-genotype C2 HBV that is predominantly endemic in China, we selected 17.3 strain as a representative isolate. With a Tet-off gene expression system, an inducible viral replication and virion production of genotype C2 HBV were achieved in a cell line carrying persistent rcDNA-cccDNA recycling, termed HepG2-17.3, can be useful for virological studies on genotype C2 HBV. Additionally, this cell line has been formatted into cell-based assay that permits particular pharmacological screening of drug candidates, such as interferon regimens, for evaluations of the inhibitory effects on genotype C2 HBV replication.
Collapse
Affiliation(s)
- Shaodong Jiang
- CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xin Wang
- CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Kaili Chen
- CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Pengyuan Yang
- CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| |
Collapse
|
|
38
|
Abstract
Hepatitis B virus (HBV) is a hepatotropic virus and an important human pathogen. There are an estimated 296 million people in the world that are chronically infected by this virus, and many of them will develop severe liver diseases including hepatitis, cirrhosis and hepatocellular carcinoma (HCC). HBV is a small DNA virus that replicates via the reverse transcription pathway. In this review, we summarize the molecular pathways that govern the replication of HBV and its interactions with host cells. We also discuss viral and non-viral factors that are associated with HBV-induced carcinogenesis and pathogenesis, as well as the role of host immune responses in HBV persistence and liver pathogenesis.
Collapse
Affiliation(s)
- Yu-Chen Chuang
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| | - Kuen-Nan Tsai
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| | - Jing-Hsiung James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| |
Collapse
|
|
39
|
Precision Medicine for Hepatocellular Carcinoma: Clinical Perspective. J Pers Med 2022; 12:jpm12020149. [PMID: 35207638 PMCID: PMC8879044 DOI: 10.3390/jpm12020149] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the major malignant diseases worldwide, characterized by growing incidence and high mortality rates despite apparent improvements in surveillance programs, diagnostic and treatment procedures, molecular therapies, and numerous research initiatives. Most HCCs occur in patients with liver cirrhosis, and the competing mortality risks from the tumor and the cirrhosis should be considered. Presently, previously identified risk factors, such as hepatitis virus infection, hepatic inflammation and fibrosis, and metabolic syndrome, may be used as chemoprevention targets. The application of precision medicine for HCC management challenges the one-size-fits-all concept; moreover, patients should no longer be treated entirely according to the histology of their tumor but based on molecular targets specific to their tumor biology. Next-generation sequencing emphasizes HCC molecular heterogeneity and aids our comprehension of possible vulnerabilities that can be exploited. Moreover, genetic sequencing as part of a precision medicine concept may work as a promising tool for postoperative cancer monitoring. The use of genetic and epigenetic markers to identify therapeutic vulnerability could change the diagnosis and treatment of HCC, which so far was based on Barcelona clinic liver cancer (BCLC) staging. In daily clinical practice, the shift from a stage-oriented to a therapeutic-oriented approach is needed to direct the choice of HCC treatment toward the potentially most effective option on an individual basis. The important factor in precision medicine is the promotion of patient management based on the individual approach, knowing that the final decision must be approved by a multidisciplinary expert team.
Collapse
|
|
40
|
Kar P, Goswami B, Mahanta J, Bhimo T, Das AK, Deka M, Lynrah KG, Kotwal MR, Bhaumik P, Jini M, Karna R, Karra VK, Kaur H. Epidemiology, Genotyping, Mutational and Phylogenetic Analysis of Hepatitis B Virus Infection in North-east India. J Clin Exp Hepatol 2022; 12:43-51. [PMID: 35068784 PMCID: PMC8766538 DOI: 10.1016/j.jceh.2021.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 04/01/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND/OBJECTIVE Hepatitis B virus (HBV) infection is a major public health problem globally. Northeast India is home to indigenous tribes with different ethnicity and high rates of drug abuse and HIV infection. The study was designed to estimate the burden of HBV infection across various spectrums of liver diseases from this region. HBV genotypes and subgenotypes play a role in the chronicity of disease, response to treatment and its progression. As very limited data are available from this region, we tried to elucidate the role of HBV genotypes, HBV mutants and their phylogenetic analysis. METHOD We designed a prospective multicentric study, and included 7464 liver disease cases, 7432 blood donors and 650 health care workers, who were screened for HBV infection. HBV DNA positive patients were genotyped and subjected to surface protein, precore and core mutation and phylogenetic analysis. RESULTS The prevalence of HBV infection with respect to different types of liver diseases, blood donors and health care workers was 9.9% (1550/15,546). 49.5% (768/1550) cases were found to be HBV DNA positive. The most common genotype was found to be genotype D 74.2% (570/768), followed by genotype C 6.5% (50/768), A 4.4% (34/768) and I 0.9% (7/768). CONCLUSION This study highlights the high hepatitis B burden in Northeast India, reflecting lacunae in health care needs of the region. Also, the different genotype distribution and presence of mutations may translate into different rates of liver disease progression, prognosis and ultimately, clinical significance. However, further prospective cohort study from Northeast India is warranted, to elucidate the clinical significance of multiple genotypes and mutation in this unique population.
Collapse
Key Words
- AFP, alpha fetoprotein
- ALT, alanine transaminase
- AVH, acute viral hepatitis
- BCP, basal core promoter mutations
- CAH: chronic active hepatitis, CHB: chronic hepatitis B
- CLD, chronic liver disease
- DNA, deoxyribose nucleic acid
- EASL, European Association for the study of the liver
- FHF, fulminant hepatic failure
- FNAC, fine needle aspiration cytology
- HBV
- HBV, hepatitis B virus
- HBcAg, icosahedral core
- HBsAg, surface proteins
- HCC, hepatocellular carcinoma
- PCR, polymerase chain reaction
- RT, reverse transcriptase
- SGOT, serum glutamic oxaloacetic transaminase
- SGPT, serum glutamic pyruvic transaminase
- SHB, small hepatitis B surface antigen
- ULN, upper limit of normal
- epidemiology
- evolution
- genotype
- mutation
Collapse
Affiliation(s)
- Premashis Kar
- Maulana Azad Medical College, University of Delhi, New Delhi, India,Address for correspondence. Premashis Kar, Director Professor of Medicine Maulana Azad Medical College, University of Delhi, New Delhi, India.
| | - Bhabadev Goswami
- Department of Gastroenterology, Gauhati Medical College, Guwahati, Assam, India
| | | | - Thngam Bhimo
- Department of Medicine, Regional Institute of Medical Sciences, Regional Medical College, Imphal, Manipur, India
| | - Anup K. Das
- Department of Medicine, Assam Medical College, Dibrugarh, Assam, India
| | - Manab Deka
- Department of Biotechnology, Gauhati University, Assam, India
| | | | | | - Pradip Bhaumik
- Department of Medicine, Agartala Govt. Medical College, Agartala, Tripura, India
| | - Moji Jini
- General Hospital, Naharlagun, Arunachal Pradesh, India
| | - Rahul Karna
- Maulana Azad Medical College, University of Delhi, New Delhi, India
| | - Vijay K. Karra
- Division of Epidemiology and Communicable Diseases, Indian Council of Medical Research, Department of Health Research, New Delhi, India
| | - Harpreet Kaur
- Division of Epidemiology and Communicable Diseases, Indian Council of Medical Research, Department of Health Research, New Delhi, India
| |
Collapse
|
|
41
|
More DNA and RNA of HBV SP1 splice variants are detected in genotypes B and C at low viral replication. Sci Rep 2021; 11:23838. [PMID: 34903774 PMCID: PMC8668879 DOI: 10.1038/s41598-021-03304-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 11/29/2021] [Indexed: 12/13/2022] Open
Abstract
HBV produces unspliced and spliced RNAs during replication. Encapsidated spliced RNA is converted into DNA generating defective virions that are detected in plasma and associated with HCC development. Herein we describe a quantitative real-time PCR detection of splice variant SP1 DNA/RNA in HBV plasma. Three PCR primers/probe sets were designed detecting the SP1 variants, unspliced core, or X gene. Plasmids carrying the three regions were constructed for the nine HBV genotypes to evaluate the three sets, which were also tested on DNA/RNA extracted from 193 HBV plasma with unknown HCC status. The assay had an LOD of 80 copies/ml and was equally efficient for detecting all nine genotypes and three targets. In testing 84 specimens for both SP1 DNA (77.4%) and RNA (82.1%), higher viral loads resulted in increased SP1 levels. Most samples yielded < 1% of SP1 DNA, while the average SP1 RNA was 3.29%. At viral load of ≤ 5 log copies/ml, the detectable SP1 DNA varied by genotype, with 70% for B, 33.3% for C, 10.5% for E, 4% for D and 0% for A, suggesting higher levels of splicing in B and C during low replication. At > 5 log, all samples regardless of genotype had detectable SP1 DNA.
Collapse
|
|
42
|
Tsuge M. The association between hepatocarcinogenesis and intracellular alterations due to hepatitis B virus infection. Liver Int 2021; 41:2836-2848. [PMID: 34559952 DOI: 10.1111/liv.15065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 09/13/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis B virus (HBV) infection is a worldwide health problem leading to severe liver dysfunction, including liver cirrhosis and hepatocellular carcinoma. Although current antiviral therapies for chronic HBV infection have been improved and can lead to a strong suppression of viral replication, it is difficult to completely eliminate the virus with these therapies once chronic HBV infection is established in the host. Furthermore, chronic HBV infection alters intracellular metabolism and signalling pathways, resulting in the activation of carcinogenesis in the liver. HBV produces four viral proteins: hepatitis B surface-, hepatitis B core-, hepatitis B x protein, and polymerase; each plays an important role in HBV replication and the intracellular signalling pathways associated with hepatocarcinogenesis. In vitro and in vivo experimental models for analyzing HBV infection and replication have been established, and gene expression analyses using microarrays or next-generation sequencing have also been developed. Thus, it is possible to clarify the molecular mechanisms for intracellular alterations, such as endoplasmic reticulum stress, oxidative stress, and epigenetic modifications. In this review, the impact of HBV viral proteins and intracellular alterations in HBV-associated hepatocarcinogenesis are discussed.
Collapse
Affiliation(s)
- Masataka Tsuge
- Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan.,Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| |
Collapse
|
|
43
|
Abstract
Hepatitis B was discovered by researchers who were investigating jaundice associated with blood transfusions as well as parenterally administered medications. Through trial and error, the HBV was identified. There are specific tests that detect HBV infection, whether it is a previous exposure or active infection. The various HBV serologies are reviewed in this work as well. Hepatitis B surface antigen has emerged as a tool in defining treatment endpoint and its significance is reviewed. HBV genotypes are distributed uniquely throughout the world, in particular, genotype C is associated with higher rates of hepatocellular carcinoma. Various HBV genotypes and their impact on the clinical course are discussed. The relationship of HBV serologies and HBV DNA to disease progression is outlined. There are specific recommendations on monitoring those infected with HBV and this is reviewed here. HBV mutations have an impact on the disease course and those of significance are also discussed.
Collapse
|
|
44
|
Tsuge M. Are Humanized Mouse Models Useful for Basic Research of Hepatocarcinogenesis through Chronic Hepatitis B Virus Infection? Viruses 2021; 13:v13101920. [PMID: 34696350 PMCID: PMC8541657 DOI: 10.3390/v13101920] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/14/2021] [Accepted: 09/20/2021] [Indexed: 12/19/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a global health problem that can lead to liver dysfunction, including liver cirrhosis and hepatocellular carcinoma (HCC). Current antiviral therapies can control viral replication in patients with chronic HBV infection; however, there is a risk of HCC development. HBV-related proteins may be produced in hepatocytes regardless of antiviral therapies and influence intracellular metabolism and signaling pathways, resulting in liver carcinogenesis. To understand the mechanisms of liver carcinogenesis, the effect of HBV infection in human hepatocytes should be analyzed. HBV infects human hepatocytes through transfer to the sodium taurocholate co-transporting polypeptide (NTCP). Although the NTCP is expressed on the hepatocyte surface in several animals, including mice, HBV infection is limited to human primates. Due to this species-specific liver tropism, suitable animal models for analyzing HBV replication and developing antivirals have been lacking since the discovery of the virus. Recently, a humanized mouse model carrying human hepatocytes in the liver was developed based on several immunodeficient mice; this is useful for analyzing the HBV life cycle, antiviral effects of existing/novel antivirals, and intracellular signaling pathways under HBV infection. Herein, the usefulness of human hepatocyte chimeric mouse models in the analysis of HBV-associated hepatocarcinogenesis is discussed.
Collapse
Affiliation(s)
- Masataka Tsuge
- Natural Science Center for Basic Research and Development, Department of Biomedical Science, Research and Development Division, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan; ; Tel.: +81-82-257-1510
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| |
Collapse
|
|
45
|
Liu Q, Tian Y, Li Y, Zhang W, Cai W, Liu Y, Ren Y, Liang Z, Zhou P, Zhang Y, Bao Y, Li Y. In vivo therapeutic effects of affinity-improved-TCR engineered T-cells on HBV-related hepatocellular carcinoma. J Immunother Cancer 2021; 8:jitc-2020-001748. [PMID: 33323464 PMCID: PMC7745518 DOI: 10.1136/jitc-2020-001748] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2020] [Indexed: 12/24/2022] Open
Abstract
Background In patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), virus-specific cytotoxic T lymphocytes (CTLs) fail to eliminate HCC cells expressing HBV antigens. As the expression of viral antigen in HBV-associated HCC may decrease to allow tumor to escape immune attacks, we hypothesized that an HBV surface antigen (HBsAg)-specific affinity-improved-T-cell receptor (TCR) will enable T cells to target HCC more effectively than corresponding wild-type-TCR. We also postulated that TCR promiscuity can be exploited to efficiently capture HBV variants that can hinder CTL-based therapeutics. Methods We applied flexi-panning to isolate affinity-improved TCRs binding to a variant antigen, the human leukocyte antigen (HLA)-A*02:01-restricted nonapeptide HBs371-379-ILSPFLPLL, from libraries constructed with a TCR cloned using the decapeptide HBs370-379-SIVSPFIPLL. The potency and safety of the affinity-improved-TCR engineered T-cells (Ai-TCR-T) were verified with potentially cross-reactive human and HBV-variant peptides, tumor and normal cells, and xenograft mouse models. Results Ai-TCR-T cells retained cognate HBV antigen specificity and recognized a wide range of HBV genotypic variants with improved sensitivity and cytotoxicity. Cell infusions produced complete elimination of HCC without recurrence in the xenograft mouse models. Elevated accumulation of CD8+ Ai-TCR-T cells in tumors correlated with tumor shrinkage. Conclusion The in vitro and in vivo studies demonstrated that HBsAg-specific Ai-TCR-T cells had safety profiles similar to those of their wild-type counterparts and significantly enhanced potency. This study presents an approach to develop new therapeutic strategies for HBV-related HCC.
Collapse
Affiliation(s)
- Qi Liu
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China.,University of the Chinese Academy of Sciences, Beijing, China
| | - Ye Tian
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Yanyan Li
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Wei Zhang
- Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Hefei, Anhui, China
| | - Wenxuan Cai
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Yaju Liu
- Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Hefei, Anhui, China
| | - Yuefei Ren
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China.,School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
| | - Zhaoduan Liang
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Peipei Zhou
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China.,Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui, China
| | - Yajing Zhang
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China.,University of the Chinese Academy of Sciences, Beijing, China
| | - Yifeng Bao
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Yi Li
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China .,University of the Chinese Academy of Sciences, Beijing, China
| |
Collapse
|
|
46
|
Shah AS, Civelli VF, Bali V, Johnson RH, Heidari A. A Case of S-Variant Hepatitis B Virus: An Immune System Escape Artist. J Investig Med High Impact Case Rep 2021; 9:23247096211045450. [PMID: 34521227 PMCID: PMC8447092 DOI: 10.1177/23247096211045450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Genomic variants of the hepatitis B virus (HBV) preS/S protein are well-known to
occur. Typically, immunity is gained through recovered HBV infection or by
immunization. Very rarely, there are certain mutations that may enable HBV
escape from the immune detection. PreS/S mutants may present with unpredictable
pathobiologic, clinical, and transmittable implications. Standard laboratory
testing for genomic HBV variants is not routinely performed by reference
guidelines. s-variant HBV management remains challenging. Herein is a case of
s-variant chronic HBV infection in a 55-year-old man. Diagnosis and treatment
are described.
Collapse
Affiliation(s)
- Amar S Shah
- UCLA at Kern Medical Center, Bakersfield, CA, USA
| | | | - Varun Bali
- UCLA at Kern Medical Center, Bakersfield, CA, USA
| | | | | |
Collapse
|
|
47
|
Qama A, Allard N, Cowie B, Davis JS, Davies J. Hepatitis B in the Northern Territory: insights into the changing epidemiology of an ancient condition. Intern Med J 2021; 51:910-922. [PMID: 32975893 PMCID: PMC8362129 DOI: 10.1111/imj.15069] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 09/04/2020] [Accepted: 09/10/2020] [Indexed: 01/04/2023]
Abstract
Background Aboriginal and Torres Strait Islander people are disproportionately affected by hepatitis B virus (HBV) infection. A proposed mismatch between standard vaccines and the HBV/C4 sub‐genotype prevalent in Aboriginal people in the Northern Territory (NT) may reduce vaccine effectiveness. Aims To determine HBV prevalence in the NT by Indigenous status and to explore patterns of immunity following implementation of universal vaccination, using a large longitudinal diagnostic dataset. Methods A retrospective analysis of all available HBV serology results in the NT from 1991 to 2011 was conducted, with HBV prevalence and vaccination status analysed according to adigenous status, age and sex using individuals' patterns of HBsAg, anti‐HBs and anti‐HBc serology over repeated tests. Results 100 790 individuals were tested (33.4% Indigenous) between 1991 and 2011 (26.1% of the 2011 NT population), with a total of 211 802 tests performed. In 2011, the proportion of HBV positive individuals in the NT was 3.17% (5.22% in Indigenous populations) compared to previous 2011 estimates of 1.70% (3.70% in Indigenous populations). The vaccine failure rate was lower than expected with only one presumed vaccinated person subsequently developing HBsAg positivity (0.02%). Evidence of suboptimal vaccine efficacy by breakthrough anti‐HBc positivity in vaccinated individuals was demonstrated in 3.1% of the vaccinated cohort, of which 86.4% identified as Indigenous (HR 1.17). No difference in HBeAg positivity or seroconversion was observed between Indigenous and non‐Indigenous individuals living with CHB. Conclusions The burden of CHB in Indigenous people in the NT has previously been underestimated. A higher HBV prevalence in the NT than described in previous cross‐sectional studies was found, including a higher prevalence in Indigenous people. Evidence of suboptimal vaccine efficacy was demonstrated predominantly in Indigenous individuals.
Collapse
Affiliation(s)
- Ashleigh Qama
- WHO Collaborating Centre for Viral Hepatitis, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.,Department of Medicine (RMH), University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Nicole Allard
- WHO Collaborating Centre for Viral Hepatitis, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.,Department of Medicine (RMH), University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia.,cohealth, Parkville, Victoria, Australia
| | - Benjamin Cowie
- WHO Collaborating Centre for Viral Hepatitis, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.,Department of Medicine (RMH), University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia.,Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Joshua S Davis
- Global and Tropical Health Division, Menzies School of Health Research, Darwin, Northern Territory, Australia.,Division of Medicine, John Hunter Hospital, Newcastle, New South Wales, Australia
| | - Jane Davies
- Global and Tropical Health Division, Menzies School of Health Research, Darwin, Northern Territory, Australia.,The Infectious Diseases Department, Royal Darwin Hospital, Darwin, Northern Territory, Australia
| |
Collapse
|
|
48
|
Abstract
Antiviral therapy has greatly improved the survival and reduced the incidence of adverse liver events such as hepatic decompensation and hepatocellular carcinoma in chronic hepatitis B patients with cirrhosis (hepatitis B virus [HBV]-cirrhosis). However, hepatitis B surface antigen loss, regarded as the ultimate goal of therapy or functional cure, was rarely achieved during long-term indefinite nucleos(t)ide analogues (Nuc) treatment. Emerging issues such as medication adherence and loss-to-follow-up may lead to increased risk of hepatic decompensation, even catastrophic life-threatening events. Studies have shown that finite therapy is feasible and reasonably safe, even in patients with HBV-cirrhosis. This review critically assesses the scientific evidence of the pros and cons for finite Nuc therapy in HBV-cirrhosis and proposes how to stop Nuc therapy and monitor the off-therapy patients. It also proposes the perspective and unsolved issues to be investigated in the future.
Collapse
Affiliation(s)
- Wen-Juei Jeng
- Liver Research Unit, Linkou Medical Center, Chang Gung University, Chang Gung Memorial Hospital, College of Medicine, Taoyuan, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Linkou Medical Center, Chang Gung University, Chang Gung Memorial Hospital, College of Medicine, Taoyuan, Taiwan
| |
Collapse
|
|
49
|
Lu H, Yi W, Sun F, Zeng Z, Zhang L, Li M, Xie Y. Comprehensive investigation of HBV-related hepatocellular carcinoma and choice of anti-HBV therapy. BIOSAFETY AND HEALTH 2021. [DOI: 10.1016/j.bsheal.2021.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
|
|
50
|
Entecavir vs Tenofovir in Hepatocellular Carcinoma Prevention in Chronic Hepatitis B Infection: A Systematic Review and Meta-Analysis. Clin Transl Gastroenterol 2021; 11:e00236. [PMID: 33031195 PMCID: PMC7544163 DOI: 10.14309/ctg.0000000000000236] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are recommended as first-line therapies for chronic hepatitis B (CHB) infection. Although both drugs reduce hepatocellular carcinoma (HCC) risk, their comparative effectiveness remains controversial. We aimed to determine whether TDF is superior to ETV in preventing HCC.
Collapse
|