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1
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Young C, Singh M, Jackson KJL, Field MA, Peters TJ, Angioletti-Uberti S, Frenkel D, Ravishankar S, Gupta M, Wang JJ, Agapiou D, Faulks ML, Al-Eryani G, Luciani F, Gordon TP, Reed JH, Danta M, Carr A, Kelleher AD, Dore GJ, Matthews G, Brink R, Bull RA, Suan D, Goodnow CC. A triad of somatic mutagenesis converges in self-reactive B cells to cause a virus-induced autoimmune disease. Immunity 2025; 58:412-430.e10. [PMID: 39818208 DOI: 10.1016/j.immuni.2024.12.011] [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: 01/30/2024] [Revised: 09/22/2024] [Accepted: 12/18/2024] [Indexed: 01/18/2025]
Abstract
The unexplained association between infection and autoimmune disease is strongest for hepatitis C virus-induced cryoglobulinemic vasculitis (HCV-cryovas). To analyze its origins, we traced the evolution of pathogenic rheumatoid factor (RF) autoantibodies in four HCV-cryovas patients by deep single-cell multi-omic analysis, revealing three sources of B cell somatic mutation converged to drive the accumulation of a large disease-causing clone. A method for quantifying low-affinity binding revealed recurring antibody variable domain combinations created by V(D)J recombination that bound self-immunoglobulin G (IgG) but not viral E2 antigen. Whole-genome sequencing revealed thousands of somatic mutations, numerically comparable to chronic lymphocytic leukemia and normal memory B cells, but with 1-2 corresponding to driver mutations found recurrently in B cell leukemia and lymphoma. V(D)J hypermutation created autoantibodies with compromised solubility in complex with self-IgG. In this virus-induced autoimmune disease, infection promotes a catastrophic confluence of somatic mutagenesis in the descendants of a single B cell.
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Affiliation(s)
- Clara Young
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
| | - Mandeep Singh
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
| | | | - Matt A Field
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Australian Institute of Tropical Health and Medicine and Centre for Tropical Bioinformatics and Molecular Biology, Smithfield, Cairns, QLD, Australia; Menzies School of Health Research, Darwin, NT, Australia
| | - Timothy J Peters
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
| | | | - Daan Frenkel
- Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK
| | | | - Money Gupta
- School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia; The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Jing J Wang
- Department of Immunology, Flinders University and SA Pathology, Bedford Park, Adelaide, SA, Australia
| | - David Agapiou
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Megan L Faulks
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | | | - Fabio Luciani
- School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia; The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Tom P Gordon
- Department of Immunology, Flinders University and SA Pathology, Bedford Park, Adelaide, SA, Australia
| | - Joanne H Reed
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Westmead Institute for Medical Research, Westmead, Sydney, NSW, Australia
| | - Mark Danta
- St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
| | - Andrew Carr
- Immunology and HIV Unit, St Vincent's Hospital, Sydney, NSW, Australia
| | - Anthony D Kelleher
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia; Immunology and HIV Unit, St Vincent's Hospital, Sydney, NSW, Australia
| | - Gregory J Dore
- St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia; The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Gail Matthews
- St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia; The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Robert Brink
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
| | - Rowena A Bull
- School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia; The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Dan Suan
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia.
| | - Christopher C Goodnow
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia.
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Xing T. Existing problems and new advice on stage criteria of natural history for chronic hepatitis B. BMC Infect Dis 2025; 25:17. [PMID: 39754052 PMCID: PMC11699759 DOI: 10.1186/s12879-024-10408-x] [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: 10/12/2024] [Accepted: 12/24/2024] [Indexed: 01/06/2025] Open
Abstract
The natural stages of chronic hepatitis B can be divided into four stages according to changes in virology, biochemistry, and pathology. However, there have been significant differences in the recommended stage criteria in the several major guidelines for chronic hepatitis B, especially regarding the immune tolerance phase. Inconsistent standards of indicators for different stages resulted in some problems, such as incorrect stage, uncertain stages and poor comparation of related studies. We propose suggestions for revisions to the stage criteria for CHB based on recent researches, including three stages: immune tolerance stage, immune clearance stage, and immune control stage. These revision suggestions rationalize some of the existing problems with the stage criteria for CHB and can significantly reduce the number of patients in the "uncertain stage" or "gray zone," which is particularly valuable in guiding clinical practice. However, further clinical studies with large samples are needed to confirm these suggestions.
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Affiliation(s)
- Tongjing Xing
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, China.
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Lim J, Hwang J, Min H, Wester M, Kim C, Valera E, Kong HJ, Bashir R. Dried Blood Matrix as a New Material for the Detection of DNA Viruses. Adv Healthc Mater 2024; 13:e2402506. [PMID: 39075818 PMCID: PMC11582504 DOI: 10.1002/adhm.202402506] [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: 07/08/2024] [Revised: 07/16/2024] [Indexed: 07/31/2024]
Abstract
The gold standard for diagnosing viruses such as the Hepatitis B Virus has remained largely unchanged, relying on conventional methods involving extraction, purification, and polymerase chain reaction (PCR). This approach is hindered by limited availability, as it is time-consuming and requires highly trained personnel. Moreover, it suffers from low recovery rates of the nucleic acid molecules for samples with low copy numbers. To address the challenges of complex instrumentation and low recovery rate of DNA, a drying process coupled with thermal treatment of whole blood is employed, resulting in the creation of a dried blood matrix characterized by a porous structure with a high surface-to-volume ratio where it also inactivates the amplification inhibitors present in whole blood. Drawing on insights from Brunauer-Emmett-Teller (BET)- Barrett-Joyner-Halenda (BJH) analysis, scanning electron microscopy (SEM), and fluorescence recovery after photobleaching (FRAP), detection assay is devised for HBV, as a demonstration, from whole blood with high recovery of DNA and simplified instrumentation achieving a limit of detection (LOD) of 10 IU mL-1. This assay can be completed in <1.5 h using a simple heater, can be applied to other DNA viruses, and is expected to be suitable for point-of-care, especially in low-resource settings.
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Affiliation(s)
- Jongwon Lim
- Nick Holonyak Jr. Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Joanne Hwang
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Hyegi Min
- Nick Holonyak Jr. Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Matthew Wester
- Nick Holonyak Jr. Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Chansong Kim
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Enrique Valera
- Nick Holonyak Jr. Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Hyun Joon Kong
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Departments of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Rashid Bashir
- Nick Holonyak Jr. Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Department of Biomedical and Translational Science, Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Chan Zuckerberg Biohub Chicago, Chicago, IL, 60642, USA
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Yoon EL, Jun DW. Precision medicine in the era of potent antiviral therapy for chronic hepatitis B. J Gastroenterol Hepatol 2022; 37:1191-1196. [PMID: 35430754 DOI: 10.1111/jgh.15856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 04/04/2022] [Indexed: 12/09/2022]
Abstract
With the wide use of potent and safe nucloes(t-)ide analogues (NAs) treatment, patient-centered care is getting important. Intensive care for comorbidity has gain utmost importance in care of aging chronic hepatitis B (CHB) patients with life-long antiviral treatment. Linkage to care of patients with CHB is essential for the goal of hepatitis B virus (HBV) eradication. As long-term suppression of HBV DNA replication does not prevent hepatocellular carcinoma (HCC), prevention of HCC is another challenge for NAs treatment. There is a possibility of hepatocarcinogenesis in the immune-tolerant phase and risk of loss of patients during active monitoring seeking the time point for antiviral treatment initiation. Initiation of NAs treatment from the immune-tolerant phase would improve the linkage to care. However, universal recommendation is premature and evidence for cost-effectiveness needs to be accumulated. Early initiation of NAs in the evidence of significant disease progression, either HBV associated or comorbidity associated, would be a better strategy to reduce the risk of HCC in patients located in the gray zone.
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Affiliation(s)
- Eileen L Yoon
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
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Zhao XA, Wang J, Wei J, Liu J, Chen G, Wang L, Wang G, Xia J, Wu W, Yin S, Tong X, Yan X, Ding W, Xiang X, Huang R, Wu C. Gamma-glutamyl Transpeptidase to Platelet Ratio Predicts Liver Injury in Hepatitis B e Antigen-negative Chronic Hepatitis B Patients With Normal Alanine Aminotransferase. J Clin Transl Hepatol 2022; 10:247-253. [PMID: 35528978 PMCID: PMC9039718 DOI: 10.14218/jcth.2021.00151] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/24/2021] [Accepted: 06/16/2021] [Indexed: 12/07/2022] Open
Abstract
BACKGROUND AND AIMS Chronic hepatitis B virus (HBV) infection is a serious health problem worldwide. Evaluating liver injury in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) with detectable HBV DNA and normal alanine aminotransferase (ALT) is crucial to guide their clinical management. We aimed to investigate the stages of liver inflammation and fibrosis as well as the predictive accuracy of gamma-glutamyl transpeptidase-to-platelet ratio (GPR) in these patients. METHODS A total of 184 treatment-naïve HBeAg-negative CHB patients with detectable HBV DNA and normal ALT were enrolled. The Scheuer scoring system was used to classify liver inflammation and fibrosis. RESULTS The distribution of patients with different liver inflammation grades were as follows: G0, 0 (0%); G1, 97 (52.7%); G2, 68 (37.0%); G3, 12 (6.5%); and G4, 7 (3.8%). The distribution of patients with different liver fibrosis stages were as follows: S0, 22 (12.0%); S1, 72 (39.1%); S2, 42 (22.8%); S3, 19 (10.3%); and S4, 29 (15.8%). The areas under the receiver operating characteristic (AUROC) curves of GPR in predicting significant inflammation, severe inflammation, and advanced inflammation were 0.723, 0.895, and 0.952, respectively. The accuracy of GPR was significantly superior to that of ALT in predicting liver inflammation. The AUROCs of GPR in predicting significant fibrosis, severe fibrosis, and cirrhosis were 0.691, 0.780, and 0.803, respectively. The predictive accuracy of GPR was significantly higher than that of aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4) in identifying advanced fibrosis and cirrhosis, and it was superior to FIB-4 but comparable to APRI in identifying significant fibrosis. CONCLUSIONS Nearly half of the HBeAg-negative CHB patients with detectable HBV DNA and normal ALT levels had significant liver inflammation or fibrosis. GPR can serve as an accurate predictor of liver inflammation and fibrosis in these patients.
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Affiliation(s)
- Xiang-An Zhao
- Department of Gastroenterology, Northern Jiangsu People’s Hospital, Clinical Medical College of Yangzhou University, Yangzhou, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Jian Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Jie Wei
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Jiacheng Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Guangmei Chen
- Department of Infectious Diseases, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Li Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Guiyang Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Juan Xia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Weihua Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Xin Tong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Xiaomin Yan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Weimao Ding
- Department of Hepatology, Huai’an No. 4 People’s Hospital, Huai’an, Jiangsu, China
| | - Xiaoxing Xiang
- Department of Gastroenterology, Northern Jiangsu People’s Hospital, Clinical Medical College of Yangzhou University, Yangzhou, Jiangsu, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
- Correspondence to: Chao Wu and Rui Huang, Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0002-1657-010X (CW), https://orcid.org/0000-0002-3189-7960 (RH). Tel: +86-25-8310-5890 (CW), +86-25-8310-6666-20201 (RH), Fax: +86-25-8330-7115 (CW), +86-25-8330-7115 (RH), E-mail: (CW), (RH)
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
- Correspondence to: Chao Wu and Rui Huang, Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0002-1657-010X (CW), https://orcid.org/0000-0002-3189-7960 (RH). Tel: +86-25-8310-5890 (CW), +86-25-8310-6666-20201 (RH), Fax: +86-25-8330-7115 (CW), +86-25-8330-7115 (RH), E-mail: (CW), (RH)
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Tseng TC, Liu CJ, Yang WT, Hsu CY, Hong CM, Su TH, Tsai CH, Chen CL, Yang HC, Liu CH, Chen HH, Chen PJ, Kao JH. Serum hepatitis B core-related antigen level stratifies risk of disease progression in chronic hepatitis B patients with intermediate viral load. Aliment Pharmacol Ther 2021; 53:908-918. [PMID: 33465271 DOI: 10.1111/apt.16266] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/27/2020] [Accepted: 01/04/2021] [Indexed: 12/23/2022]
Abstract
BACKGROUND Patients with chronic hepatitis B virus (HBV) infection are at risk of developing liver disease. Serum hepatitis B core-related antigen (HBcrAg) is a new biomarker for intrahepatic templates for HBV replication. AIM To explore whether a high HBcrAg level is associated with increased risk of cirrhosis, especially in patients with intermediate viral load (HBV DNA 2000-19 999 IU/mL) due to their moderate risk of disease progression. METHODS A total of 1673 treatment-naïve, non-cirrhotic patients with negative hepatitis B e antigen (HBeAg) and alanine aminotransferase (ALT) level <40 U/L at baseline were enrolled. We explored the relationship between baseline levels of HBcrAg and cirrhosis development in all patients, and whether a higher HBcrAg level (<10 vs ≥10 KU/mL) was associated with an increased risk of disease progression in those with intermediate viral load. RESULTS Of the 1673 patients, 104 developed cirrhosis after a mean follow-up of 15.9 years. Higher HBcrAg levels were associated with increased incidence of cirrhosis, cirrhosis-related complications, and liver-related death. In 445 patients with intermediate viral load, the cirrhosis risk stratified by HBcrAg level of 10 KU/mL yielded a hazard ratio of 3.22 (95% CI: 1.61-6.47). The risk stratification remained significant when exploring other pre-cirrhosis endpoints, including HBeAg-negative hepatitis, hepatitis flare, and HBV DNA >20 000 IU/mL after 3 years of follow-up. CONCLUSIONS In HBeAg-negative patients with normal ALT levels, higher HBcrAg levels are associated with increased risk of cirrhosis. Among those with intermediate viral load, HBcrAg <10 KU/mL defines a low-risk group for disease progression.
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Affiliation(s)
- Tai-Chung Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine Taipei, Taiwan
| | - Wan-Ting Yang
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chen-Yang Hsu
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chun-Ming Hong
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Division of Hospital Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Cheng-Hsueh Tsai
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine Taipei, Taiwan
| | - Hung-Chih Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine Taipei, Taiwan
- Department of Microbiology, National Taiwan University College of Medicine Taipei, Taiwan
| | - Chen-Hua Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsiu-Hsi Chen
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine Taipei, Taiwan
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Shehi E, Alemam A, Mantri N, Patel H. Terbinafine-Induced Hepatitis B Reactivation in a Patient With Chronic Hepatitis B. Cureus 2020; 12:e11958. [PMID: 33312827 PMCID: PMC7725446 DOI: 10.7759/cureus.11958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Reactivation of chronic inactive hepatitis B infection can be spontaneous or triggered by chemotherapy or immunosuppression. Although the pathophysiology behind this remains unclear, several mechanisms have been proposed in the literature. Data describing hepatitis B flares caused by other classes of medications are sparse. We describe a case of reactivation of chronic hepatitis B in a 48-year-old man, who presented with generalized weakness after initiating terbinafine for a fungal toenail infection. He was found to have deranged liver function tests and elevated hepatitis B viral load. Both resolved after discontinuation of terbinafine and starting tenofovir.
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Clinical utility of HBV surface antigen quantification in HBV e antigen-negative chronic HBV infection. Nat Rev Gastroenterol Hepatol 2019; 16:631-641. [PMID: 31477873 DOI: 10.1038/s41575-019-0197-8] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/25/2019] [Indexed: 12/17/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is a serious problem owing to its worldwide distribution and potential adverse sequelae that include cirrhosis and/or hepatocellular carcinoma. Current antiviral therapies have much improved outcomes, but few patients achieve the ultimate goal of hepatitis B surface antigen (HBsAg) loss (functional cure). As hepatitis B e antigen (HBeAg)-negative chronic HBV infection is the final phase prior to HBsAg loss, the management of patients in this phase together with quantification of HBsAg has attracted increasing clinical and research interest. This Review integrates the findings from research in HBsAg kinetics and discusses how they might inform our understanding and management of HBeAg-negative chronic HBV infection. Studies have shown that HBsAg levels are highly predictive of the presence of inactive HBV infection and that serial changes in HBsAg levels might predict HBsAg loss within 1-3 years. Data also suggest that quantitative HBsAg monitoring is important during hepatitis flare and antiviral therapy, especially in the timing of the decision to stop therapy and to start off-therapy retreatment. These findings have shed new light on the natural course of HBV infection and might lead to optimization of the management of HBeAg-negative chronic HBV infection and contribute to the paradigm shift from indefinite to finite therapy for patients with HBV infection.
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Choi GH, Kim GA, Choi J, Han S, Lim YS. High risk of clinical events in untreated HBeAg-negative chronic hepatitis B patients with high viral load and no significant ALT elevation. Aliment Pharmacol Ther 2019; 50:215-226. [PMID: 31135074 DOI: 10.1111/apt.15311] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 12/30/2018] [Accepted: 04/29/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND It remains unknown whether antiviral treatment for HBeAg-negative chronic hepatitis B (CHB) patients having high viral loads without significant elevation of alanine aminotransferase (ALT) levels would reduce the risks of clinical events. AIM To compare clinical outcomes of high viral load CHB patients untreated for normal or mildly elevated ALT vs those treated for ALT ≥ 2 upper limit of normal (ULN). METHODS This historical cohort study included 5414 HBeAg-negative CHB patients without cirrhosis at a tertiary hospital in Korea from 2000 to 2013. Inactive phase was defined as serum hepatitis B virus [HBV] DNA < 2000 IU/mL and persistently normal ALT (n = 3572). High viral load (HBV DNA ≥ 2000 IU/mL) patients were classified into three phases by ALT levels: Replicative (persistently normal ALT, n = 900); Mildly active (ALT 1-2ULN, n = 396); and Active (ALT ≥ 2ULN, n = 546) phases. All Active phase patients were treated with nucleos(t)ide analogues. RESULTS The mean age of the patients was 47 years without a significant difference among the groups. Compared with the treated Active phase group, the untreated Replicative phase group showed a significantly higher risk of hepatocellular carcinoma (HCC; HR 1.76; 95% CI 1.00 - 3.10, P = 0.05) and death/transplantation (HR 2.14; 5% CI 1.09 - 4.21, P = 0.03) by propensity score-matched analysis. The untreated mildly active phase patients had further increase in risk of HCC and death/transplantation compared with the treated Active phase group by unadjusted, PS-matched, competing risks, and multivariable-adjusted analyses. CONCLUSIONS Untreated high viral load HBeAg-negative CHB patients without significant ALT elevation had higher risks of clinical events than treated Active phase patients with elevated ALT.
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Affiliation(s)
- Gwang Hyeon Choi
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Gi-Ae Kim
- Departments of Internal Medicine, Kyung Hee University Medical Center, Kyung Hee University School of Medicine, Seoul, Republic of Korea
| | - Jonggi Choi
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seungbong Han
- Department of Applied Statistics, Gachon University, SeongNam, Republic of Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Mf Akbar S, Al-Mahtab M, I Khan S. Nature of Host Immunity during Hepatitis B Virus Infection and designing Immune Therapy. Euroasian J Hepatogastroenterol 2018; 8:42-46. [PMID: 29963460 PMCID: PMC6024052 DOI: 10.5005/jp-journals-10018-1256] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 02/14/2018] [Indexed: 12/23/2022] Open
Abstract
Hepatitis B virus (HBV) infections represent one of the major public health problems in global context. More than 2 billion people in the world have been infected with this virus at some point of time in their life and millions are chronically infected, indicating that chronic HBV-infected subjects remain as a living source of HBV transmission. The public health impact of this is tremendous. Considerable numbers of chronic HBV-infected individuals would eventually develop progressive liver diseases and their complications like hepatic failure, liver cirrhosis (LC), and hepatocellular carcinoma (HCC). Epidemiological studies have suggested that about 0.6 to 1.2 million people die annually from HBV-related liver diseases. These figures about death due to HBV and sufferings from HBV-related diseases indicate a notion of medical emergencies about HBV. In addition to these, the impact of HBV on health care delivery system moves beyond these numbers of HBV-related patients and HB-related deaths. This is because significant insights have already been developed about epidemiology, virology, and pathogenesis of HBV. Also, an effective and widely used preventive vaccine is available against HBV. In addition to these, antiviral drugs against HBV have been developed from early 1980s and several such drugs are now available commercially in the open market around the worldwide. Unfortunately, the ongoing therapeutic regimens could not stand the test of time and new insights about HBV pathogenesis are required for the development of new, novel, and evidence-based therapies for chronic HBV infections. How to cite this article: Akbar SMF, Al-Mahtab M, Khan SI. Nature of Host Immunity during Hepatitis B Virus Infection and designing Immune Therapy. Euroasian J Hepato-Gastroenterol 2018;8(1):42-46.
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Affiliation(s)
- Sheikh Mf Akbar
- Department of Medical Sciences, Toshiba General Hospital, Tokyo, Japan and Miyakawa Memorial Research Foundation, Tokyo Japan
| | - Mamun Al-Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Sakirul I Khan
- Department of Anatomy and Embryology, Graduate School of Medicine, Ehime University, Ehime, Japan
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Chen YL, Mo YQ, Zheng DH, Ma JD, Jing J, Dai L. Patients with Coexistence of Circulating Hepatitis B Surface Antigen and Its Antibody May Have a Strong Predisposition to Virus Reactivation During Immunosuppressive Therapy: A Hypothesis. Med Sci Monit 2017; 23:5980-5985. [PMID: 29248936 PMCID: PMC5742491 DOI: 10.12659/msm.905033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Hepatitis B virus (HBV) reactivation is a well-recognized complication in patients who undergo immunosuppressive drug therapy. Although the recommendation of antiviral prophylaxis made by the American Gastroenterological Association in 2015 focuses on the risk stratification of different immunosuppressive drugs, risk factors for HBV reactivation are also worth identifying in clinical practice. Recent studies have shown that the uncommon serological pattern of coexistent circulating HBV surface antigen (HBsAg) and its antibody (anti-HBs) was associated with double mutations (A1762T/G1764A) in the basal core promoter (BCP) region of the HBV genome, which is critical for HBV replication. Here, we depicted rheumatoid arthritis (RA) patients with coexistent HBsAg and anti-HBs in our medical center, who developed HBV reactivation during immunosuppressive drug therapy. DNA sequencing analysis of the HBV genome revealed triple mutations (A1762T, G1764A, and T1753V) in the BCP region, which could further enhance the ability of HBV replication. Hence, a novel hypothesis is advanced for the first time that patients with coexistent HBsAg and anti-HBs may have a strong predisposition to HBV reactivation due to specific BCP mutations. This hypothesis would, if correct, justify the concurrent detection of HBsAg and anti-HBs in HBV screening in patients with rheumatic diseases and quickly recognize patients with high risk of HBV reactivation. Further controlled studies are needed to confirm this hypothesis.
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Affiliation(s)
- Yu-Lan Chen
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China (mainland)
| | - Ying-Qian Mo
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China (mainland)
| | - Dong-Hui Zheng
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China (mainland)
| | - Jian-Da Ma
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China (mainland)
| | - Jun Jing
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China (mainland)
| | - Lie Dai
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China (mainland)
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Li M, Chen L, Liu LM, Li YL, Li BA, Li B, Mao YL, Xia LF, Wang T, Liu YN, Li Z, Guo TS. Performance verification and comparison of TianLong automatic hypersensitive hepatitis B virus DNA quantification system with Roche CAP/CTM system. World J Gastroenterol 2017; 23:6845-6853. [PMID: 29085227 PMCID: PMC5645617 DOI: 10.3748/wjg.v23.i37.6845] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 08/01/2017] [Accepted: 08/15/2017] [Indexed: 02/07/2023] Open
Abstract
AIM To investigate and compare the analytical and clinical performance of TianLong automatic hypersensitive hepatitis B virus (HBV) DNA quantification system and Roche CAP/CTM system.
METHODS Two hundred blood samples for HBV DNA testing, HBV-DNA negative samples and high-titer HBV-DNA mixture samples were collected and prepared. National standard materials for serum HBV and a worldwide HBV DNA panel were employed for performance verification. The analytical performance, such as limit of detection, limit of quantification, accuracy, precision, reproducibility, linearity, genotype coverage and cross-contamination, was determined using the TianLong automatic hypersensitive HBV DNA quantification system (TL system). Correlation and Bland-Altman plot analyses were carried out to compare the clinical performance of the TL system assay and the CAP/CTM system.
RESULTS The detection limit of the TL system was 10 IU/mL, and its limit of quantification was 30 IU/mL. The differences between the expected and tested concentrations of the national standards were less than ± 0.4 Log10 IU/mL, which showed high accuracy of the system. Results of the precision, reproducibility and linearity tests showed that the multiple test coefficient of variation (CV) of the same sample was less than 5% for 102-106 IU/mL; and for 30-108 IU/mL, the linear correlation coefficient r2 = 0.99. The TL system detected HBV DNA (A-H) genotypes and there was no cross-contamination during the “checkerboard” test. When compared with the CAP/CTM assay, the two assays showed 100% consistency in both negative and positive sample results (15 negative samples and 185 positive samples). No statistical differences between the two assays in the HBV DNA quantification values were observed (P > 0.05). Correlation analysis indicated a significant correlation between the two assays, r2 = 0.9774. The Bland-Altman plot analysis showed that 98.9% of the positive data were within the 95% acceptable range, and the maximum difference was -0.49.
CONCLUSION The TL system has good analytical performance, and exhibits good agreement with the CAP/CTM system in clinical performance.
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Affiliation(s)
- Ming Li
- School of Mechanical Engineering, Xi’an Jiaotong University. Xi’an 710049, Shaanxi Province, China
- Xi’an TianLong Science and Technology Co., Ltd., Xi’an 710018, Shaanxi Province, China
| | - Lin Chen
- Center of Clinical Laboratory Medicine, 302 Military Hospital of China, Beijing 100039, China
| | - Li-Ming Liu
- Department of Laboratory Medicine, Beijing Xiaotangshan Hospital, Beijing 102211, China
| | - Yong-Li Li
- Center of Clinical Laboratory Medicine, 302 Military Hospital of China, Beijing 100039, China
| | - Bo-An Li
- Center of Clinical Laboratory Medicine, 302 Military Hospital of China, Beijing 100039, China
| | - Bo Li
- Center of Clinical Laboratory Medicine, 302 Military Hospital of China, Beijing 100039, China
| | - Yuan-Li Mao
- Center of Clinical Laboratory Medicine, 302 Military Hospital of China, Beijing 100039, China
| | - Li-Fang Xia
- Center of Clinical Laboratory Medicine, 302 Military Hospital of China, Beijing 100039, China
| | - Tong Wang
- Center of Clinical Laboratory Medicine, 302 Military Hospital of China, Beijing 100039, China
| | - Ya-Nan Liu
- Center of Clinical Laboratory Medicine, 302 Military Hospital of China, Beijing 100039, China
| | - Zheng Li
- Xi’an TianLong Science and Technology Co., Ltd., Xi’an 710018, Shaanxi Province, China
| | - Tong-Sheng Guo
- Center of Clinical Laboratory Medicine, 302 Military Hospital of China, Beijing 100039, China
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Hsieh AR, Fann CSJ, Yeh CT, Lin HC, Wan SY, Chen YC, Hsu CL, Tai J, Lin SM, Tai DI. Effects of sex and generation on hepatitis B viral load in families with hepatocellular carcinoma. World J Gastroenterol 2017; 23:876-884. [PMID: 28223732 PMCID: PMC5296204 DOI: 10.3748/wjg.v23.i5.876] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 12/14/2016] [Accepted: 01/04/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To explore factors associated with persistent hepatitis B virus (HBV) infection in a cohort of hepatocellular carcinoma (HCC)-affected families and then investigate factors that correlate with individual viral load among hepatitis B surface antigen (HBsAg)-positive relatives. METHODS We evaluated non-genetic factors associated with HBV replication in relatives of patients with HCC. Relatives of 355 HCC cases were interviewed using a structured questionnaire. Demographics, relationship to index case, HBsAg status of mothers and index cases were evaluated for association with the HBV persistent infection or viral load by generalized estimating equation analysis. RESULTS Among 729 relatives enrolled, parent generation (P = 0.0076), index generation (P = 0.0044), mothers positive for HBsAg (P = 0.0007), and HBsAg-positive index cases (P = 5.98 × 10-8) were associated with persistent HBV infection. Factors associated with HBV viral load were evaluated among 303 HBsAg-positive relatives. Parent generation (P = 0.0359) and sex (P = 0.0007) were independent factors associated with HBV viral load. The intra-family HBV viral load was evaluated in families clustered with HBsAg-positive siblings. An intra-family trend of similar HBV viral load was found for 27 of 46 (58.7%) families. Male offspring of HBsAg-positive mothers (P = 0.024) and older siblings were associated with high viral load. CONCLUSION Sex and generation play important roles on HBV viral load. Maternal birth age and nutritional changes could be the reasons of viral load difference between generations.
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Akbar SMF, Al-Mahtab M, Khan MSI, Raihan R, Shrestha A. Immune therapy for hepatitis B. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:335. [PMID: 27761439 DOI: 10.21037/atm.2016.08.48] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Although several antiviral drugs are now available for treatment of patients with chronic hepatitis B (CHB), sustained off-treatment clinical responses and containment of CHB-related complications are not achieved in majority of CHB patients by antiviral therapy. In addition, use of these drugs is endowed with substantial long term risk of viral resistance and drug toxicity. The infinite treatment regimens of antiviral drugs for CHB patients are also costly and usually unbearable by most patients of developing and resource-constrained countries. Taken together, there is a pressing need to develop new and innovative therapeutic approaches for CHB patients. Immune therapy seems to be an alternate therapeutic approach for CHB patients because impaired or distorted or diminished immune responses have been detected in most of these patients. Also, investigators have shown that restoration or induction of proper types of immune responses may have therapeutic implications in CHB. Various immunomodulatory agents have been used to treat patients with CHB around the world and the outcomes of these clinical trials show that the properties of immune modulators and nature and designing of immune therapeutic regimens seem to be highly relevant in the context of treatment of CHB patients. In this review, the general properties and specific features of immune therapy for CHB have been discussed for developing the guidelines of effective regimens of immune therapy for CHB.
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Affiliation(s)
| | - Mamun Al-Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Md Sakilur Islam Khan
- Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Ruksana Raihan
- Department of Virology, AIMST University, Semeling, Bedong, Kedah, Malaysia
| | - Ananta Shrestha
- Department of Hepatology, The Liver Clinic, Liver Foundation, Kathmandu, Nepal
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Tseng TC, Liu CJ, Chen CL, Yang HC, Su TH, Wang CC, Yang WT, Kuo SFT, Liu CH, Chen PJ, Chen DS, Kao JH. Risk stratification of hepatocellular carcinoma in hepatitis B virus e antigen-negative carriers by combining viral biomarkers. J Infect Dis 2013; 208:584-593. [PMID: 23656977 DOI: 10.1093/infdis/jit209] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The serum hepatitis B virus (HBV) surface antigen (HBsAg) level can predict hepatocellular carcinoma (HCC) development in hepatitis B e antigen (HBeAg)-negative patients with an HBV DNA level of <2000 IU/mL. However, little is known regarding how well the combination of both viral biomarkers stratifies HCC risk. METHODS A total of 2165 Taiwanese HBeAg-negative noncirrhotic patients were followed for 14.9 years. The predictive power of the HBsAg level for HCC was analyzed for different viral load ranges. RESULTS In patients with HBV DNA levels of 2000-19 999 IU/mL (intermediate viral load), a positive correlation between HBsAg level and HCC development was identified after adjustment for other risk factors (P = .002). In contrast, no association was found between HBsAg level and HCC in patients with higher viral loads. HBsAg level was subsequently included to stratify HCC risk in patients with low and intermediate viral loads. Receiver operating characteristic curve analysis showed that combining HBV DNA and HBsAg level better predicts 10-year HCC development as compared to using HBV DNA level alone in the overall cohort (P = .028). CONCLUSIONS Serum HBsAg level helps stratify HCC risk in patients with intermediate viral loads. Combining HBV DNA and HBsAg levels better predicts HCC risk.
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Affiliation(s)
- Tai-Chung Tseng
- Division of Gastroenterology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital Taipei Branch, New Taipei, Taiwan
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Posthepatectomy HBV reactivation in hepatitis B-related hepatocellular carcinoma influences postoperative survival in patients with preoperative low HBV-DNA levels. Ann Surg 2013; 257:490-505. [PMID: 22868358 DOI: 10.1097/sla.0b013e318262b218] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE This study aimed to clarify the incidence of hepatitis B virus (HBV) reactivation and its significance on long-term survival after partial hepatectomy in patients with HBV-related hepatocellular carcinoma (HCC), who had preoperative low HBV-DNA level of less than 2000 IU/mL. BACKGROUND HBV reactivation is a frequent complication of systemic chemotherapy in hepatitis B surface antigen-positive patients. Surgery and anesthesia result in a generalized state of immunosuppression in the immediate postoperative period. Data on HBV reactivation and its significance after partial hepatectomy are unclear. PATIENTS AND METHODS Consecutive patients from January 2006 to December 2007 were retrospectively studied. RESULTS HBV reactivation happened in 19.1% of patients in 1 year. There were 28 patients whose HBV reactivation was detected after the diagnosis of HCC recurrence. On multivariate analysis, hepatitis B e antigen (HBeAg) positivity, preoperative HBV-DNA above the lower limit of quantification (≥200 IU/mL), Ishak inflammation score of greater than 3, preoperative transarterial chemoembolization (TACE), operation time of more than 180 minutes, blood transfusion, and without prophylactic antiviral therapy were significantly associated with an increased risk of HBV reactivation. HBV reactivation negatively influenced postoperative hepatic functions. The posthepatectomy liver failure rate in patients with HBV reactivation was significantly higher than in those without reactivation (11.8% vs 6.4%; P = 0.002). The 3-year disease-free survival (DFS) rate and overall survival (OS) rates after resection in patients with HBV reactivation were significantly lower than those without reactivation (34.1% vs 46.0%; P = 0.009, and 51.6% vs 67.2%; P < 0.001, respectively). HBeAg positivity, detectable preoperative HBV-DNA level, high Ishak inflammation score, preoperative TACE, long operation time, and blood transfusion were independent risk factors for HBV reactivation, whereas prophylactic antiviral therapy was a protective factor. HBV reactivation, HBeAg positivity, HBV-DNA level of 200 IU/mL or more, tumor diameter greater than 5 cm, presence of satellite nodules, presence of portal vein tumor thrombus, blood transfusion, and resection margin less than 1.0 cm were independent risk factors for DFS. A HBV-DNA level of 200 IU/mL or more, an Ishak fibrosis score of 4 or greater, a tumor diameter greater than 5 cm, the presence of satellite nodules, the presence of portal vein tumor thrombus, a resection margin less than 1.0 cm, no prophylactic antiviral therapy, and HBV reactivation were independent risk factors for OS. CONCLUSIONS HBV reactivation was common after partial hepatectomy for HBV-related HCC with a preoperative low HBV-DNA level of less than 2000 IU/mL. Routine prophylactic antiviral treatment should be given before partial hepatectomy.
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Basal core promoter mutation is associated with progression to cirrhosis rather than hepatocellular carcinoma in chronic hepatitis B virus infection. Br J Cancer 2012; 107:2010-5. [PMID: 23079574 PMCID: PMC3516680 DOI: 10.1038/bjc.2012.474] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background: As most cases of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) have concurrent cirrhosis, viral factors identified to be associated with HCC might be related to cirrhosis rather than HCC. Methods: Hepatitis B virus DNA levels, genotypes and precore/basal core promoter (BCP) mutants were compared between cirrhotic HCC and non-cirrhotic HCC patients. Age- and sex-matched case–control studies were performed to identify the risk factors. Results: Hepatitis B virus DNA levels showed no significant difference betwen non-cirrhotic HCC patients (n=20) and cirrhotic HCC patients (n=140) or 1 : 3 age- and sex-matched cirrhotic HCC patients (n=60), but genotype C and BCP mutant were significantly more prevalent in the latter than in the former. In multiple logistic regression, BCP mutant but not genoype C correlated significantly with the presence of cirrhosis in HCC patients. Compared with inactive carriers (n=60), non-cirrhotic HCC patients (n=20) had significantly higher HBV DNA levels but no difference in HBV genotypes and precore/BCP mutants. Furthermore, HBV DNA levels, the distribution of HBV genotypes and the prevalence of precore/BCP mutants all failed to show any significant difference between cirrhotic HCC patients (n=60) and cirrhotic patients without HCC (n=60). Conclusion: Basal core promoter mutant is associated with progression to cirrhosis rather than HCC in chronic HBV infection.
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Abstract
Large volume of new data on the natural history and treatment of chronic hepatitis B virus (HBV) infection have become available since 2008. These include further studies in asymptomatic subjects with chronic HBV infection and community-based cohorts, the role of HBV genotype/naturally occurring HBV mutations, the application of non-invasive assessment of hepatic fibrosis and quantitation of HBV surface antigen and new drug or new strategies towards more effective therapy. To update HBV management guidelines, relevant new data were reviewed and assessed by experts from the region, and the significance of the reported findings was discussed and debated. The earlier "Asian-Pacific consensus statement on the management of chronic hepatitis B" was revised accordingly. The key terms used in the statement were also defined. The new guidelines include general management, indications for fibrosis assessment, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patients receiving immune suppression or chemotherapy and patients in the setting of liver transplantation and hepatocellular carcinoma, are also included.
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Chen YC, Huang SF, Chu CM, Liaw YF. Serial HBV DNA levels in patients with persistently normal transaminase over 10 years following spontaneous HBeAg seroconversion. J Viral Hepat 2012; 19:138-46. [PMID: 22239503 DOI: 10.1111/j.1365-2893.2011.01450.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Earlier studies addressing the hepatitis B virus (HBV) DNA cut-off level for inactive chronic HBV infection largely involved patients with normal alanine aminotransferase (ALT) for only 1-2 years and based on a single time HBV DNA assay. This study was conducted to address this issue using serial HBV DNA assays in patients with persistently normal ALT (PNALT) over 10 years following spontaneous hepatitis B e antigen (HBeAg) seroconversion. Serial serum specimens (mean 9 samples per patient) of 62 patients with PNALT and no disease progression over 10 years (median 18.1 years) after spontaneous HBeAg seroconversion were assayed for HBV DNA. Excluding assays within 1 year after HBeAg seroconversion, 21% and 82.3% of the patients with PNALT had HBV DNA levels persistently lower than 4 log(10) and 5 log(10) copies/mL, respectively, and only 8% had a level ≥ 5 log(10) copies/mL in at least two assays. Of the 27 patients with PNALT defined by ALT <30 U/L for male and <19 U/L for female, only 33% had serum HBV DNA level persistently <4 log(10) copies/mL. There was no significant difference in the serial HBV DNA changes among patients with different gender, HBV genotype or age at HBeAg seroconversion. Liver biopsy in nine patients invariably showed minimal necroinflammation and one showed Ishak fibrosis score 4. These results suggest that 5 log(10) copies/mL (20,000 IU/mL) is a more appropriate cut-off HBV DNA level for inactive chronic HBV infection in the setting of PNALT.
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Affiliation(s)
- Y-C Chen
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
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Atay AE, Seven G, Yalcin K, Pasa S, Degertekin H. Evaluation of hepatitis B viraemia levels in patients with HBeAg-negative chronic hepatitis B virus infection. J Int Med Res 2012; 40:1891-1896. [PMID: 23206472 DOI: 10.1177/030006051204000529] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
OBJECTIVES To evaluate patients with chronic hepatitis B virus (HBV) infection and low-level viraemia in terms of determining HBV DNA cut-off values and levels of alanine aminotransferase (ALT) and other possible markers for discriminating between chronic hepatitis B e-antigen (HBeAg)-negative patients and hepatitis B surface antigen (HBsAg) inactive carriers. METHODS HBV-infected patients who were HBeAg-negative with undetectable HBV DNA by standard hybridization assay and high (HBeAg-negative group, n = 81) or normal (HBsAg inactive carrier group, n = 77) ALT levels were enrolled. Quantitative polymerase chain reaction assay using a COBAS Amplicor HBV monitor test was performed to detect low HBV DNA levels. RESULTS The HBV DNA level was found to be significantly higher in the HBeAg-negative chronic HBV group (mean ± SD 94,477 ± 167,528 copies/ml) compared with the HBsAg inactive carrier group (mean ± SD 19,215 ± 57,970 copies/ml). CONCLUSIONS A low level of viral replication may persist in chronic HBV-infected patients who are HBeAg-negative, and the level of HBV DNA was higher in the HBeAg-negative group than in the inactive HBsAg carrier group. Necroinflammation also persisted in the HBeAg-negative group and these patients had a higher level of ALT than the inactive HBsAg carriers.
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Affiliation(s)
- A E Atay
- Department of Internal Medicine, Baglar Hospital, Diyarbakir, Turkey.
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Tseng TC, Liu CJ, Chen CL, Wang CC, Su TH, Kuo SFT, Chen PJ, Chen DS, Kao JH. Serum Hepatitis B Virus-DNA Levels Correlate With Long-term Adverse Outcomes in Spontaneous Hepatitis B e Antigen Seroconverters. J Infect Dis 2012; 205:54-63. [DOI: 10.1093/infdis/jir687] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
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Viral load, genotypes, and mutants in hepatitis B virus-related hepatocellular carcinoma: special emphasis on patients with early hepatocellular carcinoma. Dig Dis Sci 2012; 57:232-8. [PMID: 21837473 DOI: 10.1007/s10620-011-1844-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Accepted: 07/19/2011] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS The role of viral factors in the pathogenesis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is still inconclusive. Whether virological features such as viral load or mutants might change with the progression of HCC remains unknown. A case-control study including patients with early HCC and HBsAg carriers who are presumed to be at the minimal potential of HCC as controls might better identify factors significantly associated with HCC development. METHODS Virological features were compared between 59 patients with early HCC (a solitary tumor of size ≤ 3 cm) and 101 patients with non-early HCC. A case-control study was performed by comparing 59 patients with early HCC and 1:2 age-matched inactive carriers with persistent normal alanine aminotransferase (ALT) levels. RESULTS HBV DNA levels, HBV genotypes, and the frequency of precore A1896 and basal core promoter T1762/A1764 mutations showed no significant difference between patients with early HCC and those with non-early HCC. In the case-control study, patients with early HCC had significantly higher HBV DNA levels, and higher frequencies of genotype C HBV and basal core promoter T1762/A1764 mutation, but a similar frequency of precore A1896 mutation. Multiple logistic regression analysis identified HBV DNA levels ≥ 2,000 IU/mL and basal core promoter T1762/A1764 mutation as being independent factors for HCC development. Additionally, there was a synergistic effect between high viral load and basal core promoter T1762/A1764 mutation on HCC development. CONCLUSIONS Virological features did not change significantly with the progression of HCC. HBV DNA levels ≥ 2,000 IU/mL and basal core promoter T1762/A1764 mutation were two independent viral factors for HCC.
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Andreani T. HBV-carriers: When is monitoring and surveillance sufficient? (point of view). Clin Res Hepatol Gastroenterol 2011; 35:813-8. [PMID: 21821479 DOI: 10.1016/j.clinre.2011.06.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2011] [Revised: 06/13/2011] [Accepted: 06/24/2011] [Indexed: 02/04/2023]
Abstract
Medications currently available for the treatment of hepatitis B virus (HBV) infection are highly effective but not curative. The current paradigm is to recognize patients who require long-term treatment (with its inconveniences) among the majority of healthy carriers who do not need treatment. International guidelines have been established to identify patients requiring treatment but differences concerning the cut-off levels for viral load and transaminases, or need for liver biopsy, compromise their interpretation. IMMUNE TOLERANCE PHASE: Patients with strictly defined typical forms (HBeAg-positive, normal transaminases level, very high viral load HBV-DNA more than 2 × 10(6) IU) have very limited liver injury and do not require treatment. Patients with atypical forms (low viral load HBV-DNA less than 2 × 10(6) IU) have a potential risk of more severe histological lesions, but the need for liver biopsy and treatment remains a matter of debate. Immune tolerant patients aged over 40 years should be treated because of the higher risk of hepatocellular carcinoma, even without cirrhosis. ACTIVE PHASE HBEAG-POSITIVE OR NEGATIVE: Typical forms with elevated viral load and transaminases level should be treated. Mild hepatitis with moderately elevated transaminases levels (1-2 times upper limit of normal) can cause variable degrees of liver damage, and liver biopsy is necessary. HBeAg-positive hepatitis with very high transaminases levels have a very high rate of spontaneous HBe seroconversion. Hepatitis with high transaminases levels but low viral (HBV-DNA less than 2000 UI) is possible in HBe-negative patients but unusual in HBe-positive patients. Another cause of liver disease could be involved (hepatitis D, steatosis, alcohol). INACTIVE PHASE: In the typical form, patients have a normal transaminases level and HBV-DNA less than 2000 IU; histological lesions are in general minimal. Treatment is not indicated. Atypical forms with normal transaminases levels but elevated HBV-DNA more than 2000 IU remain problematic. Forms with high-normal transaminases levels have a higher risk of complications. In the event of inactive cirrhosis, treatment is indicated if replication persists, even at a low level.
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Affiliation(s)
- Tony Andreani
- Service d'hépatologie, faculté de médecine Pierre-et-Marie-Curie, hôpital Saint-Antoine, Assistance publique-Hôpitaux de Paris, 184, rue du Faubourg-Saint-Antoine, 75571 Paris cedex 12, France.
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