|
1
|
Gavilán P, Gavilán JC, Clavijo E, Viciana I, Gonzalez-Correa JA. A prediction model for complications caused by portal hypertension or liver cancer in a Spanish cohort of chronic hepatitis B patients. Rev Clin Esp 2025; 225:184-192. [PMID: 39923933 DOI: 10.1016/j.rceng.2024.11.009] [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: 04/27/2024] [Accepted: 11/16/2024] [Indexed: 02/11/2025]
Abstract
BACKGROUND AIMS To identify risk factors associated with liver complications in patients with chronic hepatitis B infection in an unselected cohort of hepatitis B patients in southern Spain. METHODS A prospective open-cohort study was conducted on 437 patients with uncomplicated chronic hepatitis B infection in two hospitals in Málaga, southern Spain. The follow-up time ranged from 0.5 to 31.5 years (mean: 13.8±9.5 years; median: 11.4 years). The aim of this study was to evaluate the occurrence of the initial liver complication during follow-up, which is defined as the emergence of liver cancer or complications resulting from portal hypertension. Survival curves were obtained using a time-to-event method through Kaplan-Meier analysis. Multivariate Cox regression was conducted to estimate the hazard ratios of risk factors associated with complications after adjusting for multiple variables. The follow-up of the patients was carried out under conditions of usual clinical practice. Based on the weighted adjustment of these factors, we developed a Hepatitis B Complication Score (HBCS) from which it was possible to identify patients with low and high risk of complications during follow-up. RESULTS 33 out of 437 patients (7.55%) experienced liver complications, 12 (36.3%) were secondary to portal hypertension, and 21 patients (63.7%) developed liver cancer. A Multivariate Cox regression identified the following independent risk factor: Age above 45 years: HR 7.10 (2.9-17.3); low platelet count: HR 4.88 (2.1-10.9); hepatitis C coinfection: HR 4.68 (2.0-10.9); Male gender: HR 4.64 (1.5-14.2); alkaline phosphatase above 147 UI/mL: HR 4.33 (2.0-8.9); and Child score above 5 points: HR 3.83 (1.7-8.4). The Risk of Complications Score (HBCS) was developed with a high predictive capacity AUROC 0.92 (0.87-0.97). CONCLUSION An HBCS score greater than 3.07 points identifies patients at high risk of developing complications and with an increased risk of liver and all-cause mortality.
Collapse
Affiliation(s)
- P Gavilán
- Universidad de Málaga, IBIMA-Plataforma BIONAND, Departamento de Farmacología y Pediatría, Facultad de Medicina, Campus de Teatinos s/n, 29071 Málaga, Spain
| | - J-C Gavilán
- Departamento de Medicina Interna, Hospital Internacional Vithas Xanit, Benalmádena, Málaga, Spain; Servicio de Medicina Interna, Hospital Universitario Virgen de la Victoria, Campus de Teatinos s/n, 29010 Málaga, Spain.
| | - E Clavijo
- Universidad de Málaga, IBIMA-Plataforma BIONAND, Departamento de Microbiología, Facultad de Medicina, Campus de Teatinos s/n, 29071 Málaga, Spain
| | - I Viciana
- Departamento de Microbiología, Hospital Universitario Virgen de la Victoria, Málaga, Spain
| | - J-A Gonzalez-Correa
- Universidad de Málaga, IBIMA-Plataforma BIONAND, Departamento de Farmacología y Pediatría, Facultad de Medicina, Campus de Teatinos s/n, 29071 Málaga, Spain
| |
Collapse
|
|
2
|
Mak L, Yee LJ, Wong RJ, Ramers CB, Frenette C, Hsu Y. Hepatocellular carcinoma among patients with chronic hepatitis B in the indeterminate phase. J Viral Hepat 2024; 31 Suppl 2:27-35. [PMID: 38717914 PMCID: PMC11619554 DOI: 10.1111/jvh.13914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 12/15/2023] [Indexed: 12/06/2024]
Abstract
Hepatitis B virus (HBV) infection is a dynamic disease where patients progress through several stages defined by HBV e-antigen (HBeAg) status, HBV-DNA levels and transaminase elevations, with antiviral therapy indicated only in specific stages. However, some patients cannot be classified into one of the stages and are said to fall into an 'indeterminate phase' or 'grey zone'. Exact definitions of the indeterminate phase vary from guideline to guideline as a result of different cut-off values for biomarker measurements. Data suggest that as many as 50% of HBV patients may be in an indeterminate phase and may not rapidly transition out of this phase. Clinical data that suggest these patients are at increased risk of hepatocellular carcinoma (HCC) are complemented by molecular evidence of integrations of HBV-DNA into the host genome, chromosomal translocations and immune activation despite liver enzymes that may suggest lack of inflammation. Antiviral therapy reduces these hepatocarcinogenic mechanisms and is reflected in a reduction of fibrosis and HCC risk. We review key data on patients in the indeterminate phase, with emphasis on HCC as an outcome. We take a holistic approach and link new biological data with clinical observations as well as examine the potential role of antiviral therapy in reducing HCC risk among patients in the indeterminate phase. With the availability of safe and effective oral antivirals, consideration must be given as to how much residual risk of HCC should be tolerated among patients in the indeterminate phase.
Collapse
Affiliation(s)
- Lung‐Yi Mak
- Department of Medicine, Queen Mary HospitalThe University of Hong KongHong KongSpecial Administrative RegionChina
| | | | - Robert J. Wong
- Division of Gastroenterology and HepatologyStanford University School of MedicinePalo AltoCaliforniaUSA
- Division of Gastroenterology and HepatologyVeterans Affairs Palo Alto Health Care SystemPalo AltoCaliforniaUSA
| | - Christian B. Ramers
- Laura Rodriguez Research InstituteFamily Health Centers of San DiegoSan DiegoCaliforniaUSA
- University of CaliforniaSan Diego School of MedicineLa JollaCaliforniaUSA
| | | | - Yao‐Chun Hsu
- Division of Gastroenterology and HepatologyE‐Da HospitalKaohsiungTaiwan
- School of Medicine, College of MedicineI‐Shou UniversityKaohsiungTaiwan
- Institute of Biomedical InformaticsNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
- Division of Gastroenterology and HepatologyFu‐Jen Catholic University HospitalNew TaipeiTaiwan
| |
Collapse
|
|
3
|
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
|
|
4
|
Hou H, Liang L, Deng L, Ye W, Wen Y, Liu J. Comparison of Clinical Manifestations and Related Factors of Hepatocellular Carcinoma with Chronic Hepatitis B. Int J Gen Med 2024; 17:2877-2886. [PMID: 38947567 PMCID: PMC11214568 DOI: 10.2147/ijgm.s464083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 06/18/2024] [Indexed: 07/02/2024] Open
Abstract
Background The aim of this study was to describe the demographic and clinical characteristics of hepatitis B virus (HBV) associated hepatocellular carcinoma (HCC), analyse the risk factors associated with HBV-associated HCC, and to provide some references to the diagnosis and treatment of HCC. Methods This study retrospectively enrolled 730 patients, including 390 patients with chronic hepatitis B (CHB) as controls, and 340 patients with CHB complicated with HCC as patients. Relevant information and medical records of these participants were collected, including age, sex, cigarette smoking, alcoholism, diabetes mellitus (DM), hypertension, coronary heart disease (CHD), cirrhosis, occupation, ascites, HBV-DNA load, the qualitative analysis of HBsAg, HBsAb, HBeAg, HBeAb, and HBcAb serological markers, and levels of alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), gamma-glutamyltransferase (GGT), TNM stage, tumor size and tumor number. The T test, Chi-square test, non-parametric rank-sum test, logistic regression analyses were used to explore the influencing factors and their degree of association with HCC in patients with HBV. Results The proportion of smoking, alcoholism, married status, DM, hypertension, and the rate of HBV-DNA with a viral load of ≥500 copies/mL were significantly higher in the HCC group than in the controls (all p<0.05). Cirrhosis was more common among patients with CHB+HCC than in controls (p=0.013). The proportion of patients with HBsAg, HBeAb, and HBcAb positive was greater in CHB+HCC group than that in CHB group. Logistic regression analysis indicated that age ≥60 years (OR: 1.835, 95% CI: 1.020-3.302, p=0.043), HBeAb positive (OR: 9.105, 95% CI: 4.796-17.288, p<0.001), antiviral treatment with entecavir (OR: 2.209, 95% CI: 1.106-4.409, p=0.025), and GGT (OR: 1.004, 95% CI: 1.001-1.007, p=0.002) were risk factors for HCC in patients with CHB. Conclusion Advanced age, HBeAb positive, antiviral treatment with entecavir, and GGT were independent risk factors for HCC in HBV patients.
Collapse
Affiliation(s)
- Haisong Hou
- Laboratory of Pathogenic Biology, Guangdong Medical University, Zhanjiang, People’s Republic of China
- Department of Blood Transfusion, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China
| | - Liu Liang
- Department of Laboratory Medicine, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China
| | - Lihong Deng
- Department of Hepatology, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China
| | - Wanping Ye
- Department of Gastroenterology, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China
| | - Yuanzhang Wen
- Department of Hepatobiliary Surgery, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China
| | - Jun Liu
- Laboratory of Pathogenic Biology, Guangdong Medical University, Zhanjiang, People’s Republic of China
| |
Collapse
|
|
5
|
Sukowati CHC, Jayanti S, Turyadi T, Muljono DH, Tiribelli C. Hepatitis B virus genotypes in precision medicine of hepatitis B-related hepatocellular carcinoma: Where we are now. World J Gastrointest Oncol 2024; 16:1097-1103. [PMID: 38660644 PMCID: PMC11037070 DOI: 10.4251/wjgo.v16.i4.1097] [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: 01/04/2024] [Revised: 01/30/2024] [Accepted: 03/06/2024] [Indexed: 04/10/2024] Open
Abstract
Hepatitis B virus (HBV) infection is a major player in chronic hepatitis B that may lead to the development of hepatocellular carcinoma (HCC). HBV genetics are diverse where it is classified into at least 9 genotypes (A to I) and 1 putative genotype (J), each with specific geographical distribution and possible different clinical outcomes in the patient. This diversity may be associated with the precision medicine for HBV-related HCC and the success of therapeutical approaches against HCC, related to different pathogenicity of the virus and host response. This Editorial discusses recent updates on whether the classification of HBV genetic diversity is still valid in terms of viral oncogenicity to the HCC and its precision medicine, in addition to the recent advances in cellular and molecular biology technologies.
Collapse
Affiliation(s)
- Caecilia H C Sukowati
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia, Jakarta 10340, Indonesia
- Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
| | - Sri Jayanti
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia, Jakarta 10340, Indonesia
| | - Turyadi Turyadi
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia, Jakarta 10340, Indonesia
| | - David H Muljono
- Faculty of Medicine, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
- Faculty of Medicine and Health, University of Sydney, Sydney 2050, Australia
| | - Claudio Tiribelli
- Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
| |
Collapse
|
|
6
|
Campbell C, Wang T, Gillespie I, Barnes E, Matthews PC. Analysis of primary care electronic health record data of people living with hepatitis B virus: infection and hepatocellular carcinoma risk associated with socio-economic deprivation. Public Health 2024; 226:215-227. [PMID: 38091810 PMCID: PMC7615551 DOI: 10.1016/j.puhe.2023.10.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 08/28/2023] [Accepted: 10/18/2023] [Indexed: 01/15/2024]
Abstract
OBJECTIVES We set out to characterise chronic hepatitis B (CHB) in the primary care population in England and investigate risk factors for progression to hepatocellular carcinoma (HCC). STUDY DESIGN Retrospective cohort study. METHODS We identified 8039 individuals with CHB in individuals aged ≥18 years between 1999 and 2019 in the English primary care database QResearch. HCC risk factors were investigated using Cox proportional hazards modelling. RESULTS Most of those with a record of CHB were males (60%) of non-White ethnicity (>70%), and a high proportion were in the most deprived Townsend deprivation quintile (44%). Among 7029 individuals with longitudinal data, 161 HCC cases occurred. Increased HCC hazards were significantly associated with male sex (adjusted hazards ratio [aHR] 3.17, 95% confidence interval [95% CI] 1.92-5.23), in the fifth deprivation quintile as compared to the third quintile (aHR 1.69, 95% CI 1.01-2.84), with older age (for age groups 56-65 and ≥66 years, compared to 26-35 years, aHRs 2.82 [95% CI 1.45-5.46] and 3.76 [95% CI 1.79-7.9], respectively), Caribbean ethnicity (aHR 3.32, 95% CI 1.43-7.71, compared to White ethnicity), ascites (aHR 3.15, 95% CI 1.30-7.67), cirrhosis (aHR 6.55, 95% CI 4.57-9.38) and peptic ulcer disease (aHR 2.26, 95% CI 1.45-3.51). CONCLUSIONS Targeting interventions and HCC surveillance at vulnerable groups is essential to improve CHB outcomes and to support progress towards international goals for the elimination of hepatitis infection as a public health threat.
Collapse
Affiliation(s)
- C Campbell
- Nuffield Department of Medicine, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK
| | - T Wang
- Nuffield Department of Medicine, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK
| | | | - E Barnes
- NIHR Oxford Biomedical Research Centre, Oxford, UK; Department of Hepatology, Oxford University Hospitals, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
| | - P C Matthews
- NIHR Oxford Biomedical Research Centre, Oxford, UK; The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Division of Infection and Immunity, University College London, Gower Street, London WC1E 6BT, UK; Department of Infectious Diseases, University College London Hospital, Euston Road, London NW1 2BU, UK.
| |
Collapse
|
|
7
|
Keeshan A, da Silva CF, Vachon A, Giles E, Osiowy C, Coffin C, Cooper CL. Hepatitis B Virus Genotype Influence on Virological and Enzymatic Measures over Time-A Retrospective Longitudinal Cohort Study. J Clin Med 2023; 12:6807. [PMID: 37959272 PMCID: PMC10649073 DOI: 10.3390/jcm12216807] [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: 09/14/2023] [Revised: 10/12/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
HBV is a hepatotropic virus with multiple genotypes. It is uncertain if specific genotype(s) influence virological measures and/or liver markers over time. It is unclear whether nucleos(t)ide analogue therapy response is influenced by genotype. In this retrospective longitudinal study, we utilized data from The Ottawa Hospital Viral Hepatitis Program (TOHVHP) to evaluate the role of HBV genotype on viral load, liver enzymatic levels, fibrosis progression, and parenchymal inflammation and steatosis over time. HBV DNA, ALT, and AST levels, as well as transient elastography scores for fibrosis (E) and inflammation/steatosis (CAP), were modeled using mixed-effects linear regression. Interaction terms between HBV genotype and time were included to investigate if there was a difference in trends between genotypes. A total of 393 HBV patients infected with genotypes A-E were included. The mean age was 44.4 years, and 56% were male. Asian (50.5%), Black (29.1%), and White (6.4%) patients were well-represented. By multivariate analysis, we found no evidence that the trajectories of these commonly measured viral or liver measures varied over time by HBV genotype in those receiving HBV nucleos(t)ides and in those not on antiviral therapy.
Collapse
Affiliation(s)
- Alexa Keeshan
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | | | - Alicia Vachon
- Faculty of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
- Division of Infectious Diseases, Department of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Elizabeth Giles
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R2C 3A9, Canada
| | - Carla Osiowy
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R2C 3A9, Canada
| | - Carla Coffin
- Department of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Curtis L. Cooper
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON K1N 6N5, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
- Division of Infectious Diseases, Department of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| |
Collapse
|
|
8
|
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
|
|
9
|
Kafeero HM, Ndagire D, Ocama P, Kato CD, Wampande E, Walusansa A, Kajumbula H, Kateete D, Ssenku JE, Sendagire H. Mapping hepatitis B virus genotypes on the African continent from 1997 to 2021: a systematic review with meta-analysis. Sci Rep 2023; 13:5723. [PMID: 37029173 PMCID: PMC10082212 DOI: 10.1038/s41598-023-32865-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 04/04/2023] [Indexed: 04/09/2023] Open
Abstract
Hepatitis B virus (HBV) has ten genotypes (A-J) and over 40 sub-genotypes based on the divergence of ≥ 8% and 4 to < 8% in the complete genome respectively. These genotypes and sub-genotypes influence the disease prognosis, response to therapy and route of viral transmission. Besides, infection with mixed genotypes and recombinant genotypes has also been reported. This study aimed at mapping the de novo genotypes and correlate them with the immigration trends in order to inform future research on the underlying reasons for the relative distribution of HBV genotypes from a large sample size pooled from many primary studies. Data was extracted from 59 full research articles obtained from Scopus, PubMed, EMBASE, Willy library, African Journal Online (AJOL) and Google Scholar. Studies that investigated the genotypes, sub-genotypes, mixed genotypes and recombinant were included. The Z-test and regression were used for the analysis. The study protocol is registered with PROSPERO under the registration number CRD42022300220. Overall, genotype E had the highest pooled prevalence significantly higher than all the other genotypes (P < 0.001). By region, genotype A posted the highest pooled prevalence in eastern and southern Africa, E in west Africa and D in north Africa (P < 0.0001). Regarding the emerging genotypes B and C on the African continent, genotype B was significantly higher in south Africa than C (P < 0.001). In contrast, genotype C was significantly higher in east Africa than west Africa (P < 0.0001). The A1 and D/E were the most diverse sub-genotypes and genotype mixtures respectively. Finally, we observed a general progressive decrease in the prevalence of predominant genotypes but a progressive increase in the less dominant by region. Historical and recent continental and intercontinental migrations can provide a plausible explanation for the HBV genotype distribution pattern on the African continent.
Collapse
Affiliation(s)
- Hussein Mukasa Kafeero
- Department of Medical Microbiology, College of Health Sciences, Makerere University, P. O Box 7062, Kampala, Uganda.
- Department of Medical Microbiology, Habib Medical School, Faculty of Health Sciences, Islamic University in Uganda, P. O Box 7689, Kampala, Uganda.
| | - Dorothy Ndagire
- Department of Plant Sciences, Microbiology and Biotechnology, College of Natural Sciences, Makerere University, P. O Box 7062, Kampala, Uganda
| | - Ponsiano Ocama
- Department of Medicine, College of Health Sciences, Makerere University, P. O Box 7062, Kampala, Uganda
| | - Charles Drago Kato
- Department of Biomolecular Resources and Biolab Sciences, College of Veterinary Medicine, Animal Resources and Biosecurity, Makerere University, P. O Box 7062, Kampala, Uganda
| | - Eddie Wampande
- Department of Biomolecular Resources and Biolab Sciences, College of Veterinary Medicine, Animal Resources and Biosecurity, Makerere University, P. O Box 7062, Kampala, Uganda
| | - Abdul Walusansa
- Department of Medical Microbiology, Habib Medical School, Faculty of Health Sciences, Islamic University in Uganda, P. O Box 7689, Kampala, Uganda
| | - Henry Kajumbula
- Department of Medical Microbiology, College of Health Sciences, Makerere University, P. O Box 7062, Kampala, Uganda
| | - David Kateete
- Department of Molecular Biology and Immunology, College of Health Sciences, Makerere University, P. O Box 7062, Kampala, Uganda
| | - Jamilu E Ssenku
- Department of Plant Sciences, Microbiology and Biotechnology, College of Natural Sciences, Makerere University, P. O Box 7062, Kampala, Uganda
| | - Hakim Sendagire
- Department of Medical Microbiology, College of Health Sciences, Makerere University, P. O Box 7062, Kampala, Uganda
- Department of Medical Microbiology, Habib Medical School, Faculty of Health Sciences, Islamic University in Uganda, P. O Box 7689, Kampala, Uganda
| |
Collapse
|
|
10
|
Hu M, Liao G, Wei S, Qian Z, Chen H, Xia M, Xie Q, Peng J. Effective Analysis of Antiviral Treatment in Patients with HBeAg-Seropositive Chronic Hepatitis B with ALT < 2 Upper Limits of Normal: A Multi-center Retrospective Cohort Study. Infect Dis Ther 2023; 12:637-647. [PMID: 36633817 PMCID: PMC9925662 DOI: 10.1007/s40121-022-00757-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Accepted: 12/22/2022] [Indexed: 01/13/2023] Open
Abstract
INTRODUCTION Although the indications for antiviral therapy for patients with chronic hepatitis B have been gradually expanded in different guidelines, antiviral treatment efficacy remains unclear among HBeAg-seropositive patients with alanine aminotransferase (ALT) < 2 upper limits of normal (ULN). This study aimed to evaluate the efficacy of antiviral therapy for these patients. METHODS In total, 102 treatment-naive patients who were HBeAg seropositive with ALT < 2 ULN and had received nucleotide analogs were included, and their clinical data were retrospectively analyzed. RESULTS After 96-week treatment, 84.3% (n = 86), 26.5% (n = 27) and 20.6% (n = 21) patients achieved virological response, HBeAg seroclearance and HBeAg seroconversion, respectively. Logistic regression analysis revealed that baseline AST (odds ratio [OR] = 1.069, 95% confidence interval [CI] 1.014-1.127, p = 0.014), serum HBV DNA (OR = 0.540, 95% CI 0.309-0.946, p = 0.031) and quantitative HBsAg levels (OR = 0.147, 95% CI 0.036-0.597, p = 0.007) were independent factors for virological response. At baseline, HBsAg < 4.63 log10 IU/ml was identified as a strong predictor for the 96-week virological response, with a concordance rate of 0.902. Moreover, the levels of liver stiffness values (8.30 ± 3.86 vs. 6.17 ± 1.91, p < 0.001) at week 96 had significantly declined compared to baseline. CONCLUSION Nucleotide analog treatment effectively suppressed HBV DNA in patients with HBeAg-seropositive chronic hepatitis B with ALT < 2 × ULN and greatly improved liver fibrosis. The study also found that HBsAg < 4.63 log10 IU/ml was a strong predictor of the virological response.
Collapse
Affiliation(s)
- Meixin Hu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Guichan Liao
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Sufang Wei
- Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Foshan, China
| | - Zhe Qian
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hongjie Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Muye Xia
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qiuli Xie
- Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Foshan, China
| | - Jie Peng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| |
Collapse
|
|
11
|
Dieterich D, Graham C, Wang S, Kwo P, Lim YS, Liu CJ, Agarwal K, Sulkowski M. It Is Time for a Simplified Approach to Hepatitis B Elimination. GASTRO HEP ADVANCES 2022; 2:209-218. [PMID: 39132618 PMCID: PMC11307636 DOI: 10.1016/j.gastha.2022.10.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 10/04/2022] [Indexed: 08/13/2024]
Abstract
Background and Aims Hepatitis B virus (HBV) infection continues to threaten millions of lives across the globe, despite universal vaccination efforts. Current guidelines for screening, vaccination, and treatment are complex and have left too many people undiagnosed or improperly managed. Antiviral therapy has been shown to significantly reduce the incidence of liver-related complications, including liver cancer. However, the complexity of existing guidelines can make it difficult to identify which patients to target for treatment, and recommendations that are difficult to implement in real-world settings pose a barrier to eligible patients to receive therapy and contribute to health disparities in HBV care. The goal of this global expert panel was to gain consensus on a streamlined approach to HBV care to facilitate implementation of HBV intervention and treatment, especially in the primary care setting. Methods A group of 8 liver and infectious disease specialists attended a meeting in January 2021 with the objective of gaining consensus on a streamlined algorithm for HBV care that would encourage implementation of HBV intervention and treatment. Results We have created a comprehensive perspective highlighting screening optimization, diagnostic workup, treatment, and monitoring. This treatment algorithm is designed to provide a streamlined visual pathway for risk stratification and management of patients with HBV that can be adapted in various care settings. Conclusion Simplification of guidelines will be critical to achieving health equity to address this public health threat and achieve HBV elimination.
Collapse
Affiliation(s)
- Douglas Dieterich
- Division of Liver Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Camilla Graham
- Division of Infectious Disease, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Su Wang
- Center for Asian Health, Saint Barnabas Medical Center, RWJ Barnabas Health, Florham Park, New Jersey
| | - Paul Kwo
- Department of Gastroenterology and Hepatology, Stanford Medical Center, Pleasanton, California
| | - Young-Suk Lim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chun-Jen Liu
- Department of Internal Medicine and Hepatitis Research Center at the National Taiwan University Hospital, Taipei, Taiwan
| | - Kosh Agarwal
- Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, London, England
| | - Mark Sulkowski
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| |
Collapse
|
|
12
|
Stefanini B, Tonnini M, Serio I, Renzulli M, Tovoli F. Surveillance for hepatocellular carcinoma: current status and future perspectives for improvement. Expert Rev Anticancer Ther 2022; 22:371-381. [PMID: 35263211 DOI: 10.1080/14737140.2022.2052276] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is a globally relevant medical problem. Fortunately, risk factors for this tumor have been identified, and surveillance protocols developed. Patients with liver cirrhosis have the highest risk of developing HCC and have historically been included in surveillance programs. Special categories have also emerged in recent years, especially patients with eradicated HCV infection or nonalcoholic fatty liver disease. Novel serum biomarkers and magnetic resonance imaging protocols are currently being proposed to refine existing surveillance protocols. AREAS COVERED We discuss the rationale of surveillance programs for HCC and report the most recent recommendations from international guidelines about this topic. Gray areas, such as nonalcoholic fatty liver disease and the role of intrahepatic cholangiocellular carcinoma, are also discussed. EXPERT OPINION Surveillance is recognized as a tool to favor early diagnosis of HCC, access to curative treatment, and increase survival, even if the supporting evidence is mainly based on observational studies. As new randomized clinical trials are difficult to propose, future challenges will include optimizing implementation in the primary care setting and a more personalized approach, balancing the opportunities and risks of overdiagnosis of novel techniques and biomarkers.
Collapse
Affiliation(s)
- Bernardo Stefanini
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Matteo Tonnini
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Ilaria Serio
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Matteo Renzulli
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| |
Collapse
|
|
13
|
Costa APDM, da Silva MACN, Castro RS, Sampaio ALDO, Alencar Júnior AM, da Silva MC, Ferreira ADSP. PAGE-B and REACH-B Predicts the Risk of Developing Hepatocellular Carcinoma in Chronic Hepatitis B Patients from Northeast, Brazil. Viruses 2022; 14:v14040732. [PMID: 35458462 PMCID: PMC9033073 DOI: 10.3390/v14040732] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/25/2022] [Accepted: 03/29/2022] [Indexed: 12/14/2022] Open
Abstract
This study aims to evaluate the accuracy of the PAGE-B and REACH-B scores in predicting the risk of developing HCC in patients with chronic hepatitis B regularly followed up at a reference service in the State of Maranhão. A historical, longitudinal, retrospective cohort study, carried out from the review of medical records of patients with chronic Hepatitis B. PAGE-B and REACH-B scores were calculated and the accuracy of the scores in predicting the risk of HCC in the studied population was evaluated. A total of 978 patients were included, with a median age of around 47 years, most of them female and not cirrhotic. HCC was identified in 34 patients. Thrombocytopenia, high viral load, male gender and age were associated with the occurrence of HCC. The ROC curve for the PAGE-B score showed a value of 0.78 and for the REACH-B score of 0.79. The cutoff point for PAGE-B was 11 points for greater sensitivity and for REACH-B 7.5 points considering greater sensitivity and 9.5 points considering greater specificity. PAGE-B and REACH-B scores were able to predict the risk of developing HCC in the studied population. The use of risk stratification scores is useful to reduce costs associated with HCC screening.
Collapse
Affiliation(s)
- Alessandra Porto de Macedo Costa
- Center for Liver Studies, University Hospital of the Federal University of Maranhão, Saint Louis CEP 65020-070, MA, Brazil; (A.P.d.M.C.); (R.S.C.); (A.L.d.O.S.); (A.M.A.J.)
| | | | - Rogério Soares Castro
- Center for Liver Studies, University Hospital of the Federal University of Maranhão, Saint Louis CEP 65020-070, MA, Brazil; (A.P.d.M.C.); (R.S.C.); (A.L.d.O.S.); (A.M.A.J.)
| | - Ana Leatrice de Oliveira Sampaio
- Center for Liver Studies, University Hospital of the Federal University of Maranhão, Saint Louis CEP 65020-070, MA, Brazil; (A.P.d.M.C.); (R.S.C.); (A.L.d.O.S.); (A.M.A.J.)
| | - Antônio Machado Alencar Júnior
- Center for Liver Studies, University Hospital of the Federal University of Maranhão, Saint Louis CEP 65020-070, MA, Brazil; (A.P.d.M.C.); (R.S.C.); (A.L.d.O.S.); (A.M.A.J.)
| | - Márcia Costa da Silva
- Epidemiological Surveillance Service, State Health Department, Saint Louis CEP 65076-820, MA, Brazil;
| | - Adalgisa de Souza Paiva Ferreira
- Center for Liver Studies, University Hospital of the Federal University of Maranhão, Saint Louis CEP 65020-070, MA, Brazil; (A.P.d.M.C.); (R.S.C.); (A.L.d.O.S.); (A.M.A.J.)
- Correspondence: (M.A.C.N.d.S.); (A.d.S.P.F.)
| |
Collapse
|
|
14
|
Liu Z, Zhang Y, Xu M, Li X, Zhang Z. Distribution of hepatitis B virus genotypes and subgenotypes: A meta-analysis. Medicine (Baltimore) 2021; 100:e27941. [PMID: 34918643 PMCID: PMC8678021 DOI: 10.1097/md.0000000000027941] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 11/04/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) genotypes and subgenotypes have distinct geographical distributions and influence a number of clinical disease features and responses to treatment. There are many reports on the distribution of HBV genotypes, but great differences are present between studies. What's more, a meta-analysis of HBV genotype- and subgenotype-distribution by country is lacking.A comprehensive literature search was performed in PubMed and a systematic search of full-length HBV sequences and S gene sequences was conducted in the GenBank database. HBV genotypes were checked and subgenotypes were determined by phylogenetic comparison of full-length HBV sequences or S gene sequences. STATA 12.0 was used for the analysis for countries with multiple datasets. BEAST 2.5.2 was used for Bayesian phylogenetic analysis to infer the evolutionary time scales of HBV.This study includes 309 datasets from 110 countries, including 188 relevant studies, 58 full-length gene datasets, and 63 S gene datasets. The meta-analysis was performed on 274 datasets from 75 countries. The distribution of genotypes is more detailed than those described by previous studies. While the overall genotype distribution is similar to that reported in previous studies, some notable aspects were different. The main genotypes present in south-eastern Africa, North Africa, and West Africa are genotypes A, D, and E, respectively. Genotypes G and H are mainly distributed in Mexico. Genotype F is mainly distributed in central and South America, but genotypes A and D are also common in Brazil, Cuba, and Haiti.This study provides a more accurate description of the distribution of HBV genotypes and subgenotypes in different countries and suggests that the differences in genotype distribution may be related to ethnicity and human migration.
Collapse
|
|
15
|
Abstract
Hepatitis B virus (HBV) is the one of most common causes of the hepatocellular carcinoma (HCC), especially in eastern world. The aim of this review is to try to understand the relationship between HBV and HCC and to reveal the role of prevention and treatment of HBV infection in reducing the incidence of HCC. Strategies to prevent HCC due to HBV can be classified into three categories. These are primary, secondary, and tertiary preventions. Hepatitis B vaccine is now in the most vital position in preventing HBV-associated HCC. In patients with chronic hepatitis B infection, suppressing viral load with potent antivirals such as tenofovir disoproxil fumarate (TDF) and entecavir (ETV) prevents the development of HCC and improves prognosis by reducing recurrence after HCC treatments. There is currently no clear consensus on which of these drugs should be preferred. Although data on tenofovir alafenamide (TAF) are scarce, available data with TDF suggest that TAF therapy will also be a strong actor for HCC.
Collapse
|
|
16
|
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
|
|
17
|
Co-circulation of different genotype, sub-genotype and serotypes of hepatitis B virus (HBV) and its epidemiology in Assam: A north-eastern state of India. Indian J Med Microbiol 2021; 39:352-357. [PMID: 34045082 DOI: 10.1016/j.ijmmb.2021.04.012] [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: 12/12/2020] [Revised: 03/16/2021] [Accepted: 04/30/2021] [Indexed: 11/23/2022]
Abstract
PURPOSE Hepatitis B virus (HBV) infection is a global health problem. HBV has different genotypes and subgenotypes with geographical distinctiveness. AIMS To study the molecular epidemiology and distribution pattern of HBV in Assam; a distinct state of India that may have different genotypic divergence. SETTINGS AND DESIGN Patients attending a tertiary care hospital susceptive of Hepatitis B were included, irrespective of age and sex in different agro-climatic zones of Assam. METHODS Samples positive for Hepatitis B surface antigen test and COBAS®TaqMan® HBV tests were further confirmed by PCR and sequencing followed by phylogenetic analysis. STATISTICAL ANALYSIS USED Chi-square test was used to determine whether there was a significant difference among the results in this study. RESULTS An increase trend of HBV positive cases has been observed in the state. The incidence in female was lower than that of male and age group 26-35 years was most vulnerable. Genotype D, subgenotype D2 and serotype ayw3 were predominant genotype, subgenotype and serotype. The prevalence of subgenotype C3 was a new finding. Phylogenetic analysis showed that the genotypes of HBV prevailing in the state have close relationship with neighboring countries of India which may be due to increased cross border migration of population CONCLUSIONS: This comprehensive study of HBV in Assam described the distribution of HBV genotypes and subgenotypes and serotypes in different agro-climatic zones of Assam. These findings will help to formulate the roadmap for prevention and control of the disease as well as targeted therapy of HBV in this State.
Collapse
|
|
18
|
Huang D, Shen Y, Zhang W, Guo C, Liang T, Bai X. A preoperative nomogram predicts prognosis of patients with hepatocellular carcinoma after liver transplantation: a multicenter retrospective study. BMC Cancer 2021; 21:280. [PMID: 33726700 PMCID: PMC7962298 DOI: 10.1186/s12885-021-07938-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 02/19/2021] [Indexed: 12/25/2022] Open
Abstract
Background Although criteria for liver transplantation, such as the Milan criteria and Hangzhou experiences, have become popular, criteria to guide adjuvant therapy for patients with hepatocellular carcinoma after liver transplantation are lacking. Methods We collected data from all consecutive patients from 2012 to 2019 at three liver transplantation centers in China retrospectively. Univariate and multivariate analyses were used to analyze preoperative parameters, such as demographic and clinical data. Using data obtained in our center, calibration curves and the concordance Harrell’s C-indices were used to establish the final model. The validation cohort comprised the patients from the other centers. Results Data from 233 patients were used to construct the nomogram. The validation cohort comprised 36 patients. Independent predictors of overall survival (OS) were identified as HbeAg positive (P = 0.044), blood-type compatibility unmatched (P = 0.034), liver transplantation criteria (P = 0.003), and high MELD score (P = 0.037). For the validation cohort, to predict OS, the C-index of the nomogram was 0.874. Based on the model, patients could be assigned into low-risk (≥ 50%), intermediate-risk (30–50%), and high-risk (≤ 30%) groups to guide adjuvant therapy after surgery and to facilitate personalized management. Conclusions The OS in patients with hepatocellular carcinoma after liver transplantation could be accurately predicted using the developed nomogram.
Collapse
Affiliation(s)
- Dabing Huang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China.,Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Hangzhou, 310003, Zhejiang, China
| | - Yinan Shen
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China.,Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Hangzhou, 310003, Zhejiang, China
| | - Wei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Chengxiang Guo
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China.,Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Hangzhou, 310003, Zhejiang, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China. .,Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China. .,Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Hangzhou, 310003, Zhejiang, China.
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China. .,Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China. .,Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Hangzhou, 310003, Zhejiang, China.
| |
Collapse
|
|
19
|
Campbell C, Wang T, McNaughton AL, Barnes E, Matthews PC. Risk factors for the development of hepatocellular carcinoma (HCC) in chronic hepatitis B virus (HBV) infection: a systematic review and meta-analysis. J Viral Hepat 2021; 28:493-507. [PMID: 33305479 PMCID: PMC8581992 DOI: 10.1111/jvh.13452] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/19/2020] [Accepted: 11/23/2020] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading contributors to cancer mortality worldwide and is a leading cause of death in individuals with chronic hepatitis B virus (HBV) infection. It is uncertain how the presence of other metabolic factors and comorbidities influences HCC risk in HBV. Therefore, we performed a systematic literature review and meta-analysis to seek evidence for significant associations. MEDLINE, EMBASE and Web of Science databases were searched from 1 January 2000 to 24 June 2020 for studies investigating associations of metabolic factors and comorbidities with HCC risk in individuals with chronic HBV infection, written in English. We extracted data for meta-analysis and generated pooled effect estimates from a fixed-effects model. Pooled estimates from a random-effects model were also generated if significant heterogeneity was present. We identified 40 observational studies reporting on associations of diabetes mellitus (DM), hypertension, dyslipidaemia and obesity with HCC risk. Only DM had a sufficient number of studies for meta-analysis. DM was associated with >25% increase in hazards of HCC (fixed-effects hazards ratio [HR] 1.26, 95% confidence interval (CI) 1.20-1.32, random-effects HR 1.36, 95% CI 1.23-1.49). This association was attenuated towards the null in a sensitivity analysis restricted to studies adjusted for metformin use. In conclusion, in adults with chronic HBV infection, DM is a significant risk factor for HCC, but further investigation of the influence of antidiabetic drug use and glycaemic control on this association is needed. Enhanced screening of individuals with HBV and diabetes may be warranted.
Collapse
Affiliation(s)
- Cori Campbell
- Nuffield Department of MedicineUniversity of OxfordOxfordUK
| | - Tingyan Wang
- Nuffield Department of MedicineUniversity of OxfordOxfordUK
| | | | - Eleanor Barnes
- Nuffield Department of MedicineUniversity of OxfordOxfordUK,Department of HepatologyOxford University NHS Foundation TrustJohn Radcliffe HospitalOxfordUK
| | - Philippa C. Matthews
- Nuffield Department of MedicineUniversity of OxfordOxfordUK,Department of Infectious Diseases and MicrobiologyOxford University Hospitals NHS Foundation TrustJohn Radcliffe HospitalOxfordUK,NIHR BRCJohn Radcliffe HospitalOxfordUK
| |
Collapse
|
|
20
|
Hanif H, Khan MM, Ali MJ, Shah PA, Satiya J, Lau DT, Aslam A. A New Endemic of Concomitant Nonalcoholic Fatty Liver Disease and Chronic Hepatitis B. Microorganisms 2020; 8:microorganisms8101526. [PMID: 33020450 PMCID: PMC7601829 DOI: 10.3390/microorganisms8101526] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 09/28/2020] [Accepted: 09/30/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) infection remains a global public problem despite the availability of an effective vaccine. In the past decades, nonalcoholic fatty liver disease (NAFLD) has surpassed HBV as the most common cause of chronic liver disease worldwide. The prevalence of concomitant chronic hepatitis B (CHB) and NAFLD thus reaches endemic proportions in geographic regions where both conditions are common. Patients with CHB and NAFLD are at increased risk of liver disease progression to cirrhosis and hepatocellular carcinoma. Due to the complexity of the pathogenesis, accurate diagnosis of NAFLD in CHB patients can be challenging. Liver biopsy is considered the gold standard for diagnosing and determining disease severity, but it is an invasive procedure with potential complications. There is a growing body of literature on the application of novel noninvasive serum biomarkers and advanced radiological modalities to diagnose and evaluate NAFLD, but most have not been adequately validated, especially for patients with CHB. Currently, there is no approved therapy for NAFLD, although many new agents are in different phases of development. This review provides a summary of the epidemiology, clinical features, diagnosis, and management of the NAFLD and highlights the unmet needs in the areas of CHB and NAFLD coexistence.
Collapse
Affiliation(s)
- Hira Hanif
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Muzammil M. Khan
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Mukarram J. Ali
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Pir A. Shah
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
- Department of Internal Medicine, University of Texas, San Antonio, TX 78229, USA
| | - Jinendra Satiya
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Daryl T.Y. Lau
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
- Correspondence: (D.T.Y.L.); (A.A.)
| | - Aysha Aslam
- Department of Medicine, Louis A Weiss Memorial Hospital, Chicago, IL 60640, USA
- Correspondence: (D.T.Y.L.); (A.A.)
| |
Collapse
|
|
21
|
Li W, Deng R, Liu S, Wang K, Sun J. Hepatitis B virus-related hepatocellular carcinoma in the era of antiviral therapy: The emerging role of non-viral risk factors. Liver Int 2020; 40:2316-2325. [PMID: 32666675 DOI: 10.1111/liv.14607] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 06/17/2020] [Accepted: 07/09/2020] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC), one of the major malignant lethal tumours, is most prevalent in Asian patients with chronic hepatitis B virus (HBV) infection. Both viral and non-viral factors contribute to the development of HCC. It is established that viral factors associated with HBV DNA level, HBV genotype, designated gene mutation, HBV DNA integration, HBx protein, hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) and HBV RNA are correlated with hepatocarcinogenesis. Before the introduction of antiviral therapy, viral factors once attracted more attention during the development of HCC. With the widespread use of antiviral therapy, predominantly nucleos(t)ide analogues (NAs), most patients with chronic hepatitis B (CHB) have achieved sustained viral control. The role of non-viral factors, especially modifiable factors, is anticipated to be reinforced in the future. Herein, we reviewed the modifiable non-viral risk factors of HBV-related HCC, in the hope of providing substantial evidence for further development of novel precautionary measures for HCC. In addition, the therapeutic interventions for reducing the risk of HCC, like potential conventional pharmaceutical interventions and lifestyle modification are also discussed in this review. Future studies that would explore the specific mechanism of HBV-related HCC development in patients with satisfactory viral control and related precision treatment are warranted.
Collapse
Affiliation(s)
- Wanying Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Rui Deng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shi Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Kaifeng Wang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
22
|
Xia Z, He L, Xiong L, Wen T. The comparison of different antiviral therapies on the prognosis of hepatitis B virus-related hepatocellular carcinoma after curative treatments: A network meta-analysis. Medicine (Baltimore) 2020; 99:e20877. [PMID: 32871973 PMCID: PMC7437757 DOI: 10.1097/md.0000000000020877] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE The purpose of this study was to evaluate the efficacy of different nucleos(t)ide analogues in the prognosis of HBV-related hepatocellular carcinoma (HCC) patients after curative treatment by network meta-analysis. METHODS Literature retrieval was conducted in globally recognized databases, namely, PubMed, EMBASE, Cochrane Library databases, and Science Citation Index Expanded, to address relative studies investigating nucleot(s)ide analogues for HBV-related HCC patients after curative resection. Relative parametric data, including 1-, 3-, and 5-year overall survival rate and 1-, 3-, and 5-year recurrence-free survival rate were quantitatively pooled and estimated. The inconsistency factor, the cumulative ranking curve, and the publication bias were evaluated. RESULTS Fourteen observational studies of 2481 adults performed between 2000 and 2019 were eligible. In terms of overall survival, ADV (Adefovir dipivoxil) (Odds ratio (OR): 2.35, 95% confidence interval (CI): 1.17-4.73), Lamivudine (OR: 2.08, 95% CI: 1.78-5.58), and Entecavir (OR: 2.14, 95% CI: 1.59-2.88) were found to be more beneficial than control group while ADV has the highest probability of having the most efficacious treatment (SCURA values 66.3) for 5-year overall survival. In late recurrence-free survival, ADV (OR = 1.88, 95% CI: 1.77-4.60), Entecavir (OR = 1.96, 95% CI: 1.36-2.55), and Lamivudine (OR = 1.73, 95% CI: 1.06-2.82) all had better significant prognosis than patients without antiviral therapy postoperatively and patients with ADV as postoperative antiviral therapy has significantly recurrence-free survival benefit at 5-year follow-up compared to those undertaking Entecavir (OR = 1.96, 95% CI: 1.52-7.38) and Lamivudine (OR = 1.39, 95% CI: 1.09-3.01). Moreover, the application of ADV possessed the highest possibility of having the best clinical effects on 1- (surface under the cumulative ranking probabilities (SUCRA), 64.7), 3- (SUCRA, 64.7), and 5-year (SUCRA, 70.4) recurrence survival rate for HBV-related HCC patients. CONCLUSIONS Patients with postoperative nucleos(t)ide analogues antiviral therapy had better survival benefit than those without antiviral therapy for HBV-related HCC patients after curative treatment. Additionally, nucleotide analogues like ADV and Tenofovir disoproxil fumarate has better impact on early and late recurrence-free survival of patients after curative treatment than those undertaking nucleoside analogues.
Collapse
Affiliation(s)
- Zijing Xia
- Department of Rheumatology and Immunology
| | - Linye He
- Department of Thyroid & Parathyroid Surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, Sichuan Province
| | - Li Xiong
- Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016
| | - Tianfu Wen
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, Sichuan Province, PR China
| |
Collapse
|
|
23
|
Evolution of etiology, presentation, management and prognostic tool in hepatocellular carcinoma. Sci Rep 2020; 10:3925. [PMID: 32127619 PMCID: PMC7054529 DOI: 10.1038/s41598-020-61028-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 02/06/2020] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, but its current status is unclear. We aimed to investigate the evolution of etiology, presentation, management and prognostic tool in HCC over the past 12 years. A total of 3349 newly diagnosed HCC patients were enrolled and retrospectively analyzed. The comparison of survival was performed by the Kaplan-Meier method with the log-rank test. Hepatitis B and C virus infection in HCC were continuously declining over the three time periods (2004–2007, 2008–2011, 2012–2015; p < 0.001). At diagnosis, single tumor detection rate increased to 73% (p < 0.001), whereas vascular invasion gradually decreased to 20% in 2012–2015 (p < 0.001). Early stage HCC gradually increased from 2004–2007 to 2012–2015 (p < 0.001). The probability of patients receiving curative treatment and long-term survival increased from 2004–2007 to 2012–2015 (p < 0.001). The Cancer of Liver Italian Program (CLIP) and Taipei Integrated Scoring (TIS) system were two more accurate staging systems among all. In conclusion, the clinical presentations of HCC have significantly changed over the past 12 years. Hepatitis B and C virus-associated HCC became less common, and more patients were diagnosed at early cancer stage. Patient survival increased due to early cancer detection that results in increased probability to undergo curative therapies.
Collapse
|
|
24
|
Sagnelli E, Macera M, Russo A, Coppola N, Sagnelli C. Epidemiological and etiological variations in hepatocellular carcinoma. Infection 2020; 48:7-17. [PMID: 31347138 DOI: 10.1007/s15010-019-01345-y] [Citation(s) in RCA: 138] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 07/16/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer and a leading cause of cancer-related deaths worldwide. The major risk factors for HCC development are chronic liver disease and cirrhosis due to hepatitis B virus (HBV) and/or hepatitis C virus (HCV), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, intake of aflatoxin-contaminated food, diabetes, and obesity. RESULTS In Western countries, the number of NASH-related HCC cases is increasing, that of HBV- or HCV-related cases is declining due to the wide application of HBV universal vaccination and the introduction of effective therapies against HBV and HCV infections, and that of alcohol-related cases remaining substantially unchanged. Nevertheless, the burden of HCC is expected to increase worldwide in the next few decades, due to the population growth and aging expected in coming years. Overall, the abovementioned changes and future variations in lifestyle and in the impact of environmental factors in Western countries and a decreasing exposure to dietary aflatoxins and improved socio-economic conditions in developing countries will create new HCC epidemiology in the next few decades. CONCLUSION A substantial further reduction in cases of HCC requires a wider application of universal HBV vaccination and effective treatment of HBV- and HCV-related chronic hepatitis and cirrhosis, more effective campaigns to favor correct dietary habits and reduce alcohol consumption and the intensification of studies on HCC pathogenesis for future optimized prevention strategies.
Collapse
Affiliation(s)
- Evangelista Sagnelli
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via L. Armanni 5, 80131, Naples, Italy.
| | - Margherita Macera
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via L. Armanni 5, 80131, Naples, Italy
| | - Antonio Russo
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via L. Armanni 5, 80131, Naples, Italy
| | - Nicola Coppola
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via L. Armanni 5, 80131, Naples, Italy
| | - Caterina Sagnelli
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via L. Armanni 5, 80131, Naples, Italy
| |
Collapse
|
|
25
|
Qin JM. Postoperative recurrent factors and therapeutic and preventive strategies for hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2019; 27:1407-1418. [DOI: 10.11569/wcjd.v27.i23.1407] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China. The recurrence rate is about 50% at 3 years and over 70% at 5 years after hepatectomy for HCC. The high recurrence rate seriously affects the curative effect and long-term survival of patients with HCC, and is the primary cause of death after operation. Postoperative recurrence of HCC is a complex multi-step, multi-factorial process involving three factors: the body, microenvironment, and tumor tissue, which include body immunity, local pH value, interstitial pressure, vascular osmotic pressure, inflammatory reaction, tumor cell adhesion, extracellular matrix degradation, cell migration, cell proliferation, and tumor angiogenesis. HCC recurrence is closely related to abnormal gene expression and related molecular function changes, but the molecular mechanism has not been fully elucidated. How to treat the recurrence of HCC after operation directly affects the prognosis of patients with HCC, and treatments include reoperation, liver transplantation, local minimally invasive treatment, radiotherapy, molecular targeted drugs, immunotherapy, and traditional Chinese medicine treatment. It is difficult to cure or control tumor progression by a single therapy. Two or more therapeutic methods need to be combined organically to achieve a synergistic therapeutic effect. According to the specific situation of patients with HCC, it is key to analyze the individual characteristics of patients, to combine the clinical experience of clinicians and the best evidence, to adopt the individualized treatment plan, and to choose the appropriate treatment methods. For HCC patients with high-risk factors for recurrence, selecting the appropriate treatment is important to reduce the recurrence of HCC after operation and prolong the survival of patients.
Collapse
Affiliation(s)
- Jian-Min Qin
- Department of General Surgery, the Third Hospital Affiliated to Naval Military Medical University, Shanghai 201805, China
| |
Collapse
|
|
26
|
Xiong F, Bao X, Gu N, Guo J, Wang J, Ma Y, Yu L, Gao Y, Tan B, Lu J. The combination therapy of Peginterferonα and entecavir for HBeAg-positive chronic hepatitis B with high HCC risk. INFECTION GENETICS AND EVOLUTION 2019; 78:104101. [PMID: 31689542 DOI: 10.1016/j.meegid.2019.104101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 10/27/2019] [Accepted: 10/30/2019] [Indexed: 02/06/2023]
Abstract
The population of HBV infection with family history of hepatocellular carcinoma (HCC) is the high risk group for the development of HCC. The aim of this study was to evaluate the effect of the de novo combination therapy including pegylated-interferon α-2a (PEG-IFNα-2a) and entecavir (ETV) in this high risk population. The study recruited 58 Hepatitis B e Antigen (HBeAg)-Positive CHB patients patients with HBV-DNA > 107 IU/mL, genotype B or C and HCC family history and were treated for 48 weeks. Patients without HBeAg loss at the 48th week were 40 patients and extended the combination therapy to 96 weeks. All patients were followed up to 120 weeks. The rate of HBeAg loss and HBsAg loss was 12/40(30.0%) and 2/40(5.0%) at week 120 respectively. When logistic regression analysis was used to identify viables of HBeAg loss, HBV-DNA levels <20 IU/mL at week 48 was found to have a 6.02 fold increased probability (95% CI = 1.17-30.40, P = .03) of HBeAg loss. Patients with HBV-DNA levels <20 IU/mL at week 48 had a high probability of HBeAg loss 8/17(47.1%), HBsAg loss 2/17(11.8%), compared to 4/23(17.4%), 0/23(0%) in patients with HBV-DNA ≥ 20 IU/mL. Combination therapy for 96 weeks was well tolerated. During the combination therapy, low-level viremia during treatment is reversely associated with response. The combination therapy of PEG-IFNα and ETV was suggested to extend to 96 weeks when HBV-DNA was completed suppressed at week 48.
Collapse
Affiliation(s)
- Fang Xiong
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Xuli Bao
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Na Gu
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Jia Guo
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Jinhuan Wang
- International Medical Department, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Yanpin Ma
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Lele Yu
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Yao Gao
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Bingqin Tan
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Jun Lu
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
| |
Collapse
|
|
27
|
Zhao Z, Qin Z, Zhou L, Xiang L, You J, Cao R, Wang H, Wang B, Li M. The impact of IFNL3 genotype on interferon treatment outcome in patients chronically infected with hepatitis B virus: A meta-analysis. Microb Pathog 2019; 134:103598. [PMID: 31201901 DOI: 10.1016/j.micpath.2019.103598] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 06/11/2019] [Accepted: 06/11/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Polymorphisms near the interferon lambda 3 (IFNL3, also known as IL28B) have been proposed to be associated with interferon (IFN)-induced hepatitis C virus (HCV) clearance, but the impact of IFNL3 variations on the result of IFN-based therapy in chronic hepatitis B (CHB) infection is still poor understood. METHODS The purpose of this study was to evaluate the relationship between the IFNL3 polymorphisms and the effectiveness of IFN therapy in patients infected with CHB by means of meta-analysis. PubMed and Embase were utilized to identify relevant studies. Odds ratio (OR) and 95% confidence interval (CI) were analysed together to assess the strength of the association. Subgroup analysis was mainly performed according to HBeAg. RESULTS Twelve studies of 1645 CHB patients met the inclusion criteria and were selected in our meta-analysis. One polymorphism, rs12979860, near to the IFNL3 gene had significant association with the response of CHB patients to IFN-based therapy (OR = 2.35, 95% CI: 1.61-3.42 in allelic model). Another polymorphism, rs8099917, had a similar result (OR = 1.57, 95% CI: 1.03-2.40 in dominant model; and OR = 1.88, 95% CI: 1.21-2.90 in allelic model). When stratified by HBeAg, the antiviral outcome was markedly influenced by both two SNPs in HBeAg positive group (for rs12979860, OR = 1.90, 95% CI: 1.31-2.76 and OR = 2.07, 95% CI: 1.26-3.41 in dominant and allelic models respectively; for rs8099917, OR = 1.67, 95% CI: 1.04-2.67 in dominant model and OR = 1.77, 95% CI: 1.10-2.85 in allelic model). CONCLUSION We concluded that two polymorphisms (rs12979860 and rs8099917) of IFNL3 may play a crucial role in the IFN-based treatment of CHB, especially in HBeAg positive group.
Collapse
Affiliation(s)
- Zhongyi Zhao
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China.
| | - Zhen Qin
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China
| | - Linlin Zhou
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China
| | - Li Xiang
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China
| | - Jiangzhou You
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China
| | - Ranran Cao
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China
| | - Hongren Wang
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China
| | - Baoning Wang
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China.
| | - Mingyuan Li
- Department of Microbiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China; State Key Laboratory of Oral Diseases (Sichuan University), Chengdu, Sichuan, 610041, China.
| |
Collapse
|
|
28
|
Liu X, Baecker A, Wu M, Zhou JY, Yang J, Han RQ, Wang PH, Jin ZY, Liu AM, Gu X, Zhang XF, Wang XS, Su M, Hu X, Sun Z, Li G, Fu A, Jung SY, Mu L, He N, Li L, Zhao JK, Zhang ZF. Family history of liver cancer may modify the association between HBV infection and liver cancer in a Chinese population. Liver Int 2019; 39:1490-1503. [PMID: 31228882 PMCID: PMC6705127 DOI: 10.1111/liv.14182] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 06/07/2019] [Accepted: 06/08/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS The potential interaction between family history of liver cancer and HBV infection on liver cancer has not been fully examined. METHODS We conducted a population-based case-control study composed of 2011 liver cancer cases and 7933 controls in Jiangsu province, China from 2003 to 2010. Data on major risk or protective factors were collected and HBV/HCV sero-markers were assayed using blood samples. Semi-Bayes (SB) adjustments were applied to provide posterior estimates. RESULTS Both family history of liver cancer (adjusted odds ratios [OR]: 4.32, 95% confidence intervals [CI]: 3.25-5.73) and hepatitis B surface antigen (HBsAg) positivity (adjusted OR: 9.94, 95% CI: 8.33-11.87) were strongly associated with liver cancer development. For individuals with different combinations of serological markers, the adjusted ORs were 8.45 (95% CI: 5.16-13.82) for HBsAg- and HBcAb-positive; 7.57 (95% CI: 4.87-11.77) for HBsAg-, HBeAg- and HBcAb-positive; and 3.62 (95% CI: 2.47-5.31) for HBsAg-, HBeAb- and HBcAb-positive, compared to all negatives in HBV serological markers. One log increase in HBV DNA level was associated with 17% increased risk (adjusted OR: 1.17, 95% CI: 1.03-1.32). The SB-adjusted OR of HBV-positive individuals with family history of liver cancer was 41.34 (95% posterior interval [PI]: 23.69-72.12) compared with those HBV-negative without family history. Relative excess risk due to additive interaction, the attributable proportion and synergy index were 73.13, 0.87 and 8.04 respectively. Adjusted ratio of OR for multiplicative interaction was 2.84 (95% CI: 1.41-5.75). CONCLUSIONS Super-additive and super-multiplicative interactions may exist between family history of liver cancer and HBV infection on the development of liver cancer.
Collapse
Affiliation(s)
- Xing Liu
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Aileen Baecker
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California
| | - Ming Wu
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Jin-Yi Zhou
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Jie Yang
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Ren-Qiang Han
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Pei-Hua Wang
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Zi-Yi Jin
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Ai-Min Liu
- Dafeng Center for Disease Control and Prevention, Dafeng, Jiangsu, China
| | - Xiaoping Gu
- Dafeng Center for Disease Control and Prevention, Dafeng, Jiangsu, China
| | - Xiao-Feng Zhang
- Ganyu Center for Disease Control and Prevention, Ganyu, Jiangsu, China
| | - Xu-Shan Wang
- Ganyu Center for Disease Control and Prevention, Ganyu, Jiangsu, China
| | - Ming Su
- Chuzhou County Center for Disease Control and Prevention, Chuzhou, Jiangsu, China
| | - Xu Hu
- Chuzhou County Center for Disease Control and Prevention, Chuzhou, Jiangsu, China
| | - Zheng Sun
- Tongshan County Center for Disease control and Prevention, Tongshan, Jiangsu, China
| | - Gang Li
- Tongshan County Center for Disease control and Prevention, Tongshan, Jiangsu, China
| | - Alan Fu
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California
| | - Su Yon Jung
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California
- School of Nursing, UCLA, Los Angeles, California
| | - Lina Mu
- Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, The State University of New York, Buffalo, New York
| | - Na He
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Liming Li
- Department of Epidemiology, School of Public Health, Peking University, Beijing, China
| | - Jin-Kou Zhao
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, China
| | - Zuo-Feng Zhang
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California
- Center for Human Nutrition, David Geffen School of Medicine, UCLA, Los Angeles, California
| |
Collapse
|
|
29
|
Haga H, Saito T, Okumoto K, Tomita K, Katsumi T, Mizuno K, Nishina T, Watanabe H, Ueno Y. Incidence of development of hepatocellular carcinoma in Japanese patients infected with hepatitis B virus is equivalent between genotype B and C in long term. J Viral Hepat 2019; 26:866-872. [PMID: 30924226 DOI: 10.1111/jvh.13099] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 02/01/2019] [Accepted: 02/21/2019] [Indexed: 12/19/2022]
Abstract
Hepatitis B virus (HBV) genotypes B (HBV/B) and C (HBV/C) are the most prevalent genotypes among Japanese patients with hepatitis. Reportedly, HBV/C infection has been associated with more severe disease progression, manifesting as developing cirrhosis and hepatocellular carcinoma (HCC), than HBV/B infection. However, no long-term studies have examined the development of HCC in HBV/B-infected patients in Japan. The aims of our study were to compare the incidence of HCC in HBV/B- or HBV/C-infected patients. A total of 241 patients were followed up among 295 hepatitis B surface antigen (HBsAg)-positive carriers. Genotypes of HBV were A in 1% (4/295), B in 61% (179/295), C in 37% (110/295) and D in 1% (2/295) patients, and 96% of HBV/B were infected with subgenotype Bj. The mean age at HCC diagnosis was significantly higher in HBV/B than in HBV/C (67.0 ± 10.0 vs 57.7 ± 8.0 years, P < 0.001). The value of FIB-4 index was significantly higher in HBV/B than in HBV/C (P < 0.01). The rate of HCC was higher in HBV/C than in HBV/B, and a significant difference was observed until the 20-year observation period (P = 0.048). However, thereafter, HCC associated with HBV/B increased, and no significant difference was observed between HBV/B and HBV/C. HCC development was consistently observed even in HBV/B infection, especially among elderly patients with advanced fibrosis compared with HBV/C. HBV/B-infected patients developed HCC later in life, and in the long term, we found no differences in incidence of HCC development rates between these two genotypes.
Collapse
Affiliation(s)
- Hiroaki Haga
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Takafumi Saito
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan.,School of Nursing, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Kazuo Okumoto
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Kyoko Tomita
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Tomohiro Katsumi
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Kei Mizuno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Taketo Nishina
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Hisayoshi Watanabe
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| |
Collapse
|
|
30
|
Jia J, Li Y, Wei C, Guo R, Xu H, Jia Y, Wu Y, Li Y, Wei Z, Qi X, Li Z, Gao X. Factors associated with disease progression and viral replication in patients with chronic hepatitis B virus infection. Exp Ther Med 2019; 17:4730-4740. [PMID: 31086607 DOI: 10.3892/etm.2019.7482] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 03/07/2019] [Indexed: 12/26/2022] Open
Abstract
Hepatitis B virus (HBV) infection remains a severe clinical concern in China. Of note, the progression of HBV infection varies between different populations. To identify the factors that influence the disease progression and prognosis, a total of 478 chronic HBV-infected patients were enrolled, and liver function parameters, HBV DNA levels and hepatic fibrosis indices were analyzed. First, the results demonstrated a significant difference in hepatitis B e antigen (HBeAg) expression between male and female patients (χ2=4.061, P=0.044). Furthermore, when comparing either HBeAg-negative or -positive male and female patients, males exhibited a greater variation in HBV DNA levels. Although significant differences between male and female patients in certain abnormal ratios of liver function parameters were identified, a trend in the differences was observed in the HBeAg-negative and -positive groups. When considering age, the results of the present study confirmed that HBV DNA levels decreased with advanced age, and the values of the majority of biomarkers exhibited an evident decreasing trend with increasing age. In addition, it was demonstrated that all HBeAg seropositive patients had higher levels of hepatic fibrosis indexes and higher abnormal ratios of hepatic fibrosis values in their serum when compared with those of HBeAg seronegative patients, particularly with regard to serum IV collagen. The present results revealed that HBV DNA replication was closely associated with liver function; however, it was notable that in HBeAg-negative patients, the association between HBV DNA levels and liver function was particularly significant among subjects aged <61. Furthermore, this result was not observed in HBeAg-positive patients. In conclusion, the present study indicated the importance of host factors (including sex and age) and viral factors (including HBeAg expression pattern and HBV DNA levels) in the progression of chronic HBV infection, and its influence regarding prognosis and treatment. The present results provide a foundation for clinical management strategies for chronic HBV infection, particularly in individual schemes.
Collapse
Affiliation(s)
- Jing Jia
- Institute of Clinical Research and Translational Medicine, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Yonghong Li
- Institute of Clinical Research and Translational Medicine, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Chaojun Wei
- Institute of Clinical Research and Translational Medicine, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Rui Guo
- Institute of Clinical Research and Translational Medicine, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Hui Xu
- Institute of Clinical Research and Translational Medicine, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Yanjuan Jia
- Institute of Clinical Research and Translational Medicine, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Yu Wu
- Institute of Clinical Research and Translational Medicine, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Yuanting Li
- Institute of Clinical Research and Translational Medicine, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Zhenhong Wei
- Department of Blood Transfusion, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Xiaoming Qi
- Institute of Clinical Research and Translational Medicine, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Zhenhao Li
- Institute of Clinical Research and Translational Medicine, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Xiaoling Gao
- Institute of Clinical Research and Translational Medicine, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| |
Collapse
|
|
31
|
He L, Xia Z, Shen J, Zhang X, Peng W, Li C, Wen T. The different effects of adefovir dipivoxil and telbivudine on the prognosis of hepatitis b virus-related hepatocellular carcinoma patients after curative resection. Medicine (Baltimore) 2019; 98:e14386. [PMID: 30732177 PMCID: PMC6380752 DOI: 10.1097/md.0000000000014386] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Numerous studies suggested that antiviral therapy could reduce the recurrence in hepatocellular carcinoma (HCC) patients after hepatectomy. The impact of nucleotide and nucleoside analogues on prognosis of chronic hepatitis B (CHB) related HCC remains to be explored. We aimed to investigate the role of the telbivudine and adefovir dipivoxil on the prognosis of CHB-related HCC patients after hepatectomy.One hundred eighty-eight CHB-related patients who received hepatectomy from February 2010 to February 2017 were divided into telbivudine (LdT) and adefovir dipivoxil (ADV) groups. The characteristics and survival information of both groups were retrospectively compared and analyzed.One hundred eleven and 77 patients received telbivudine and adefovir dipivoxil monotherapy, respectively. Alanine aminotransferase (ALT), total bilirubin level, status of hepatitis B e antigen (HBeAg), serum HBV-DNA level were compared between groups. OS and DFS in ADV-treatment group were significantly better than it in LdT-treatment group (P < .05). In the subgroups analysis, we found that ADV treatment was significantly associated with better DFS and OS among patients with cirrhosis, HBeAg-negative patients, or those with detectable HBV-DNA.CHB-related HCC patients receiving long-term ADV-treatment had a better OS and DFS than patients receiving LdT-treatment after hepatectomy.
Collapse
Affiliation(s)
- Linye He
- Department of Liver Surgery & Liver Transplantation Center
| | - Zijing Xia
- Division of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Junyi Shen
- Department of Liver Surgery & Liver Transplantation Center
| | - Xiaoyun Zhang
- Department of Liver Surgery & Liver Transplantation Center
| | - Wei Peng
- Department of Liver Surgery & Liver Transplantation Center
| | - Chuan Li
- Department of Liver Surgery & Liver Transplantation Center
| | - Tianfu Wen
- Department of Liver Surgery & Liver Transplantation Center
| |
Collapse
|
|
32
|
Kim JH, Kim YD, Lee M, Jun BG, Kim TS, Suk KT, Kang SH, Kim MY, Cheon GJ, Kim DJ, Baik SK, Choi DH. Modified PAGE-B score predicts the risk of hepatocellular carcinoma in Asians with chronic hepatitis B on antiviral therapy. J Hepatol 2018; 69:1066-1073. [PMID: 30075230 DOI: 10.1016/j.jhep.2018.07.018] [Citation(s) in RCA: 170] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 07/03/2018] [Accepted: 07/14/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Recently, the PAGE-B score and Toronto HCC risk index (THRI) have been developed to predict the risk of hepatocellular carcinoma (HCC) in Caucasian patients with chronic hepatitis B (CHB). We aimed to validate PAGE-B scores and THRI in Asian patients with CHB and suggested modified PAGE-B scores to improve the predictive performance. METHODS From 2007 to 2017, we examined 3,001 Asian patients with CHB receiving entecavir/tenofovir therapy. We assessed the performances of PAGE-B, THRI, CU-HCC, GAG-HCC, and REACH-B for HCC development. A modified PAGE-B score (mPAGE-B) was developed (derivation set, n = 2,001) based on multivariable Cox models. Bootstrap for internal validation and external validation (validation set, n = 1,000) were performed. RESULTS The five-year cumulative HCC incidence rates were 6.6% and 7.2% in the derivation and validation datasets after entecavir/tenofovir onset. In the derivation dataset, age, gender, serum albumin levels, and platelet counts were independently associated with HCC. The mPAGE-B score was developed based on age, gender, platelet counts, and serum albumin levels (time-dependent area under receiver operating characteristic curves [AUROC] = 0.82). In the validation set, the PAGE-B and THRI showed similar AUROCs to CU-HCC, GAG-HCC, and REACH-B at five years (0.72 and 0.73 vs. 0.70, 0.71, and 0.61 respectively; all p >0.05 except REACH-B), whereas the AUROC of mPAGE-B at five years was 0.82, significantly higher than the five other models (all p <0.01). HCC incidence rates after initiation of entecavir/tenofovir therapy in patients with CHB were significantly decreased in all risk groups in long-term follow-up periods. CONCLUSION Although PAGE-B and THRI are applicable in Asian patients with CHB receiving entecavir/tenofovir therapy, mPAGE-B scores including additional serum albumin levels showed better predictive performance than the PAGE-B score. LAY SUMMARY PAGE-B scores and Toronto HCC risk index were developed to predict the risk of hepatocellular carcinoma (HCC) in Caucasian patients with CHB under potent antiviral therapy. This study validated these two scores in Asian patients with CHB and suggested that modified PAGE-B scores could improve the predictive performance. A modified PAGE-B score, which is based only on a patient's age, gender, baseline platelet counts, and serum albumin levels at treatment initiation, represents a reliable and easily available risk score to predict HCC development during the first five years of antiviral treatment in Asian patients with CHB. With a scoring range from 0 to 21 points, a modified PAGE-B score differentiates the HCC risk. A modified PAGE-B score significantly differentiates the five-year HCC risk: low ≤8 points and high ≥13 points.
Collapse
Affiliation(s)
- Ji Hyun Kim
- Department of Internal Medicine, Kangwon National University Hospital, Chuncheon, Republic of Korea
| | - Young Don Kim
- Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Republic of Korea
| | - Minjong Lee
- Department of Internal Medicine, Kangwon National University Hospital, Chuncheon, Republic of Korea.
| | - Baek Gyu Jun
- Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Republic of Korea
| | - Tae Suk Kim
- Department of Internal Medicine, Kangwon National University Hospital, Chuncheon, Republic of Korea
| | - Ki Tae Suk
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon Sacred Heart Hospital, Chuncheon, Republic of Korea
| | - Seong Hee Kang
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Moon Young Kim
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Gab Jin Cheon
- Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Republic of Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon Sacred Heart Hospital, Chuncheon, Republic of Korea
| | - Soon Koo Baik
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Dae Hee Choi
- Department of Internal Medicine, Kangwon National University Hospital, Chuncheon, Republic of Korea.
| |
Collapse
|
|
33
|
Datta S, Dasgupta D, Ghosh A, Ghosh S, Manna A, Datta S, Chatterjee M, Chowdhury A, Banerjee S. Oncogenic potential of hepatitis B virus subgenotype D1 surpasses D3: significance in the development of hepatocellular carcinoma. Carcinogenesis 2018; 39:283-292. [PMID: 29228221 DOI: 10.1093/carcin/bgx145] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 12/06/2017] [Indexed: 12/15/2022] Open
Abstract
Despite widespread distribution of hepatitis B virus (HBV)-genotype D, the clinical implications of its ten subgenotypes (D1-D10) have not been well documented. Here, we have investigated the impact of two major circulating HBV/D subgenotypes, D1 and D3 in Eastern India towards pathogenesis of liver disease progression to hepatocellular carcinoma (HCC). HBV subgenotypes were determined using full-length genome sequences of HBV isolates from patients with chronic hepatitis B (CHB), liver cirrhosis (LC) and HCC. Impact of D1 and D3 on viral lifecycle and disease progression was assessed by several in vitro assays. Phylogenetic tree analysis revealed that HBV/D1 and HBV/D3 were the two predominating HBV subgenotypes circulating in Eastern India. Interestingly, the frequency of patients infected with HBV/D1 was noticed progressively rising from CHB to HCC through LC while the increasing frequency of HBV/D3 declined suddenly in HCC implicating HBV/D1 might have greater oncogenic potential than HBV/D3. Similar to higher viral load noted in HCC patients infected with HBV/D1 than HBV/D3, the larger amount of intracellular/extracellular viral DNA and secreted HBsAg levels in transfected cell lines also implicated that HBV/D1 might replicate faster than HBV/D3. Again, higher expression of marker genes related to endoplasmic reticulum stress, epithelial-mesenchymal transition, DNA double strand breaks, angiogenesis etc. and faster rate of cellular migration and anchorage independent growth cumulatively suggested that compared to HBV/D3, HBV/D1 generates more liver injuries which eventually culminates into HCC. Therefore, our results highlight the importance of determination of subgenotypes of HBV in CHB patients, so that high-risk individual can be monitor periodically that may help to detect HCC at early stages.
Collapse
Affiliation(s)
- Somenath Datta
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Debanjali Dasgupta
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Alip Ghosh
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Suchandrima Ghosh
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Alak Manna
- Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata,, India
| | - Simanti Datta
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Mitali Chatterjee
- Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata,, India
| | - Abhijit Chowdhury
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Soma Banerjee
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| |
Collapse
|
|
34
|
Lai JCT, Wong GLH, Yip TCF, Tse YK, Lam KLY, Lui GCY, Chan HLY, Wong VWS. Chronic Hepatitis B Increases Liver-Related Mortality of Patients With Acute Hepatitis E: A Territorywide Cohort Study From 2000 to 2016. Clin Infect Dis 2018; 67:1278-1284. [PMID: 30265321 DOI: 10.1093/cid/ciy234] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 03/20/2018] [Indexed: 08/08/2023] Open
Abstract
BACKGROUND The epidemiology of acute hepatitis A and E has been changing over the last 2 decades. The impact of concomitant chronic hepatitis B (CHB) on clinical outcomes remains unclear. We aimed to evaluate the morbidity and mortality of patients with acute hepatitis A or E with and without underlying CHB. METHODS We identified consecutive patients with acute hepatitis A or E based on hepatitis serology from the electronic medical records of the Hospital Authority of Hong Kong from January 2000 to December 2016. Hepatic events, all-cause mortality, and liver-related mortality within 30 days of the diagnosis of acute hepatitis were evaluated. RESULTS The cohort included 1068 cases of acute hepatitis A and 846 cases of acute hepatitis E. More patients with acute hepatitis E than those with acute hepatitis A had underlying CHB (13.5% vs 8.0%; P < .001). Patients with hepatitis E had more all-cause mortality (3.9% vs 0.6%; P < .001), liver-related mortality (2.0% vs 0.3%; P < .001), and hepatic events (2.8% vs 0.3%; P < .001) within 30 days from diagnosis. In patients with acute hepatitis E, underlying renal failure (adjusted hazard ratio [aHR], 3.90; P < .001) and age ≥50 years (aHR, 3.25; P = .036) were associated with 30-day all-cause mortality, whereas CHB (aHR, 3.34; P = .02) was associated with 30-day liver-related mortality. CONCLUSIONS The mortality is higher in patients with acute hepatitis E than in those with hepatitis A. Coexisting CHB is the independent risk factor for liver-related mortality in patients with acute hepatitis E.
Collapse
Affiliation(s)
- Jimmy Che-To Lai
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
- State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Terry Cheuk-Fung Yip
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Yee-Kit Tse
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Kelvin Long-Yan Lam
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Grace Chung-Yan Lui
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Henry Lik-Yuen Chan
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
- State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| |
Collapse
|
|
35
|
Lin CL, Kao JH. Review article: the prevention of hepatitis B-related hepatocellular carcinoma. Aliment Pharmacol Ther 2018; 48:5-14. [PMID: 29722445 DOI: 10.1111/apt.14683] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 02/08/2018] [Accepted: 04/03/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Ample evidence indicates an aetiological association of persistent hepatitis B virus (HBV) infection with hepatocellular carcinoma (HCC). Several viral, host and external risk factors for the development of HBV-related HCC have been documented. AIMS To summarise and discuss the risk stratification and the preventive strategies of HBV-related HCC. METHODS Recent published studies identified from PubMed were comprehensively reviewed. The key words included chronic hepatitis B, HBV, hepatocellular carcinoma, prevention and antiviral therapy. RESULTS The incidence of HCC is extremely high in HBV hyperendemic areas. For HBV patients left untreated, significant risk factors for HCC include male gender, aging, advanced hepatic fibrosis, persistent serum transaminase elevation, specific HBV entry receptor (NTCP) genotype, PM2.5 exposure, HBeAg positivity, HBV genotype C/D/F, high proportion of core promoter mutation, pre-S deletion, high serum levels of HBV DNA and HBsAg as well as co-infection with HCV, HDV and HIV. Primary prevention of HBV-related HCC can be achieved through universal HBV vaccination and anti-viral prophylaxis for high viraemic mothers. The goal of secondary prevention has been reached by effective anti-viral therapy to reduce the risk of HCC development in chronic hepatitis B patients. However, whether HCC is prevented or delayed deserves further examination. Finally, several studies confirmed the tertiary preventive effect of anti-viral therapy in reducing risk of HCC recurrence after curative therapies. CONCLUSIONS Through the strategies of three-level prevention, the global burden of HBV-related HCC should decline over time and even be eliminated in conjunction with HBV cure.
Collapse
Affiliation(s)
- C-L Lin
- Department of Gastroenterology, Taipei City Hospital, Taipei, Taiwan.,Department of Psychology, National Chengchi University, Taipei, Taiwan
| | - J-H Kao
- Graduate Institute of Clinical Medicine, National Taiwan University, College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Research, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan
| |
Collapse
|
|
36
|
Yang Y, Gao J, Tan YT, Li HL, Wang J, Ma X, Zheng W, Shu XO, Xiang YB. Individual and combined effects of hepatitis B surface antigen level and viral load on liver cancer risk. J Gastroenterol Hepatol 2018; 33:1131-1137. [PMID: 29065440 PMCID: PMC5902426 DOI: 10.1111/jgh.14032] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 09/11/2017] [Accepted: 10/16/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatitis B surface antigen (HBsAg) and viral load are both hallmarks of hepatitis B virus (HBV) infection and have potential to stratify liver cancer risk. METHODS We carried out a nested case-control study including 211 liver cancer cases and 221 controls who were seropositive for HBsAg within two population-based cohorts in Shanghai. Logistic regression was performed to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS Risk of liver cancer was positively related to increasing levels of HBV-DNA and HBsAg in dose-response manners. Compared with subjects with HBV-DNA < 2000 IU/ml, the adjusted ORs increased from 2.11 (95%CI: 0.99-4.50) to 10.47 (95%CI: 5.06-21.68) for those with HBV-DNA level at 2000-19 999 to ≥ 20 000 IU/ml. Compared with subjects at a low level of HBsAg (0.05-99 IU/ml), the adjusted ORs increased from 1.82 (95%CI: 0.90-3.68) to 2.21 (95%CI: 1.10-4.43) for those with HBsAg level at 100-999 to ≥ 1000 IU/ml. Compared with subjects with HBV-DNA < 2000 IU/ml and HBsAg < 100 IU/ml, the adjusted ORs were increased from 2.20 (95%CI: 1.07-4.49) for those with HBV-DNA < 2000 and HBsAg ≥ 100 IU/ml to 6.94 (95%CI: 3.39-14.23) for those with HBV-DNA ≥ 2000 IU/ml and HBsAg < 1000 IU/ml, and 16.15 (95%CI: 7.60-34.32) for those with HBV-DNA ≥ 2000 IU/ml and HBsAg ≥ 1000 IU/ml. CONCLUSION Elevated levels of HBV-DNA and HBsAg are associated with increased risks of liver cancer. Chronic HBsAg carriers may be suggested to simultaneously lower the viral load to < 2000 IU/ml and HBsAg level to < 100 IU/ml to lower their liver cancer risk.
Collapse
Affiliation(s)
- Yang Yang
- State Key Laboratory of Oncogene and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China,Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China
| | - Jing Gao
- State Key Laboratory of Oncogene and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China,Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China
| | - Yu-Ting Tan
- State Key Laboratory of Oncogene and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China,Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China
| | - Hong-Lan Li
- State Key Laboratory of Oncogene and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China,Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China
| | - Jing Wang
- State Key Laboratory of Oncogene and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China,Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China
| | - Xiao Ma
- State Key Laboratory of Oncogene and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China,Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medicine Center, Nashville TN 37203-1738, USA
| | - Xiao-Ou Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medicine Center, Nashville TN 37203-1738, USA
| | - Yong-Bing Xiang
- State Key Laboratory of Oncogene and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China,Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China
| |
Collapse
|
|
37
|
Xie Y. Hepatitis B Virus-Associated Hepatocellular Carcinoma. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1018:11-21. [PMID: 29052129 DOI: 10.1007/978-981-10-5765-6_2] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Liver cancer is the fifth most common cancer worldwide in men and the ninth in women. It is also the second most common cause of cancer mortality. Hepatocellular carcinoma (HCC) is the most common type of liver cancer. About 350 million people globally are chronically infected with HBV. Chronic hepatitis B virus (HBV) infection accounts for at least 50% cases of HCC worldwide. Other non-HBV factors may increase HCC risk among persons with chronic HBV infection. Both indirect and direct mechanisms are involved in HCC oncogenesis by HBV. HCC-promoting HBV factors include long-lasting infection, high levels of HBV replication, HBV genotype, HBV integration, specific HBV mutants, and HBV-encoded oncoproteins (e.g., HBx and truncated preS2/S proteins). Recurrent liver inflammation caused by host immune responses during chronic HBV infection can lead to liver fibrosis and cirrhosis and accelerate hepatocyte turnover rate and promote accumulation of mutations. Major breakthroughs have been achieved in the prevention of HBV-associated HCC with HBV vaccines and antiviral therapies.
Collapse
Affiliation(s)
- Youhua Xie
- Key Laboratory of Medical Molecular Virology (Ministries of Education and Health), Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
| |
Collapse
|
|
38
|
Zhang Y, Huang J, Chen J, Yang K, Chen J, Xu L, Zhou Z, Chen M. The mutation of hepatitis B virus and the prognosis of hepatocellular carcinoma after surgery: a pilot study. Cancer Manag Res 2018; 10:599-611. [PMID: 29628773 PMCID: PMC5877868 DOI: 10.2147/cmar.s160047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background Although hepatitis B virus (HBV) is still one of the most common etiological factors for hepatocellular carcinoma (HCC), the association between the HBV mutations and the clinical characteristics and prognosis of HBV-related HCC patients (HBV-HCC) after surgical resection remains largely unknown. Materials and methods A cohort of 131 consecutive patients who received hepatectomy for HBV-HCC were retrospectively enrolled. The HBV genotype and 14 genomic mutations, which have been reported to relate to HCC in liver samples, were sequenced. The associations between the genomic mutations and clinical characteristics and outcomes were analyzed. Results Both A1762T/G1764A mutation and Pre S deletion related to worse overall survival (OS, p=0.040 and p<0.001, respectively) and disease-free survival (DFS, p=0.040 and p<0.001, respectively), G1899A mutation related to worse OS (p=0.030), A1762T/G1764A mutation correlated with tumor size (r=0.204, p=0.019), G1899A mutation correlated with vascular invasion (r=0.332, p<0.001), and Pre S deletion correlated with alpha-fetoprotein (AFP; r=0.254, p=0.003) positively. Multivariate analysis with Cox proportional hazards model revealed that both A1762T/G1764A mutation and Pre S deletion were independent prognostic factors for OS (hazard ratio [HR]=3.701, 95% CI=1.390–9.855, p=0.009, and HR=4.816, 95% CI=2.311–10.032, p<0.001, respectively) and DFS (HR=3.245, 95% CI=1.400–7.521, p=0.006, and HR=2.437, 95% CI=1.311–4.530, p<0.001, respectively), and patients with dual mutations were found to have the worst OS and DFS (p<0.001 and p<0.001, respectively). Patients with A1762T/G1764A mutation or Pre S deletion were more likely to have early recurrence (p=0.042 and p=0.019, respectively). Conclusion HBV DNA genomic mutations in A1762T/G1764A and Pre S deletion were associated with worse prognoses and early recurrence for HBV-HCC patients after surgery.
Collapse
Affiliation(s)
- Yaojun Zhang
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Junting Huang
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Jinbin Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Keli Yang
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Jiancong Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Li Xu
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Zhongguo Zhou
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Minshan Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| |
Collapse
|
|
39
|
Liao R, Fu YP, Wang T, Deng ZG, Li DW, Fan J, Zhou J, Feng GS, Qiu SJ, Du CY. Metavir and FIB-4 scores are associated with patient prognosis after curative hepatectomy in hepatitis B virus-related hepatocellular carcinoma: a retrospective cohort study at two centers in China. Oncotarget 2018; 8:1774-1787. [PMID: 27662665 PMCID: PMC5352096 DOI: 10.18632/oncotarget.12152] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Accepted: 09/14/2016] [Indexed: 12/17/2022] Open
Abstract
Although Metavir and Fibrosis-4 (FIB-4) scores are typically used to assess the severity of liver fibrosis, the relationship between these scores and patient outcome in hepatocellular carcinoma (HCC) is unclear. The aim of this study was to evaluate the prognostic value of the severity of hepatic fibrosis in HBV-related HCC patients after curative resection. We examined the prognostic roles of the Metavir and preoperative FIB-4 scores in 432 HBV-HCC patients who underwent curative resection at two different medical centers located in western (Chongqing) and eastern (Shanghai) China. In the testing set (n = 108), the Metavir, FIB-4, and combined Metavir/FIB-4 scores were predictive of overall survival (OS) and recurrence-free survival (RFS). Additionally, they were associated with several clinicopathologic variables. In the validation set (n = 324), the Metavir, FIB-4, and combined Metavir/FIB-4 scores were associated with poor prognosis in HCC patients after curative resection. Importantly, in the negative alpha-fetoprotein subgroup (≤ 20 ng/mL), the FIB-4 index (I vs. II) could discriminate between patient outcomes (high or low OS and RFS). Thus Metavir, preoperative FIB-4, and combined Metavir/FIB-4 scores are prognostic markers in HBV-HCC patients after curative hepatectomy.
Collapse
Affiliation(s)
- Rui Liao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yi-Peng Fu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ting Wang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhi-Gang Deng
- Department of General Surgery, Mianyang Central Hospital, Mianyang, China
| | - De-Wei Li
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Gen-Sheng Feng
- Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, California, USA
| | - Shuang-Jian Qiu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cheng-You Du
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
40
|
Liu Z, Song C, Wen J, Xu L, Liu Y, Zhu J, Zhu L, Hu Z, Ma H, Liu L. Hepatitis B virus genotypes, expression quantitative trait loci for ZNRD1-AS1 and their interactions in hepatocellular carcinoma. Oncotarget 2018; 7:44076-44083. [PMID: 27286450 PMCID: PMC5190080 DOI: 10.18632/oncotarget.9854] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 05/01/2016] [Indexed: 12/13/2022] Open
Abstract
Genetic variants in zinc ribbon domain-containing 1 antisense RNA 1 (ZNRD1-AS1) have been reported to be associated with development of hepatocellular carcinoma (HCC). We sought to determine the influences of ZNRD1-AS1 polymorphisms and their interactions with Hepatitis B virus (HBV) genotypes on the risk of HCC. In this study, we conducted a large population case-control study with 1,507 HBV-related HCC cases and 1,560 HBV persistent carriers. Three single-nucleotide polymorphisms (SNPs) in ZNRD1-AS1 (rs3757328, rs6940552 and rs9261204) were genotyped using a TaqMan allelic discrimination assay, and the HBV genotypes were identified by multiplex PCR. We found consistently significant associations between the ZNRD1-AS1 rs6940552 and rs9261204 SNPs with an increased risk of HCC (additive genetic model: adjusted OR = 1.16, 95% CI = 1.03-1.32 for rs6940552; adjusted OR =1.20, 95% CI = 1.06-1.35 for rs9261204) and found a borderline association between rs3757328 and HCC risk. Besides, we observed a dose-dependent relationship between increasing numbers of variant alleles of the SNPs and HCC risk (P for trend <0.001). Moreover, we observed a stronger combined effect of the three SNPs on HCC risk among the subjects infected with non-B genotype HBV (adjusted OR = 1.26, 95% CI = 1.05-1.50) compared with HBV B-related genotypes (adjusted OR = 0.89, 95% CI = 0.69-1.15; P= 0.029 for heterogeneity test). We also found that a multiplicative interaction between the variant alleles and the HBV genotype significantly affected HCC susceptibility (P = 0.030). Together, these results indicate that ZNRD1-AS1 may influence HCC risk accompanied by HBV genotypes.
Collapse
Affiliation(s)
- Zhenzhen Liu
- Digestive Endoscopy Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ci Song
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Juan Wen
- Nanjing Maternity and Child Health Care Institute, Nanjing Maternity and Child Health Care Hospital Affiliated with Nanjing Medical University, Nanjing, China
| | - Lu Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yao Liu
- Pathology Center and Department of Pathology, Soochow University, Suzhou, China
| | - Jian Zhu
- Qidong Liver Cancer Institute, The First People's Hospital of Qidong, Qidong, China
| | - Liguo Zhu
- Department of Infection Diseases, Jiangsu Province Center for Disease Prevention and Control, Nanjing, China
| | - Zhibin Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Hongxia Ma
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Li Liu
- Digestive Endoscopy Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
41
|
Yin F, Xie Y, Fan H, Zhang J, Guo Z. Mutations in hepatitis B virus polymerase are associated with the postoperative survival of hepatocellular carcinoma patients. PLoS One 2017; 12:e0189730. [PMID: 29287068 PMCID: PMC5747429 DOI: 10.1371/journal.pone.0189730] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2017] [Accepted: 11/30/2017] [Indexed: 12/15/2022] Open
Abstract
Proofreading deficiencies of hepatitis B virus polymerase result in frequent DNA mutations in the hepatitis B virus genome. Here, we performed sequencing analysis of the hepatitis B virus polymerase gene to assess its association with the postoperative survival in 92 patients with HBV-related hepatocellular carcinoma by using the Kaplan–Meier method. The 2525, 2733, 2738, 2768, 2946, 3063, 3066, 3109, 31, 529, 735, 939, 1078, 1137, 1383, 1461, 1485, 1544, and 1613 mutation sites were identified as being associated with HCC outcomes by the log-rank test. After adjusting for clinical characteristics by using the Cox hazard model, site 31 (relative risk, 8.929; 95% confidence interval, 3.433–23.22; P = 0.000) in the spacer domain and sites 529 (relative risk, 5.656; 95% confidence interval, 1.599–19.999; P = 0.007) and 1078 (relative risk, 3.442; 95% confidence interval, 1.070–11.068; P = 0.038) in the reverse transcriptase domain of hepatitis B virus polymerase were identified as independent predictors of postoperative survival in hepatitis B virus related hepatocellular carcinoma. The mutations at the 31 (Ser314Pro), 529 (Asp480Asn), and 1078 (Ser663Ala) sites all resulted in amino acid changes in hepatitis B virus polymerase and were associated with shortened life-span. The 31 and 529 sites were located in the overlapping region for the PreS and S genes but did not induce amino acid substitution in these two regions. Our finding of the correlation between hepatitis B virus DNA polymerase mutations and hepatocellular carcinoma survival will help identify the patients subgroup with poor prognosis, and help the clinicians to refine the therapeutic decision individualized.
Collapse
Affiliation(s)
- Fei Yin
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Ying Xie
- Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, Shijiazhuang, P.R. China
| | - Haiyan Fan
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Jingjing Zhang
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Zhanjun Guo
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
- * E-mail:
| |
Collapse
|
|
42
|
Lee HW, Park HJ, Jin B, Dezhbord M, Kim DY, Han KH, Ryu WS, Kim S, Ahn SH. Effect of S267F variant of NTCP on the patients with chronic hepatitis B. Sci Rep 2017; 7:17634. [PMID: 29247233 PMCID: PMC5732244 DOI: 10.1038/s41598-017-17959-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 12/02/2017] [Indexed: 01/05/2023] Open
Abstract
Sodium taurocholate cotransporting polypeptide (NTCP) was identified as an entry receptor for hepatitis B virus (HBV) infection. The substitution of serine at position 267 of NTCP with phenylalanine (S267F) is an Asian-specific variation that hampers HBV entry in vitro. In this study, we aimed to evaluate the prevalence of S267F polymorphism in Korean patients with chronic hepatitis B (CHB) and its association with disease progression and potential viral evolution in the preS1 domain of HBV. We found that the frequency of the S267F variant of NTCP in CHB patients and controls was 2.7% and 5.7% (P = 0.031), respectively, and that those who had S267F variant were less susceptible to chronic HBV infection. The frequency of the S267F variant in CHB, cirrhosis and hepatocellular carcinoma (HCC) patients was 3.3%, 0.9%, and 3.5%, respectively. Thus, the S267F variant correlated significantly with a lower risk for cirrhosis (P = 0.036). Sequencing preS1 domain of HBV from the patients who had S267F variant revealed no significant sequence change compared to the wild type. In conclusion, the S267F variant of NTCP is clinically associated with a lower risk of chronic HBV infection and cirrhosis development, which implicates suppressing HBV entry could reduce the disease burden.
Collapse
Affiliation(s)
- Hye Won Lee
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Jung Park
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Bora Jin
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | | | - Do Young Kim
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Wang-Shick Ryu
- Department of Biochemistry, Yonsei University, Seoul, Korea.,Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, Korea
| | - Seungtaek Kim
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea. .,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea. .,Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, Korea.
| | - Sang Hoon Ahn
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
| |
Collapse
|
|
43
|
Rajoriya N, Combet C, Zoulim F, Janssen HLA. How viral genetic variants and genotypes influence disease and treatment outcome of chronic hepatitis B. Time for an individualised approach? J Hepatol 2017; 67:1281-1297. [PMID: 28736138 DOI: 10.1016/j.jhep.2017.07.011] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 06/27/2017] [Accepted: 07/12/2017] [Indexed: 12/12/2022]
Abstract
Chronic hepatitis B virus (HBV) infection remains a global problem. Several HBV genotypes exist with different biology and geographical prevalence. Whilst the future aim of HBV treatment remains viral eradication, current treatment strategies aim to suppress the virus and prevent the progression of liver disease. Current strategies also involve identification of patients for treatment, namely those at risk of progressive liver disease. Identification of HBV genotype, HBV mutants and other predictive factors allow for tailoured treatments, and risk-surveillance pathways, such as hepatocellular cancer screening. In the future, these factors may enable stratification not only of treatment decisions, but also of patients at risk of higher relapse rates when current therapies are discontinued. Newer technologies, such as next-generation sequencing, to assess drug-resistant or immune escape variants and quasi-species heterogeneity in patients, may allow for more information-based treatment decisions between the clinician and the patient. This article serves to discuss how HBV genotypes and genetic variants impact not only upon the disease course and outcomes, but also current treatment strategies. Adopting a personalised genotypic approach may play a role in future strategies to combat the disease. Herein, we discuss new technologies that may allow more informed decision-making for response guided therapy in the battle against HBV.
Collapse
Affiliation(s)
- Neil Rajoriya
- Toronto Centre for Liver Diseases, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada
| | - Christophe Combet
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Lyon 69XXX, France
| | - Fabien Zoulim
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Lyon 69XXX, France; Department of Hepatology, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France
| | - Harry L A Janssen
- Toronto Centre for Liver Diseases, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.
| |
Collapse
|
|
44
|
Zhang W, Wang X, Wang Y, Zhao X, Duan W, Wang Q, Wu X, Kong Y, Ma H, You H, Ou X, Jia J. Effective viral suppression is necessary to reduce hepatocellular carcinoma development in cirrhotic patients with chronic hepatitis B: Results of a 10-year follow up. Medicine (Baltimore) 2017; 96:e8454. [PMID: 29095292 PMCID: PMC5682811 DOI: 10.1097/md.0000000000008454] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
High viral load is an independent risk factor for development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Antiviral therapy can reduce but not eliminate the risk of HCC. The aim of this study was to identify the risk factors for HCC development in CHB patients during antiviral therapy.CHB patients with HBV DNA level ≥10 copies/mL, with or without compensated cirrhosis receiving adefovir were followed up every 6 months for 10 years (2004-2014). The primary endpoint was the development of HCC. The cumulative incidence and risk factors of HCC were evaluated by the Kaplan-Meier method and multivariate Cox proportional hazards models.At baseline, 28 of the 120 patients (23.3%) were cirrhotic. One patient developed HCC within 1 year, and therefore 119 patients were analyzed. At the end-point of follow-up, 59.7% (71/119) patients achieved virological remission (VR). Overall, 16 patients developed HCC, giving a 10-year cumulative incidence of 15.73%. Multivariate analysis showed that cirrhosis at baseline and failure to achieve VR were significant risk factors for HCC. The 10-year incidence of HCC was significantly higher in cirrhotic than noncirrhotic patients (43.16% vs. 7.05%, P < .0001). For cirrhotic patients, the 10-year incidence of HCC was significantly higher in patients without VR than those with VR (62.24% vs. 27.78%, P = .0139).Cirrhosis at baseline and failure to achieve VR during antiviral therapy were significant risk factors for HCC development in CHB patients. Effective viral suppression is necessary to reduce HCC development in cirrhotic CHB patients.
Collapse
Affiliation(s)
- Wei Zhang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Xiaoming Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Yu Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Xinyan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Weijia Duan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Qianyi Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Xiaoning Wu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Yuanyuan Kong
- Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University; National Clinical Research Center for Digestive Disease, Beijing, China
| | - Hong Ma
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| |
Collapse
|
|
45
|
Gao Z, Du G, Pang Y, Fu Z, Liu C, Liu Y, Zhou B, Kong D, Shi B, Jiang Z, Jin B. Adjuvant transarterial chemoembolization after radical resection contributed to the outcomes of hepatocellular carcinoma patients with high-risk factors. Medicine (Baltimore) 2017; 96:e7426. [PMID: 28816936 PMCID: PMC5571673 DOI: 10.1097/md.0000000000007426] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
We aim to investigate the effects of postoperative adjuvant transarterial chemoembolization (TACE) on survival and recurrence in hepatocellular carcinoma (HCC) patients after radical resection. A total of 320 HCC patients underwent radical resection between January 2010 and January 2014 in Qilu Hospital, Shandong University were divided into 4 groups according to the frequency of postoperative adjuvant TACE. Patients were further stratified into subgroups (tumor diameter ≤5 or >5 cm) with low or high risk factors for recurrence or death. A low risk factor for recurrence or death was defined as Edmondson grade I/II without microvascular invasion (MiVI), while a high risk factor was defined as Edmondson grade III/IV or with MiVI. Survival data and recurrence rates were compared using the Kaplan-Meier method. Uni- and multivariate analyses were based on the Cox proportional analysis. Compared to those received no TACE, patients underwent 2 (log-rank, χ = 9.054, P = .003) or 3 (log-rank, χ = 4.228, P = .04) TACE showed delayed recurrence. Patients received 2 or 3 TACE showed extended overall survival (OS) compared with the other patients. No statistical differences were found between all the disease-free survival (DFS) and OS in low-risk subgroups. In the patients of the high-risk subgroup with a tumor diameter of ≤5, those received 2 TACE showed delayed recurrence compared with those received no TACE, and TACE (twice or thrice) can improve OS. For those of the high-risk subgroup with a tumor diameter of >5, TACE (twice or thrice) can delay recurrence and improve OS. Adjuvant TACE (twice or thrice) after radical resection is beneficial for HCC patients with poor differentiation and MiVI, especially for those with a tumor diameter of >5 cm.
Collapse
Affiliation(s)
- Zhendong Gao
- Department of General Surgery, Qilu Hospital of Shandong University
- School of Medicine, Shandong University, Jinan
| | - Gang Du
- Department of General Surgery, Qilu Hospital of Shandong University
| | - Yuguang Pang
- Department of General Surgery, Renmin Hospital of Lingcheng, Dezhou, China
| | - Zhihao Fu
- Department of General Surgery, Qilu Hospital of Shandong University
- School of Medicine, Shandong University, Jinan
| | - Chongzhong Liu
- Department of General Surgery, Qilu Hospital of Shandong University
| | - Yi Liu
- Department of General Surgery, Qilu Hospital of Shandong University
| | - Binghai Zhou
- Department of General Surgery, Qilu Hospital of Shandong University
- School of Medicine, Shandong University, Jinan
| | - Du Kong
- Department of General Surgery, Qilu Hospital of Shandong University
- School of Medicine, Shandong University, Jinan
| | - Binyao Shi
- Department of General Surgery, Qilu Hospital of Shandong University
- School of Medicine, Shandong University, Jinan
| | - Zhengcheng Jiang
- Department of General Surgery, Qilu Hospital of Shandong University
- School of Medicine, Shandong University, Jinan
| | - Bin Jin
- Department of General Surgery, Qilu Hospital of Shandong University
| |
Collapse
|
|
46
|
Matsuo J, Do SH, Yamamoto C, Nagashima S, Chuon C, Katayama K, Takahashi K, Tanaka J. Clustering infection of hepatitis B virus genotype B4 among residents in Vietnam, and its genomic characters both intra- and extra-family. PLoS One 2017; 12:e0177248. [PMID: 28753615 PMCID: PMC5533320 DOI: 10.1371/journal.pone.0177248] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Accepted: 04/24/2017] [Indexed: 02/07/2023] Open
Abstract
Vietnam has a high rate of hepatitis B virus (HBV) infection and a high mortality rate from hepatocellular carcinoma. We performed a detailed genetic analysis of 48 residents and four families from Binh Thuan Province, a southern coastal area of Vietnam. The route of infection and genomic characteristics related to hepatocellular carcinoma (HCC) were studied in HBV spread among carriers that we detected in our previous hepatitis survey. The HBV genotype was B4 in 91.7% and C1 in 8.3% of the cases. The intra-family’s HBV sequence homology was high at 96.8–99.4%. However, it was also high at 99.4–99.8% among residents of the same age and sex as family members. In addition, full genome analysis was performed in 21 cases. The core region of all 20 isolates with genotype B4 was a recombinant of genotype C, and pre-S deletion was found in 20% of cases. The promoter mutation G1613A was found in 13.6% of cases, and a 24 bp insertion from nt1673 in the X region was found in 6.3% of cases. The phylogenetic tree and homology analysis of the HBV full genome suggested the probability and its possibility of horizontal transmission not only within families nor vertical transmission but within cohorts of the same generation in the population. Moreover, the HBV genotype B4 isolates were found not only to be recombinants of genotype C, which results in a high cancer risk, but also to have other risk of HCC, pre-S deletions, the G1613A mutation, and X region insertions corresponding to the promoter. These genomic characters were suggested to be one of the factors to explain the high HCC mortality rate in Vietnam.
Collapse
Affiliation(s)
- Junko Matsuo
- Department of Epidemiology, Infectious Disease Control and Prevention, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Son Huy Do
- Binh Thuan Medical College, Phan Thiet City, Binh Thuan Province, Vietnam
| | - Chikako Yamamoto
- Department of Epidemiology, Infectious Disease Control and Prevention, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shintaro Nagashima
- Department of Epidemiology, Infectious Disease Control and Prevention, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Channarena Chuon
- Department of Epidemiology, Infectious Disease Control and Prevention, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Keiko Katayama
- Department of Epidemiology, Infectious Disease Control and Prevention, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Takahashi
- Department of Medical Sciences, Toshiba General Hospital, Tokyo, Japan
| | - Junko Tanaka
- Department of Epidemiology, Infectious Disease Control and Prevention, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- * E-mail:
| |
Collapse
|
|
47
|
Zhu MY, Zou X, Li Q, Yu DM, Yang ZT, Huang D, Chen J, Gong QM, Zhang DH, Zhang Y, Chen L, Chen PZ, Zhang XX. A novel noninvasive algorithm for the assessment of liver fibrosis in patients with chronic hepatitis B virus infection. J Viral Hepat 2017; 24:589-598. [PMID: 28130852 DOI: 10.1111/jvh.12682] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023]
Abstract
Several noninvasive blood biomarkers have been established for the assessment of liver fibrosis in patients with chronic hepatitis B virus (HBV) infection, but their clinical performance remains inconclusive. Here, we compared the diagnostic performance of these biomarkers and developed a novel algorithm for assessing liver fibrosis. Six hundred and sixteen chronically HBV-infected and treatment-naïve patients who underwent liver biopsy were enrolled and randomly divided into training (N=410) and internal validation cohorts (N=206). One hundred and fifty-nine patients from another centre were recruited as an external validation cohort. Receiver operating characteristic (ROC) curves were used to analyse the performance of the gamma-glutamyltransferase-to-platelet ratio (GPR), red cell volume distribution width-to-platelet ratio (RPR), FIB-4 index, aspartate aminotransferase-to-platelet ratio index (APRI) and HBV DNA level against liver histology, and a novel algorithm was developed using the recursive partitioning and regression tree (RPART) method. In the training cohort, the area under the ROC curve of FIB-4 was significantly higher than that of APRI (P=.038) but was comparable to those of GPR, RPR and HBV DNA; however, the performance of the biomarkers was similar among the validation cohort. The established RPR-HBV DNA algorithm performed better in the training cohort than any individual blood biomarker, and the corresponding sensitivity, specificity, positive predictive value and negative predictive value were 63%, 90%, 72% and 80%, respectively. In the internal and external validation cohorts, the performance of the algorithm in assessing liver fibrosis was also superior to that of other biomarkers. These results suggest that the established RPR-HBV DNA algorithm might improve the diagnostic accuracy of liver fibrosis in treatment-naïve patients with chronic HBV infection, although additional studies are warranted to confirm these findings.
Collapse
Affiliation(s)
- M-Y Zhu
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - X Zou
- Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
| | - Q Li
- Department of Hepatitis, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - D-M Yu
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Z-T Yang
- Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - D Huang
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - J Chen
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Q-M Gong
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - D-H Zhang
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Y Zhang
- Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.,Collaborative Innovation Center of Systems Biomedicine, Shanghai, China
| | - L Chen
- Department of Hepatitis, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - P-Z Chen
- Translational Medicine Research Center, Ruijin Hospital North, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - X-X Zhang
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Translational Medicine Research Center, Ruijin Hospital North, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
48
|
Qiu JF, Ye JZ, Feng XZ, Qi YP, Ma L, Yuan WP, Zhong JH, Zhang ZM, Xiang BD, Li LQ. Pre- and post-operative HBsAg levels may predict recurrence and survival after curative resection in patients with HBV-associated hepatocellular carcinoma. J Surg Oncol 2017. [PMID: 28628729 DOI: 10.1002/jso.24628] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE To investigate pre- and post-operative levels of HBsAg influence prognosis of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative resection. METHODS Medical records were retrospectively analyzed for 881 patients with HBV-related HCC treated by curative resection. Patients were classified as having high or low serum HBsAg levels (≥200 or <200 ng/mL) pre- or post-operatively. RESULTS OS and RFS were better for patients with low pre-operative serum levels of HBsAg than for those with high levels. Similarly, OS was better among patients with low post-operative serum levels of HBsAg than among those with high levels. RFS, in contrast, was similar between these two groups. After generating propensity score-matched pairs of patients, OS was higher in patients with falling post-operative HBsAg levels than in those with rising levels. In contrast, RFS was similar between these two groups. Antiviral nucleoside analog therapy prolonged OS in patients with high pre-operative HBsAg levels. CONCLUSIONS Low pre- and post-operative levels of HBsAg may be associated with better long-term survival in patients with HBV-related HCC. Pre-operative serum levels of HBsAg ≥200 ng/mL may identify patients more likely to benefit from antiviral treatment.
Collapse
Affiliation(s)
- Jing-Feng Qiu
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Jia-Zhou Ye
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Xu-Zhuo Feng
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Ya-Peng Qi
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Liang Ma
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Wei-Ping Yuan
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Jian-Hong Zhong
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Zhi-Ming Zhang
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Bang-De Xiang
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Le-Qun Li
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| |
Collapse
|
|
49
|
Xu W, Yu J, Wong VWS. Mechanism and prediction of HCC development in HBV infection. Best Pract Res Clin Gastroenterol 2017; 31:291-298. [PMID: 28774411 DOI: 10.1016/j.bpg.2017.04.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 04/28/2017] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis B virus (HBV) infection remains one of the leading causes of hepatocellular carcinoma (HCC) globally. Over the past few decades, the risk factors of HCC in patients with chronic hepatitis B have been well characterized, and can be divided into host and viral factors. A few groups have also derived and validated HCC prediction scores based on these risk factors. In general, the scores have high negative predictive value in identifying a low risk group who may not need HCC surveillance in the next 3-5 years. The scores have been tested originally in Asian patients, and results on their performance in the Caucasian population are conflicting. Furthermore, new research has identified genetic factors and new virological markers (e.g. hepatitis B surface antigen and core-related antigen levels) for HCC, but they are yet to be applied in routine clinical practice.
Collapse
Affiliation(s)
- Weiqi Xu
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Jun Yu
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - Vincent Wai-Sun Wong
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
| |
Collapse
|
|
50
|
Natural history of acute and chronic hepatitis B: The role of HBV genotypes and mutants. Best Pract Res Clin Gastroenterol 2017; 31:249-255. [PMID: 28774406 DOI: 10.1016/j.bpg.2017.04.010] [Citation(s) in RCA: 121] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 04/28/2017] [Indexed: 01/31/2023]
Abstract
Molecular epidemiologic studies reveal remarkable differences in the geographical distribution of hepatitis B virus (HBV) genotypes. The frequency of mutants among HBV genotypes also varies. The role of HBV genotypes/mutants in the pathogenesis of HBV infection and natural history of HBV infection has been extensively investigated. The distribution of HBV genotypes in acute hepatitis B patients reflects the predominant genotypes in a given geographic area. In chronic hepatitis B patients, genotype C and D have a higher frequency of basal core promoter A1762T/G1764A mutations than genotype A and B. HBV genotypes C, D and F carry a higher lifetime risk of cirrhosis and HCC development than genotype A and B. HBV pre-S/S gene mutations were associated with immune escape of hepatitis B immunoglobulin or vaccine-induced immunity. Mutations in the pre-S, core promoter and X regions correlate with an increased risk of cirrhosis and HCC. In summary, HBV genotypes and mutants are associated with the disease progression and long-term outcome of HBV infection. They may serve as viral genetic markers for risk stratification of chronic hepatitis B patients in clinical practice.
Collapse
|