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Cornberg M, Sandmann L, Jaroszewicz J, Kennedy P, Lampertico P, Lemoine M, Lens S, Testoni B, Lai-Hung Wong G, Russo FP. EASL Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2025:S0168-8278(25)00174-6. [PMID: 40348683 DOI: 10.1016/j.jhep.2025.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Accepted: 03/20/2025] [Indexed: 05/14/2025]
Abstract
The updated EASL Clinical Practice Guidelines on the management of hepatitis B virus (HBV) infection provide comprehensive, evidence-based recommendations for its management. Spanning ten thematic sections, the guidelines address diagnostics, treatment goals, treatment indications, therapeutic options, hepatocellular carcinoma surveillance, management of special populations, HBV reactivation prophylaxis, post-transplant care, HBV prevention strategies, and finally address open questions and future research directions. Chronic HBV remains a global health challenge, with over 250 million individuals affected and significant mortality due to cirrhosis and hepatocellular carcinoma. These guidelines emphasise the importance of early diagnosis, risk stratification based on viral and host factors, and tailored antiviral therapy. Attention is given to simplified algorithms, vaccination, and screening to support global HBV elimination targets. The guidelines also discuss emerging biomarkers and evolving definitions of functional and partial cure. Developed through literature review, expert consensus, and a Delphi process, the guidelines aim to equip healthcare providers across disciplines with practical tools to optimise HBV care and outcomes worldwide.
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Shechter O, Sausen DG, Dahari H, Vaillant A, Cotler SJ, Borenstein R. Functional Cure for Hepatitis B Virus: Challenges and Achievements. Int J Mol Sci 2025; 26:3633. [PMID: 40332208 PMCID: PMC12026623 DOI: 10.3390/ijms26083633] [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: 02/24/2025] [Revised: 03/31/2025] [Accepted: 04/04/2025] [Indexed: 05/08/2025] Open
Abstract
The Hepatitis B Virus (HBV) presents a formidable global health challenge, impacting hundreds of millions worldwide and imposing a considerable burden on healthcare systems. The elusive nature of the virus, with its ability to establish chronic infection and evade immune detection, and the absence of curative agents have prompted efforts to develop novel therapeutic approaches beyond current antiviral treatments. This review addresses the challenging concept of a functional cure for HBV, a state characterized by the suppression of HBV and HBsAg, mitigating disease progression and transmission without a complete cure. We provide an overview of HBV epidemiology and its clinical impact, followed by an exploration of the current treatment landscape and its limitations. The immunological basis of a functional cure is then discussed, exploring the intricate interplay between the virus and the host immune response. Emerging therapeutic approaches, such as RNA interference-based interventions, entry inhibitors, nucleic acid polymers, and therapeutic vaccines, are discussed with regard to their success in achieving a functional cure. Lastly, the review underscores the urgent need for innovative strategies to achieve a functional cure for HBV.
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Affiliation(s)
- Oren Shechter
- Eastern Virginia Medical School, Norfolk, VA 23501, USA;
| | | | - Harel Dahari
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA; (H.D.); (S.J.C.)
| | - Andrew Vaillant
- Replicor Inc., 6100 Royalmount Ave., Montreal, QC H4P 2R2, Canada;
| | - Scott J. Cotler
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA; (H.D.); (S.J.C.)
| | - Ronen Borenstein
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA; (H.D.); (S.J.C.)
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Mon HC, Lee PC, Chi CT, Huang YH. Effect of immune checkpoint inhibitors on patients with hepatitis B virus infection. J Chin Med Assoc 2025; 88:93-97. [PMID: 39726106 DOI: 10.1097/jcma.0000000000001202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2024] Open
Abstract
Hepatitis B virus (HBV) infection is regarded as a major health concern worldwide. In patients with chronic HBV infection, exhausted virus-specific CD8+ T cells, resulting from the activation of the programmed cell death protein 1 and programmed death ligand 1 axis, play a key role in the chronicity of infection. Functional cure for HBV, defined as the seroclearance of hepatitis B surface antigen (HBsAg), is viewed as the optimal goal of chronic HBV infection treatment because HBsAg loss is associated with a low risk of hepatocellular carcinoma and a relatively favorable prognosis. Both interferon treatment and finite antiviral therapy are associated with positive HBV outcomes. Overall, combining immune checkpoint inhibitors with nucleos(t)ide analogs appears to be a promising approach for achieving HBsAg loss, particularly in patients with low HBsAg levels.
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Affiliation(s)
- Hsien-Chen Mon
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Pei-Chang Lee
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chen-Ta Chi
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yi-Hsiang Huang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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Gu S, Tang L, Guo L, Zhong C, Fu X, Ye G, Zhong S, Li X, Wen C, Zhou Y, Wei J, Chen H, Novikov N, Fletcher SP, Moody MA, Hou J, Li Y. Circulating HBsAg-specific B cells are partially rescued in chronically HBV-infected patients with functional cure. Emerg Microbes Infect 2024; 13:2409350. [PMID: 39470771 PMCID: PMC11523254 DOI: 10.1080/22221751.2024.2409350] [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: 07/13/2024] [Revised: 09/09/2024] [Accepted: 09/23/2024] [Indexed: 11/01/2024]
Abstract
It is well established that humoral immunity targeting hepatitis B virus surface antigen (HBsAg) plays a critical role in viral clearance and clinical cure. However, the functional changes in HBsAg-specific B cells before and after achieving functional cure remain poorly understood. In this study, we characterized circulating HBsAg-specific B cells and identified functional shifts and B-cell epitopes directly associated with HBsAg loss. The phenotypes and functions of HBV-specific B cells in patients with chronic HBV infection were investigated using a dual staining method and the ELISpot assay. Epitope mapping was performed to identify B cell epitopes associated with functional cure. Hyperactivated HBsAg-specific B cells in patients who achieved HBsAg loss were composed of enriched resting memory and contracted atypical memory fractions, accompanied by sustained co-expression of multiple inhibitory receptors and increased IL-6 secretion. The frequency of HBsAb-secreting B cells was significantly increased after achieving a functional cure. The rHBsAg displayed a weaker immunomodulatory effect on B cells than rHBeAg and rHBcAg in vitro. Notably, sera from patients with HBsAg loss reacted mainly with peptides S60, S61, and S76, suggesting that these are dominant linear B-cell epitopes relevant for functional cure. Intriguingly, patients reactive with S76 showed a higher frequency of the HLA class II DQB1*05:01 allele. Taken together, HBsAg-specific B cells were partially restored in patients after achieving a functional cure. Functional cure-related epitopes may be promising targets for developing therapeutic vaccines to treat HBV infection and promote functional cure.
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Affiliation(s)
- Shuqin Gu
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
- Infectious Diseases Division, Department of Pediatrics, Duke University, Durham, NC, USA
| | - Libo Tang
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
| | - Ling Guo
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
- Department of Infectious Diseases, Peking University Shenzhen Hospital, Shenzhen, China
| | - Chunxiu Zhong
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
| | - Xin Fu
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
| | - Guofu Ye
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
| | - Shihong Zhong
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
| | - Xiaoyi Li
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
- UNC HIV Cure Center, Institute of Global Health and Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Chunhua Wen
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
- Department of Hematology, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Yang Zhou
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
- Infectious Diseases Division, Department of Pediatrics, Duke University, Durham, NC, USA
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Jinling Wei
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-sen University, Guangzhou, China
| | - Haitao Chen
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Nikolai Novikov
- Department of Biology, Gilead Sciences, Foster City, CA, USA
| | | | - M. Anthony Moody
- Infectious Diseases Division, Department of Pediatrics, Duke University, Durham, NC, USA
- Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC, USA
| | - Jinlin Hou
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
| | - Yongyin Li
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
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Mahajan A, Kharawala S, Desai S, Kendrick S, Das J, Gielen V. Association of Hepatitis B Surface Antigen Levels With Long-Term Complications in Chronic Hepatitis B Virus Infection: A Systematic Literature Review. J Viral Hepat 2024; 31:746-759. [PMID: 39150061 DOI: 10.1111/jvh.13988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 07/09/2024] [Accepted: 07/17/2024] [Indexed: 08/17/2024]
Abstract
Chronic hepatitis B virus (HBV) infection is a global issue and can lead to cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B surface antigen (HBsAg) is an important marker of HBV infection and HBsAg quantification could be a useful tool in clinical practice. This systematic literature review aimed to explore the association between HBsAg titres and long-term disease outcomes and evaluate the relationship between HBsAg titres, or changes in HBsAg titres, and clinical and treatment characteristics in patients with chronic HBV infection. Structured searches were performed in MEDLINE and Embase (January 2000 to 31 March 2023). Eighty-two studies were included, comprising 51% retrospective cohort studies, mostly conducted in Asia (85%). HBsAg levels were shown to predict the long-term development of cirrhosis and HCC in patients who were untreated prior to and during follow-up; however, these data were inconclusive in mixed and treated populations. HBsAg titres were significantly associated with various virological markers including serum HBV DNA, HBcrAg, HBeAg, HBV RNA levels, intrahepatic covalently closed circular DNA (cccDNA) and intrahepatic HBsAg expression. HBsAg titres generally declined over time; this decline was more pronounced in early (HBeAg-positive) than later disease phases (HBeAg-negative). Higher decline in HBsAg levels was consistently associated with subsequent HBsAg seroclearance and a greater decline in total intrahepatic HBV DNA and cccDNA levels. In conclusion, this review showed that HBsAg levels and rates of decline could inform assessment, management and prediction of outcomes in chronic HBV infection. Further studies in broader, more diverse populations and treated patients are needed.
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Affiliation(s)
| | | | | | | | - Joyeta Das
- Research and Development, GSK, Brentford, Middlesex, UK
| | - Vera Gielen
- Research and Development, GSK, Brentford, Middlesex, UK
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Koroglu M, Ayvaz MA, Bakan SB, Sirin A, Akyuz U. Can quantitative surface antigen levels and systemic immune-inflammation index be predictive as a new indicator for the initiation of treatment in chronic hepatitis b? Eur J Gastroenterol Hepatol 2024; 36:489-497. [PMID: 38407853 DOI: 10.1097/meg.0000000000002737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/27/2024]
Abstract
OBJECTIVES The natural history of chronic HBV infection (CHB) is generally divided into four phases: HBeAg-positive chronic HBV infection (EPCI) and -hepatitis (EPCH), HBeAg-negative chronic HBV infection (ENCI) and -hepatitis (ENCH). This study aimed to investigate changes in serum quantitative surface antigen (qHBsAg), systemic immune-inflammation index (SII) and systemic inflammatory response index (SIRI) in a large number of CHB patients. METHOD Three hundred seventy-two CHB patients who underwent liver biopsy between January 2015 and February 2020 were evaluated. RESULTS The SII-values were strongly significant between EPCI-EPCH ( P = 0.002), however, there was significant difference between ENCI-ENCH ( P = 0.025). Considering the SIRI results, there was a significant difference between both EPCI-EPCH ( P = 0.009) and ENCI-ENCH ( P = 0.118). In HBeAg-positive patients HBV-DNA, qHBsAg, and SII were found to be predictive ( P = 0.029, P = 0.039, P = 0.027, respectively) while in HBeAg-negative patients, age, AST, HBV-DNA, qHBsAg, SII, and SIRI were found to be predictive ( P = 0.047, P = 0.084, P = <0.001, P = 0.001, P = 0.012, P = 0.002, respectively). In EPCH phase, whereby accuracy rate results of HBV-DNA, qHBsAg, and SII were 75.3%, 73.4%, and 60.4%, respectively, while in the ENCH phase the accuracy rates of age, AST, HBV-DNA, qHBsAg, SII, and SIRI values were 57.8%, 65.6%, 68.3%, 63.8%, 57.3% and 53.2%, respectively. CONCLUSION HBV-DNA, qHBsAg, and SII are predictive in EPCH patients. Age, AST, HBV-DNA, qHBsAg, SII and SIRI are all predictive in ENCH patients. In patients with CHB, we recommend using SII to distinguish between EPCI-EPCH and ENCI-ENCH. Based on its sensitivity and features, we believe that qHBsAg and SII are suitable measuring instruments in discrimination both of EPCI-EPCH and ENCI-ENCH.
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Affiliation(s)
- Mehmet Koroglu
- University of Health Sciences, Fatih Sultan Mehmet Training and Research Hospital, Department of Gastroenterology, Istanbul, Turkey
| | - Muhammed Ali Ayvaz
- Klinikum Fuessen, Department of Gastroenterology, Teaching hospital of the Ludwig-Maximilian University, Munich, Germany
| | - Suat Baran Bakan
- University of Health Sciences, Fatih Sultan Mehmet Training and Research Hospital, Department of Internal Medicine, Istanbul
| | - Abdullatif Sirin
- Duzce University Hospital, Department of Gastroenterology, Duzce
| | - Umit Akyuz
- University of Health Sciences, Fatih Sultan Mehmet Training and Research Hospital, Department of Gastroenterology, Istanbul, Turkey
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Wen C, Wang Y, Tian H, Lei Y, Wang Z, Cai D, Zhou Z, Shi X. Clinical cure induced by pegylated interferon α-2b in the advantaged population of chronic hepatitis B virus infection: a retrospective cohort study. Front Cell Infect Microbiol 2024; 13:1332232. [PMID: 38292859 PMCID: PMC10824921 DOI: 10.3389/fcimb.2023.1332232] [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: 11/02/2023] [Accepted: 12/22/2023] [Indexed: 02/01/2024] Open
Abstract
Background Among the advantaged population with clinical cure of chronic hepatitis B, chronic inactive hepatitis B virus carriers (IHCs) and nucleoside analog-experienced patients have similar serological manifestations. This study established non-interferon-treated groups as controls to compare the efficacy of pegylated interferon α-2b (Peg-IFNα-2b) in achieving clinical cure between IHCs and nucleoside analog (NA)-experienced patients. Method A total of 270 patients were enrolled in this observational study. The IHC cohort comprised 55 patients who received Peg-IFNα-2b (Peg-IFN group), and the other 70 patients did not receive any antiviral treatment (untreated group). Patients treated with NAs were divided into two groups: one group (70 patients) receiving NA add-on Peg-IFNα-2b therapy regimen (NA add-on Peg-IFN group) and another group (75 patients) receiving continuous NA monotherapy (NA group). The primary endpoints were hepatitis B surface antigen (HBsAg) clearance and HBsAg seroconversion at 48 weeks and 72 weeks. Results At 48 weeks, 65.5% (36/55) and 52.9% (37/70) patients achieved HBsAg clearance in the Peg-IFN group and NA add-on Peg-IFN group, respectively (p = 0.156). HBsAg seroconversion was achieved in 47.3% (26/55) of the Peg-IFN group and 34.3% (24/70) of the NA add-on Peg-IFN group (p = 0.141). At the follow-up of 72 weeks, 36 patients in the Peg-IFN group achieved HBsAg loss (65.5%, 36/55), and 33 patients in the NA add-on Peg-IFN group achieved HBsAg clearance (47.1%, 33/70), which were significantly higher than in the Peg-IFN group (p = 0.041). The HBsAg seroconversion rates in the Peg-IFN group and NA add-on Peg-IFN group at 72 weeks were 45.5% (25/55) and 32.9% (23/70), respectively (p = 0.151). No patient achieved HBsAg clearance or seroconversion in the NA group and untreated group. Furthermore, the receiver operating characteristic curve showed baseline HBsAg< 72 IU/mL, and the decline of HBsAg of more than 80% and 98% from baseline to 12 and 24 weeks provided good predictions for HBsAg clearance. Meanwhile, 77% of patients with baseline HBsAg< 100 IU/mL achieved a clinical cure at 48 weeks. Conclusion Peg-IFNα-2b results in a high rate of HBsAg clearance and seroconversion in both IHCs and NA-experienced patients, especially for those patients who have HBsAg below 100 IU/mL.
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Affiliation(s)
| | | | | | | | | | | | | | - Xiaofeng Shi
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Tseng TC. Novel biomarkers for chronic hepatitis B management. Clin Liver Dis (Hoboken) 2024; 23:e0155. [PMID: 38872784 PMCID: PMC11168842 DOI: 10.1097/cld.0000000000000155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 02/13/2024] [Indexed: 06/15/2024] Open
Affiliation(s)
- Tai-Chung Tseng
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, 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
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Yang HC. Revisiting the natural history of chronic hepatitis B infection. Clin Liver Dis (Hoboken) 2024; 23:e0195. [PMID: 38872766 PMCID: PMC11168840 DOI: 10.1097/cld.0000000000000195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 03/25/2024] [Indexed: 06/15/2024] Open
Affiliation(s)
- Hung-Chih Yang
- Department and Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Liaw YF. Perspectives on Outcome Prediction in Patients With Chronic Hepatitis B Virus Infection. GASTRO HEP ADVANCES 2023; 3:162-166. [PMID: 39129948 PMCID: PMC11307897 DOI: 10.1016/j.gastha.2023.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 11/09/2023] [Indexed: 08/13/2024]
Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
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Chtourou A, Gargouri S, Elleuch E, Feki L, Smaoui F, Taktak A, Mnif K, Kassis M, Hammami A, Ben Jemaa M, Karray H. Large spontaneous HBV DNA fluctuations and potential usefulness of a single-point measurement of combined HBV DNA and quantitative HBsAg for the exclusion of HBeAg-negative chronic hepatitis B: A prospective Tunisian cohort study. Arab J Gastroenterol 2023; 24:223-229. [PMID: 37989673 DOI: 10.1016/j.ajg.2023.09.002] [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: 03/17/2022] [Revised: 03/10/2023] [Accepted: 09/04/2023] [Indexed: 11/23/2023]
Abstract
BACKGROUND AND STUDY AIM During the natural course of HBeAg-negative chronic hepatitis B (CHB), fluctuations in hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) levels are often observed, making the classification of patients difficult. We aimed to describe spontaneous short-term HBV DNA level fluctuations and to assess the usefulness of qHBsAg in Tunisian patients with HBeAg-negative chronic HBV infection. PATIENTS AND METHODS We included 174 treatment-naive Tunisian patients with HBeAg-negative chronic HBeAg-negative HBV infection. A prospective 1-year follow-up was conducted with serial determinations of HBV DNA, ALT levels, and qHBsAg. The patients were classified into three groups: inactive carriers (G1), patients with negative HBeAg CHB (G2), and patients with an "indeterminate state" (G3). For the latter group, a liver biopsy was indicated. RESULTS Only genotype D was detected. During follow-up, 21.6% and 19.5% of patients with a low initial (<2,000 IU/ml) and intermediate viral load (2,000-20,000 IU/ml) experienced a subsequent increase in their HBV DNA levels above 2,000 and 20,000 IU/ml, respectively. Significant variations in viral load were observed in 61.1% of patients at 6-month intervals. Among the 174 patients, 89 (51.1%) belonged to G1, 33 (19%) to G2, and 52 (29.9%) to G3. Fourteen patients have undergone a liver biopsy, of whom seven showed moderate to severe liver disease. Combination of HBV DNA < 2,000 IU/ml and qHBsAg < 832 IU/ml excluded CHB in 98.4% of cases. A cutoff point for qHBsAg < 100 IU/ml associated with an annual decline of > 0.5 log 10 IU/ml is a good predictor marker of functional cure for hepatitis B. CONCLUSIONS This study highlights the large short-term fluctuations in HBV DNA in patients with HBeAg-negative chronic HBeAg-negative HBV infection with genotype D. Thus, using the cutoff value of 832 for qHBsAg combined with that of 2,000 for HBV DNA makes it possible to exclude CHB for most patients.
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Affiliation(s)
- Amel Chtourou
- Laboratory of Microbiology, Habib Bourguiba University Hospital, Rue El Ferdaous, 3029 Sfax, Tunisia; Faculty of Medicine of Sfax, Avenue Majida Boulila, 3003 Sfax, Tunisia; University of Sfax, Sfax, Tunisia.
| | - Saba Gargouri
- Laboratory of Microbiology, Habib Bourguiba University Hospital, Rue El Ferdaous, 3029 Sfax, Tunisia; Faculty of Medicine of Sfax, Avenue Majida Boulila, 3003 Sfax, Tunisia; University of Sfax, Sfax, Tunisia.
| | - Emna Elleuch
- Faculty of Medicine of Sfax, Avenue Majida Boulila, 3003 Sfax, Tunisia; University of Sfax, Sfax, Tunisia; Infectious Diseases Department, Hedi Chaker University Hospital, route el ain, km 0.5, Sfax, Tunisia
| | - Lamia Feki
- Laboratory of Microbiology, Habib Bourguiba University Hospital, Rue El Ferdaous, 3029 Sfax, Tunisia; Faculty of Medicine of Sfax, Avenue Majida Boulila, 3003 Sfax, Tunisia; University of Sfax, Sfax, Tunisia.
| | - Fahmi Smaoui
- Laboratory of Microbiology, Habib Bourguiba University Hospital, Rue El Ferdaous, 3029 Sfax, Tunisia; Faculty of Medicine of Sfax, Avenue Majida Boulila, 3003 Sfax, Tunisia; University of Sfax, Sfax, Tunisia.
| | - Awatef Taktak
- Laboratory of Microbiology, Habib Bourguiba University Hospital, Rue El Ferdaous, 3029 Sfax, Tunisia; Faculty of Medicine of Sfax, Avenue Majida Boulila, 3003 Sfax, Tunisia; University of Sfax, Sfax, Tunisia.
| | - Khouloud Mnif
- Faculty of Medicine of Sfax, Avenue Majida Boulila, 3003 Sfax, Tunisia; University of Sfax, Sfax, Tunisia; Infectious Diseases Department, Hedi Chaker University Hospital, route el ain, km 0.5, Sfax, Tunisia.
| | - Mondher Kassis
- University of Sfax, Sfax, Tunisia; Department of Social Medicine, Faculty of Medicine of Sfax, Avenue Majida Boulila, 3003 Sfax, Tunisia.
| | - Adnene Hammami
- Laboratory of Microbiology, Habib Bourguiba University Hospital, Rue El Ferdaous, 3029 Sfax, Tunisia; Faculty of Medicine of Sfax, Avenue Majida Boulila, 3003 Sfax, Tunisia; University of Sfax, Sfax, Tunisia.
| | - Mounir Ben Jemaa
- Faculty of Medicine of Sfax, Avenue Majida Boulila, 3003 Sfax, Tunisia; University of Sfax, Sfax, Tunisia; Infectious Diseases Department, Hedi Chaker University Hospital, route el ain, km 0.5, Sfax, Tunisia.
| | - Hela Karray
- Laboratory of Microbiology, Habib Bourguiba University Hospital, Rue El Ferdaous, 3029 Sfax, Tunisia; Faculty of Medicine of Sfax, Avenue Majida Boulila, 3003 Sfax, Tunisia; University of Sfax, Sfax, Tunisia.
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Lin HC, Liu J, Pan MH, Lee MH, Batrla-Utermann R, Lu SN, Jeng WJ, Yang HI, Chen CJ. Rapid Decline Rather Than Absolute Level of HBsAg Predicts Its Seroclearance in Untreated Chronic Hepatitis B Patients From Taiwanese Communities. Clin Transl Gastroenterol 2023; 14:e00586. [PMID: 36988242 PMCID: PMC10461935 DOI: 10.14309/ctg.0000000000000586] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/07/2023] [Accepted: 03/14/2023] [Indexed: 03/30/2023] Open
Abstract
INTRODUCTION Hepatitis B surface antigen (HBsAg) clearance leads to favorable outcomes in patients with chronic hepatitis B. HBsAg levels <200 IU/mL with HBsAg decline >0.5 log 10 IU/mL in 1 year have been reportedly predictive of HBsAg loss. This study aimed to use the REVEAL-hepatitis B virus cohort to validate and simplify this prediction rule and verify whether the simplified algorithm can be used among various clinical subgroups. METHOD We analyzed 707 patients with untreated chronic hepatitis B who had 3 or more HBsAg measurements within 5 years before HBsAg seroclearance or last visit, greater than 1 year apart from one another. Rapid HBsAg decline was defined as HBsAg decline >0.5 log 10 IU/mL in 1 year or >1 log 10 IU/mL in 2 years. Sensitivity, specificity, positive predictive values, and negative predictive values were compared to assess the predictability of HBsAg seroclearance. RESULTS During a median follow-up of 10.7 years, 41 of the 707 patients cleared serum HBsAg. HBsAg levels at all measurements were lower ( P < 0.0001) and HBsAg decline was greater ( P < 0.0001) in patients with seroclearance compared with non-seroclearance patients. The predictive accuracy of predicting 1-year HBsAg loss using only the rapid decline algorithm (sensitivity = 0.4412, specificity = 0.9792, positive predictive value = 0.5172, negative predictive value = 0.972) was the same as the model combining rapid HBsAg decline and HBsAg levels <200 IU/mL. The simplified algorithm including only the rapid decline performed similarly among various levels of HBsAg, hepatitis B virus DNA, and alanine aminotransferase and was independent of inactive carrier state. DISCUSSION HBsAg decline >0.5 log 10 IU/mL/yr was a practical predictor of HBsAg seroclearance within 1 year in our community-based untreated cohort.
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Affiliation(s)
- Hsin-Che Lin
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan
| | - Jessica Liu
- Perinatal Epidemiology and Health Outcomes Research Unit, Division of Neonatology, Department of Pediatrics, School of Medicine, Stanford University and Lucile Packard Children's Hospital, Palo Alto, California, USA
| | - Mei-Hung Pan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | | | - Sheng-Nan Lu
- Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Kaohsiung Branch, Kaohsiung, Taiwan
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan
- Chang Gung University College of Medicine, Taoyuan City, Taiwan
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan
| | - Chien-Jen Chen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
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Tseng TC, Chiang C, Liu CJ, Hong CM, Su TH, Yang HC, Yang WT, Liu CH, Chen PJ, Kao JH. Low Hepatitis B Core-Related Antigen Levels Correlate Higher Spontaneous Seroclearance of Hepatitis B Surface Antigen in Chronic Hepatitis B Patients With High Hepatitis B Surface Antigen Levels. Gastroenterology 2023; 164:669-679.e6. [PMID: 36642151 DOI: 10.1053/j.gastro.2023.01.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 11/07/2022] [Accepted: 01/03/2023] [Indexed: 01/17/2023]
Abstract
BACKGROUND & AIMS Seroclearance of hepatitis B surface antigen (HBsAg) indicates functional cure for hepatitis B virus (HBV) infection. Low HBsAg levels can predict HBsAg seroclearance over time. However, little is known about the association between hepatitis B core-related antigen (HBcrAg) levels and spontaneous seroclearance of HBsAg. METHODS We conducted a retrospective cohort study including 2614 treatment-naïve patients with chronic HBV infection who received long-term follow-up at the National Taiwan University Hospital. The primary end point was spontaneous HBsAg seroclearance. We aimed to explore whether HBcrAg levels could predict HBsAg seroclearance, especially for patients with HBsAg levels >1000 IU/mL. RESULTS There were 465 patients who cleared HBsAg with 32,414.72 person-years of follow-up, with a mean clearance rate of 1.43% per year. We found that lower HBcrAg levels at baseline were associated with an increased likelihood of HBsAg seroclearance (log rank P < .001). When restricting the study population to 1539 patients with HBsAg levels >1000 IU/mL, only HBcrAg <10,000 U/mL (vs ≥100,000 U/mL) served as an independent viral predictor for HBsAg seroclearance, with adjusted hazard ratio of 1.95 (95% CI, 1.16-3.27). In contrast to the late decline of HBsAg levels (5-9 years before HBsAg seroclearance), HBcrAg levels became undetectable 10-14 years before HBsAg seroclearance. This finding was confirmed by the different annual HBsAg seroclearance rates in the first and second decades of follow-up (0.97% vs 3.75%; P < .001) in patients achieving undetectable HBcrAg levels. CONCLUSIONS Lower serum HBcrAg levels were associated with increased probability of HBsAg seroclearance over time. In patients with HBsAg levels >1000 IU/mL, clearing HBcrAg may serve as an early biomarker for HBsAg seroclearance.
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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
| | - Chieh Chiang
- Department of Mathematics, Tamkang University, New Taipei City, 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
| | - 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
| | - Hung-Chih Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, 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
| | - Wan-Ting Yang
- Hepatitis Research Center, National Taiwan University Hospital, 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
| | - 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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14
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Clinical Utility of Quantitative HBV Core Antibodies for Solving Diagnostic Dilemmas. Viruses 2023; 15:v15020373. [PMID: 36851587 PMCID: PMC9965363 DOI: 10.3390/v15020373] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 01/20/2023] [Accepted: 01/26/2023] [Indexed: 01/31/2023] Open
Abstract
The present-day management of hepatitis B virus (HBV) infection relies on constant and appropriate monitoring of viral activity, disease progression and treatment response. Traditional HBV infection biomarkers have many limitations in predicting clinical outcomes or therapy success. Quantitation of HBV core antibodies (qAnti-HBc) is a new non-invasive biomarker that can be used in solving multiple diagnostic problems. It was shown to correlate well with infection phases, level of hepatic inflammation and fibrosis, exacerbations during chronic infection and presence of occult infection. Further, the level of qAnti-HBc was recognised as predictive of spontaneous or therapy-induced HBeAg and HBsAg seroclearance, relapse after therapy discontinuation, re-infection after liver transplantation and viral reactivation upon immunosuppression. However, qAnti-HBc cannot be relied upon as a single diagnostic test to solve all dilemmas, and its diagnostic and prognostic power can be much improved when combined with other diagnostic biomarkers (HBV DNA, HBeAg, qHBsAg and anti-HBs antibodies). The availability of commercial qAnti-HBc diagnostic kits still needs to be improved. The comparison of results from different studies and definitions of universal cut-off values continue to be hindered because many methods are only semi-quantitative. The clinical utility of qAnti-HBc and the methods used for its measurement are the focus of this review.
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15
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Coffin CS, Haylock-Jacobs S, Doucette K, Ramji A, Ko HH, Wong DK, Elkhashab M, Bailey R, Uhanova J, Minuk G, Tsoi K, Wong A, Ma MM, Tam E, Brahmania M, Nudo C, Zhu J, Lowe CF, Osiowy C, Lethebe BC, Congly SE, Chan EKH, Villasis-Keever A, Sbarigia U, Cooper CL, Fung S. Clinical Outcomes and Quantitative HBV Surface Antigen Levels in Diverse Chronic Hepatitis B Patients in Canada: A Retrospective Real-World Study of CHB in Canada (REVEAL-CANADA). Viruses 2022; 14:2668. [PMID: 36560672 PMCID: PMC9781785 DOI: 10.3390/v14122668] [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: 10/14/2022] [Revised: 11/16/2022] [Accepted: 11/18/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Hepatitis B surface antigen (HBsAg) loss is associated with improved clinical outcomes for individuals with chronic hepatitis B (CHB); however, the effects of varying HBsAg levels on clinical outcomes in diverse cohorts are understudied. METHODS In this cross-sectional, multicentre, retrospective study, the data on adult subjects enrolled in the Canadian HBV Network with CHB seen from 1 January 2012 to 30 January 2021 with the treatment and virologic data within 1 year of HBsAg testing were analyzed. Patients were tested for HBsAg using qualitative (for HBsAg-negative samples) and/or commercial quantitative assays. Fibrosis or hepatic necroinflammation was determined by the liver stiffness measurement (LSM). The baseline data were summarized using descriptive statistics and compared by using univariable/multivariable analyses. RESULTS This study included 844 CHB patients, with a median age of 49.6 years (IQR 40.1-60.5), and 37% were female. In total, 751 patients (78.6%) had known ethnicity data, and 76.7% self-reported as Asian, 11.4% as Black, 6.8% as White, and 4.8% as other. Among the 844 patients, 237 (28.0%) were HBsAg (-) (1000 IU/mL. Overall, 80% (682) had known HBeAg status at the last follow-up, and the majority (87.0%) were HBeAg-negative. In addition, 54% (461/844) had prior antiviral therapy, 19.7% of which (16.3, 23.7, n = 91) were HBsAg (-). The treated patients had a lower risk of cirrhosis (16.46, 95% CI 1.89-143.39, p = 0.01) or HCC (8.23, 95% CI 1.01-67.39, p = 0.05) than the untreated patients. A lower proportion of the HBsAg-loss group had cirrhosis (5.7% vs. 10.9%, p = 0.021) and HCC (0.9% vs. 6.2%, p = 0.001). CONCLUSION In this retrospective, ethnically diverse cohort study, CHB patients who received antiviral therapy and/or had HBsAg loss were less likely to develop cirrhosis and HCC, confirming the results of the studies in less diverse cohorts. No association was found between the qHBsAg level and fibrosis determined with LSM. Individuals who achieved HBsAg loss had low-level qHBsAg within 1 year of seroclearance.
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Affiliation(s)
- Carla S. Coffin
- Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | | | - Karen Doucette
- Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Alnoor Ramji
- Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Hin Hin Ko
- Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - David K. Wong
- Department of Medicine, University of Toronto, Toronto, ON M5G 2CV, Canada
| | | | | | - Julia Uhanova
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Gerald Minuk
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Keith Tsoi
- Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada
| | - Alexander Wong
- Department of Medicine, University of Saskatchewan, Regina, SK S7N 5A2, Canada
| | - Mang M. Ma
- Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Edward Tam
- Pacific Gastroenterology Associates, Vancouver, BC V6Z 2K5, Canada
| | - Mayur Brahmania
- Multi Organ Transplant Unit, Department of Medicine, Division of Gastroenterology, Western University, London, ON N6A 3K7, Canada
| | - Carmine Nudo
- Cité-de-la-Santé de Laval, Laval, QC H7M 3L9, Canada
| | - Julie Zhu
- Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Christopher F. Lowe
- Division of Medical Microbiology, Providence Health Care, Vancouver, BC V6Z 1Y6, Canada
| | - Carla Osiowy
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada
| | - B. Cord Lethebe
- Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Stephen E. Congly
- Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | | | | | | | - Curtis L. Cooper
- Department of Medicine, Division of infectious Diseases, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Scott Fung
- Department of Medicine, University of Toronto, Toronto, ON M5G 2CV, Canada
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16
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Liaw YF. Perspectives on current controversial issues in the management of chronic HBV infection. J Gastroenterol 2022; 57:828-837. [PMID: 36053366 DOI: 10.1007/s00535-022-01918-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 08/18/2022] [Indexed: 02/04/2023]
Abstract
Clinical and basic research in the past decades has achieved consensus in the understanding of chronic hepatitis B virus (HBV) infection and the management of chronic hepatitis B and HBV-cirrhosis. However, debatable challenges to the existing consensus in the concept and/or definitions have emerged. These include (1). alanine aminotransferase upper limit of normal: traditional laboratory-defined vs fixed; (2). nomenclature for phases of chronic HBV infection: classical vs EASL proposal; (3). indication of antiviral therapy: to treat patients vs to treat HBV; (4). finite vs indefinite long-term antiviral therapy: A. finite therapy in HBV-cirrhosis; B. retreatment decision: biochemical markers vs HBsAg/ALT kinetics. The pros and cons of these controversial issues were reviewed, assessed, and discussed in depth based on relevant lines of scientific evidence, intended to clarify or solve these controversial issues.
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Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 199, Tung Hwa North Road, Taipei, 105, Taiwan.
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17
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Sheng Q, Wang N, Zhang C, Fan Y, Li Y, Han C, Wang Z, Wei S, Dou X, Ding Y. HBeAg-negative Patients with Chronic Hepatitis B Virus Infection and Normal Alanine Aminotransferase: Wait or Treat? J Clin Transl Hepatol 2022; 10:972-978. [PMID: 36304490 PMCID: PMC9547271 DOI: 10.14218/jcth.2021.00443] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/25/2021] [Accepted: 02/27/2022] [Indexed: 12/04/2022] Open
Abstract
Alanine aminotransferase (ALT) is a common clinical indicator of liver inflammation. The current Chinese guidelines for the management of chronic hepatitis B (CHB) recommend antiviral treatment for patients with detectable hepatitis B virus (HBV) DNA and persistent ALT levels (ALTs) exceeding the upper limit of normal. However, it has been recently reported that patients with chronic HBV infection, especially HBeAg-negative patients with persistently normal ALTs, may have liver biopsy findings of significant inflammation and fibrosis. For HBeAg-negative patients with chronic HBV infection and normal ALTs, many controversial questions have been asked. To treat or not? When to initiate the treatment? Which drug is appropriate? In this review, we summarize the available data on the management of HBeAg-negative patients with chronic HBV infection and normal ALTs with the aim of improving the current clinical management.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Xiaoguang Dou
- Correspondence to: Xiaoguang Dou and Yang Ding, Department of Infectious Diseases, Shengjing Hospital of China Medical University, No. 39 HuaXiang Road, TieXi District,Shenyang, Liaoning 110022, China. ORCID: https://orcid.org/0000-0003-1856-7331 (XGD), https://orcid.org/0000-0002-7066-2865 (YD). Tel: +86-18940251121 (XGD), +86-13332434847 (YD), Fax: +86-24-25998744, E-mail: (XGD), (YD)
| | - Yang Ding
- Correspondence to: Xiaoguang Dou and Yang Ding, Department of Infectious Diseases, Shengjing Hospital of China Medical University, No. 39 HuaXiang Road, TieXi District,Shenyang, Liaoning 110022, China. ORCID: https://orcid.org/0000-0003-1856-7331 (XGD), https://orcid.org/0000-0002-7066-2865 (YD). Tel: +86-18940251121 (XGD), +86-13332434847 (YD), Fax: +86-24-25998744, E-mail: (XGD), (YD)
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18
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Leroy V, Chevaliez S, Decraecker M, Roulot D, Nana J, Asselah T, Causse X, Durantel D, Thibaut V, Ganne-Carrié N, Bureau C, de Lédinghen V, Bourlière M. Non-invasive diagnosis and follow-up of chronic infection with hepatitis B virus. Clin Res Hepatol Gastroenterol 2022; 46:101773. [PMID: 34332134 DOI: 10.1016/j.clinre.2021.101773] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 07/23/2021] [Indexed: 02/04/2023]
Abstract
Diagnosis of chronic hepatitis B virus (HBV) infection, initial staging of infection and monitoring of treated and untreated patients are mainly based on clinical, biological and imaging criteria allowing a complete non-invasive management for the majority of patients. Along to the conventional virological tools, rapid diagnostic tests and blotting paper tests for HBV DNA are validated alternatives. After diagnosis, the initial work-up should include HIV, HCV and HDV serologies, HBeAg status, and HBsAg and HBV DNA quantification. Assessment of severity (inflammation and fibrosis) is based on ALT serum levels and non-invasive evaluation of liver fibrosis by elastography or blood tests, which must be interpreted cautiously using specific cut-offs and taking into account ALT levels. Taken together, these parameters allow disease classification and treatment decision. Decision of hepatocellular carcinoma screening by ultra-sound every six months may be difficult in non-cirrhotic patients and the use of risk-scores such as PAGE-B is encouraged. Chronic HBV infection often has a dynamic and often unpredictable profile and regular monitoring is mandatory. In untreated patients, regular (3-12 months) follow-up should include ALT and HBV DNA serum levels. Periodical HBsAg quantification and non-invasive evaluation of liver fibrosis may refine disease outcome and prognosis. In treated patients, checking efficacy is mainly based on HBV DNA negativity. In patients with advanced fibrosis, evolution of liver stiffness can be useful for portal hypertension evaluation, but its improvement should not be considered to stop hepatocellular carcinoma screening. Finally, new parameters (HBV RNA, HBcrAg) are promising but their use is still restricted for research.
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Affiliation(s)
- Vincent Leroy
- Service d'hépatologie, Hôpital Henri-Mondor, APHP, & INSERM U955, UPEC, Créteil, France.
| | - Stéphane Chevaliez
- Service d'hépatologie, Hôpital Henri-Mondor, APHP, & INSERM U955, UPEC, Créteil, France
| | - Marie Decraecker
- Service d'hépato-gastroentérologie, Hôpital Haut-Lévêque, CHU Bordeaux, Pessac & INSERM U1053, Université de Bordeaux, Bordeaux, France
| | - Dominique Roulot
- Service d'hépatologie, Hôpital Avicenne, APHP; université Sorbonne Paris Nord, Bobigny, France
| | - Jean Nana
- Service d'hépato-gastroentérologie, Centre Hospitalier de Voiron, CHU Grenoble-Alpes, Voiron, France
| | - Tarik Asselah
- Service d'hépatologie, Hôpital Beaujon, APHP, Clichy, France
| | - Xavier Causse
- Service d'hépato-gastroentérologie et oncologie digestive, CHR Orléans, Orléans, France
| | | | | | - Nathalie Ganne-Carrié
- Service d'hépatologie, Hôpital Avicenne, APHP; université Sorbonne Paris Nord, Bobigny, France
| | - Christophe Bureau
- Service d'hépatologie, Hôpital Rangueil, CHU Toulouse, Toulouse, France
| | - Victor de Lédinghen
- Service d'hépato-gastroentérologie, Hôpital Haut-Lévêque, CHU Bordeaux, Pessac & INSERM U1053, Université de Bordeaux, Bordeaux, France
| | - Marc Bourlière
- Service d'hépato-gastroentérologie, Hôpital Saint Joseph & INSERM UMR 1252 IRD SESSTIM Aix Marseille Université, Marseille, France
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Yang JY, Wu YH, Pan MYC, Chiou YT, Lee RKL, Li TN, Wang LHC. Chemical-induced degradation of PreS2 mutant surface antigen via the induction of microautophagy. Antiviral Res 2022; 207:105417. [PMID: 36122619 DOI: 10.1016/j.antiviral.2022.105417] [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: 03/27/2022] [Revised: 08/29/2022] [Accepted: 09/09/2022] [Indexed: 11/02/2022]
Abstract
Naturally evolved immune-escape PreS2 mutant is an oncogenic caveat of liver cirrhosis and hepatocellular carcinoma (HCC) during chronic hepatitis B virus (HBV) infection. PreS2 mutant is prevalent in above 50% of patients with HCC. In addition, intrahepatic expression of PreS2 mutant large surface antigen (PreS2-LHBS) induces endoplasmic reticulum stress, mitochondria dysfunction, cytokinesis failure, and subsequent chromosome hyperploidy. As PreS2-LHBS has no enzymatic activity, the development of PreS2-specific inhibitors can be challenging. In this study, we aim to identify inhibitors of PreS2-LHBS via the induction of protein-specific degradation. We set up a large-scale protein stability reporter platform and applied an FDA-approved drug library for the screening. We identified ABT199 as a negative modulator of PreS2-LHBS, which induced the degradation of PreS2-LHBS without affecting the general cell viability in both hepatoma and immortalized hepatocytes. Next, by affinity purification screening, we found that PreS2-LHBS interacted with HSC70, a microautophagy mediating chaperone. Simultaneously, inhibitions of lysosomal degradation or microautophagy restored the expression of PreS2-LHBS, suggesting microautophagy is involved in ABT199-induced PreS2-LHBS degradation. Notably, a 24-hr treatment of ABT199 was sufficient for the reduction of DNA damage and cytokinesis failure in PreS2-LHBS expressing hepatocytes. In addition, a persistent treatment of ABT199 for 3 weeks reversed chromosome hyperploidy in PreS2-LHBS cells and suppressed anchorage-independent growth of HBV-positive hepatoma cells. Together, this study identified ABT-199 as a negative modulator of PreS2-LHBS via mediating microautophagy. Our results indicated that long-term inhibition of PreS2-LHBS may serve as a novel strategy for the therapeutic prevention of HBV-mediated HCC.
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Affiliation(s)
- Joey Yi Yang
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan
| | - Yi-Hsuan Wu
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan
| | - Max Yu-Chen Pan
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan
| | - Yu-Ting Chiou
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan
| | - Richard Kuan-Lin Lee
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan
| | - Tian-Neng Li
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan
| | - Lily Hui-Ching Wang
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
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Lok J, Dusheiko G, Carey I, Agarwal K. Review article: novel biomarkers in hepatitis B infection. Aliment Pharmacol Ther 2022; 56:760-776. [PMID: 35770458 DOI: 10.1111/apt.17105] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 06/08/2022] [Accepted: 06/12/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Chronic hepatitis B remains a global health problem with an estimated 296 million people affected worldwide. Individuals are at risk of serious complications such as cirrhosis and hepatocellular carcinoma and accurately predicting these clinical endpoints has proven difficult. However, several viral biomarkers have recently been developed, including quantitative HBV surface antigen (qHBsAg), hepatitis B RNA (HBV RNA) and core-related antigen (HBcrAg), and shown promise in a range of clinical settings. AIMS To critically appraise these novel biomarkers, exploring their potential uses, availability of assays and areas for future development. METHODS We performed a literature search of PubMed, identifying articles published in the field of hepatitis B biomarkers between 2010 and 2022. RESULTS Novel biomarkers such as HBcrAg, HBV RNA and qHBsAg may be useful in predicting treatment outcomes, stratifying the risk of future complications and estimating off-treatment viral reactivation. Furthermore, HBV RNA and HBcrAg titres may accurately reflect cccDNA transcriptional activity, and this is particularly informative in the context of nucleoside analogue therapy. On a cautionary note, most studies have been performed in Caucasian or Asian populations, and methods for detecting HBV RNA lack standardisation. CONCLUSION Novel viral biomarkers have the potential to provide additional insights into the natural history of infection and allow a more bespoke, cost-effective framework of care. However, access remains limited, and further efforts are needed to validate their use in ethnically diverse populations, confirm predictive cut-off values, and establish their role in the era of novel antiviral therapies.
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Affiliation(s)
- James Lok
- Institute of Liver Studies, King's College Hospital, London, UK
| | | | - Ivana Carey
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, UK
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21
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qHBsAg for the Identification of Liver Histological Abnormalities in HBeAg-Negative Chronic Hepatitis B Patients with Normal and Mildly Elevated ALT Levels. Can J Gastroenterol Hepatol 2022; 2022:8695196. [PMID: 35875362 PMCID: PMC9303505 DOI: 10.1155/2022/8695196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 06/09/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUNDS Noninvasive detection of histological abnormalities remains challenging in patients with HBeAg-negative chronic HBV infection with normal or mildly elevated levels of alanine aminotransferase (ALT). This study aimed to assess the utility of serum quantitative hepatitis B surface antigen (qHBsAg) in identifying significant histological lesions in this population. METHODS This is a single-center study with retrospective analysis of 392 treatment-naive patients of HBeAg-negative chronic HBV infection with normal or mildly elevated levels of ALT. RESULTS In this cohort, significant necroinflammation and fibrosis were found in 69.4% and 61.5% of patients, respectively. Patients with qHBsAg >1000 IU/mL (N = 236) had more hepatic inflammation of ≥G2 (75.4% vs. 60.9%, P < 0.01) or fibrosis ≥ S2 (66.1% vs. 54.5%, P < 0.05) compared to those without (N = 156). Serum HBsAg (cutoff point = 1000 IU/mL), aspartate aminotransferase (AST) level (cutoff point = 25 IU/L), age (cutoff point = 40 years), and HBV family history were identified as independent predictors of significant histological abnormalities in multivariate logistic analysis. CONCLUSIONS A significantly higher proportion of patients with histological abnormalities were found in patients with qHBsAg >1000 IU/mL than those without. The qHBsAg level together with age, AST, and family history of HBV infection could be used as an algorithm to help noninvasive patient selection for antiviral therapy.
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Lim J, Choi WM, Shim JH, Lee D, Kim KM, Lim YS, Lee HC, Choi J. Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate in treatment-naïve chronic hepatitis B. Liver Int 2022; 42:1517-1527. [PMID: 35343041 DOI: 10.1111/liv.15261] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/21/2022] [Accepted: 03/24/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND AIMS We used real-world data to evaluate the efficacy and safety of tenofovir alafenamide (TAF) compared with tenofovir disoproxil fumarate (TDF) in treatment-naïve patients with CHB. METHODS We analysed 2747 patients with CHB under TAF (n = 502) or TDF (n = 2245) treatments. Virological responses (VR: HBV DNA <15 IU/ml), on-treatment ALT normalization, the incidence of HCC, renal function and lipid profiles were compared between these groups. Propensity score matching of 495 pairs was conducted for these comparisons. RESULTS The mean age of the total cohort was 48.6 years and 58.2% of the subjects were male. Cirrhosis had a 33.3% prevalence in the population. VRs at 12, 24 and 36 months were achieved in 70.3%, 81.2% and 83.3% of the TAF and 67.9%, 84.3% and 86.1% in the TDF cases respectively (p > 0.05 for all). Normalized ALT, as determined by local laboratory criteria (<40 U/L), occurred in 79.7%, 90.6% and 86.2% of TAF the group and 78.2%, 85.8% and 85.7% of the TDF group at 12, 24 and 36 months respectively (p > 0.05 for all). The HCC risk did not statistically differ across the entire cohort or in the PS-matched cohort. The TAF group showed a lower median increase in serum creatinine from baseline during the early study period. Compared with the TAF, the TDF group showed significant decreases in total cholesterol, triglyceride and HDL, but not in LDL. CONCLUSIONS Real-word data indicate that TAF has comparable efficacies to TDF in terms of VR and ALT normalization, with no higher risk of HCC.
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Affiliation(s)
- Jihye Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Won-Mook Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju Hyun Shim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Danbi Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Yuan SY, Yu HB, Yang Z, Qin YP, Ren JH, Cheng ST, Ren F, Law BYK, Wong VKW, Ng JPL, Zhou YJ, He X, Tan M, Zhang ZZ, Chen J. Pimobendan Inhibits HBV Transcription and Replication by Suppressing HBV Promoters Activity. Front Pharmacol 2022; 13:837115. [PMID: 35721154 PMCID: PMC9204083 DOI: 10.3389/fphar.2022.837115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 05/10/2022] [Indexed: 12/03/2022] Open
Abstract
Current anti-HBV therapeutic strategy relies on interferon and nucleos(t)ide-type drugs with the limitation of functional cure, inducing hepatitis B surface antigen (HBsAg) loss in very few patients. Notably, the level of HBsAg has been established as an accurate indicator to evaluate the drug efficacy and predict the disease prognosis, thus exploring a novel drug targeting HBsAg will be of great significance. Herein, by screening 978 compounds from an FDA-approved drug library and determining the inhibitory function of each drug on HBsAg level in HepG2.2.15 cells supernatant, we identified that pimobendan (Pim) has a powerful antiviral activity with relatively low cytotoxicity. The inhibitory effect of Pim on HBsAg as well as other HBV markers was validated in HBV-infected cell models and HBV-transgenic mice. Mechanistically, real-time PCR and dual-luciferase reporter assay were applied to identify the partial correlation of transcription factor CAAT enhancer-binding protein α (C/EBPα) with the cccDNA transcription regulated by Pim. This indicates Pim is an inhibitor of HBV transcription through suppressing HBV promoters to reduce HBV RNAs levels and HBsAg production. In conclusion, Pim was identified to be a transcription inhibitor of cccDNA, thereby inhibiting HBsAg and other HBV replicative intermediates both in vitro and in vivo. This report may provide a promising lead for the development of new anti-HBV agent.
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Affiliation(s)
- Si-Yu Yuan
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Hai-Bo Yu
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Zhen Yang
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Yi-Ping Qin
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Ji-Hua Ren
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Sheng-Tao Cheng
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Fang Ren
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Betty Yuen Kwan Law
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Vincent Kam Wai Wong
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Jerome P. L. Ng
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Yu-Jiao Zhou
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Xin He
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Ming Tan
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Zhen-Zhen Zhang
- Chongqing Key Laboratory of Child Infection and Immunity, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Department of Infectious Diseases, The Children’s Hospital of Chongqing Medical University, Chongqing, China
- *Correspondence: Zhen-Zhen Zhang, ; Juan Chen,
| | - Juan Chen
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
- *Correspondence: Zhen-Zhen Zhang, ; Juan Chen,
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24
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Choi HS, Tonthat A, Janssen HL, Terrault NA. Aiming for Functional Cure With Established and Novel Therapies for Chronic Hepatitis B. Hepatol Commun 2022; 6:935-949. [PMID: 34894108 PMCID: PMC9035586 DOI: 10.1002/hep4.1875] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 11/11/2021] [Accepted: 11/18/2021] [Indexed: 12/22/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains difficult to cure due to the persistent, self-replenishing nature of the viral genome and impaired host immune responses. Current treatment goals for chronic hepatitis B (CHB) are to prevent or significantly delay liver-related adverse outcomes and death, and two types of treatments are available: nucleos(t)ide analogues (NAs) and interferons (IFNs). NAs effectively suppress HBV replication, and IFNs improve serological response rates, thereby decreasing the risk of adverse outcomes. However, their efficacy in attaining serological responses, especially functional cure (i.e., loss of serum hepatitis B surface antigen), is very limited. Various strategies such as stopping antiviral therapy or combining therapies have been investigated to enhance response, but efficacy is only modestly improved. Importantly, the development of novel direct-acting antivirals and immunomodulators is underway to improve treatment efficacy and enhance rates of functional cure. The present review provides an overview of the treatment goals and indications, the possibility of expanding indications, and the safety and efficacy of different treatment strategies involving established and/or novel therapies as we continue our search for a cure.
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Affiliation(s)
- Hannah S.J. Choi
- Toronto Center for Liver DiseaseToronto General HospitalTorontoONCanada
| | - Alexander Tonthat
- Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
| | | | - Norah A. Terrault
- Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
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25
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Fainboim H, Di Benedetto N, Paz S, Mendizabal M, Campuzano S, Elizalde M, Tadey L, Deluchi G, Bouzas MB, Mammana L, Flichman D. Quantitative HBsAg an unreliable marker for diagnosis and disease progression in genotype F chronic HBeAg-negative infections. J Viral Hepat 2022; 29:298-301. [PMID: 35152530 DOI: 10.1111/jvh.13657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 02/01/2022] [Indexed: 12/09/2022]
Affiliation(s)
- Hugo Fainboim
- Unidad de Hepatopatías Infecciosas, Hospital de Infecciosas F. J. Muñiz, Buenos Aires, Argentina
| | | | - Silvia Paz
- Unidad de Hepatopatías Infecciosas, Hospital de Infecciosas F. J. Muñiz, Buenos Aires, Argentina
| | | | - Soledad Campuzano
- Unidad de Hepatopatías Infecciosas, Hospital de Infecciosas F. J. Muñiz, Buenos Aires, Argentina
| | - Mercedes Elizalde
- Instituto de Investigaciones Biomédicas en Retrovirus y Síndrome de Inmunodeficiencia Adquirida (INBIRS), Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Luciana Tadey
- Unidad de Virología, Hospital de Infecciosas "Francisco J. Muñiz", Buenos Aires, Argentina
| | - Gabriel Deluchi
- Unidad de Virología, Hospital de Infecciosas "Francisco J. Muñiz", Buenos Aires, Argentina
| | - María Belén Bouzas
- Unidad de Virología, Hospital de Infecciosas "Francisco J. Muñiz", Buenos Aires, Argentina
| | - Lilia Mammana
- Unidad de Virología, Hospital de Infecciosas "Francisco J. Muñiz", Buenos Aires, Argentina
| | - Diego Flichman
- Instituto de Investigaciones Biomédicas en Retrovirus y Síndrome de Inmunodeficiencia Adquirida (INBIRS), Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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26
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2022; 28:276-331. [PMID: 35430783 PMCID: PMC9013624 DOI: 10.3350/cmh.2022.0084] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 01/10/2023] Open
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Terrault NA, Wahed AS, Feld JJ, Cooper SL, Ghany MG, Lisker-Melman M, Perrillo R, Sterling RK, Khalili M, Chung RT, Rosenthal P, Fontana RJ, Sarowar A, Lau DTY, Wang J, Lok AS, Janssen HLA. Incidence and prediction of HBsAg seroclearance in a prospective multi-ethnic HBeAg-negative chronic hepatitis B cohort. Hepatology 2022; 75:709-723. [PMID: 34743343 PMCID: PMC8943823 DOI: 10.1002/hep.32231] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 10/20/2021] [Accepted: 10/24/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Achieving HBsAg loss is an important landmark in the natural history of chronic hepatitis B (CHB). A more personalized approach to prediction of HBsAg loss is relevant in counseling patients. This study sought to develop and validate a prediction model for HBsAg loss based on quantitative HBsAg levels (qHBsAg) and other baseline characteristics. METHODS The Hepatitis B Research Network (HBRN) is a prospective cohort including 1240 untreated HBeAg-negative patients (1150 adults, 90 children) with median follow-up of 5.5 years. Incidence rates of HBsAg loss and hepatitis B surface antibody (anti-HBs) acquisition were determined, and a predictor score of HBsAg loss using readily available variables was developed and externally validated. RESULTS Crude incidence rates of HBsAg loss and anti-HBs acquisition were 1.6 and 1.1 per 100 person-years (PY); 67 achieved sustained HBsAg loss for an incidence rate of 1.2 per 100 PY. Increased HBsAg loss was significantly associated with older age, non-Asian race, HBV phenotype (inactive CHB vs. others), HBV genotype A, lower HBV-DNA levels, and lower and greater change in qHBsAg. The HBRN-SQuARe (sex,∆quantHBsAg, age, race) score predicted HBsAg loss over time with area under the receiver operating characteristic curve (AUROC) (95% CIs) at 1 and 3 years of 0.99 (95% CI: 0.987-1.00) and 0.95 (95% CI 0.91-1.00), respectively. In validation in another cohort of 1253 HBeAg-negative patients with median follow-up of 3.1 years, HBRN SQuARe predicted HBsAg loss at 1 and 3 years with AUROC values of 0.99 (0.98-1.00) and 0.88 (0.77-0.99), respectively. CONCLUSION HBsAg loss in predominantly untreated patients with HBeAg-negative CHB can be accurately predicted over a 3-year horizon using a simple validated score (HBRN SQuARe). This prognostication tool can be used to support patient care and counseling.
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Affiliation(s)
- NA Terrault
- Gastrointestinal and Liver Diseases Division, Keck Medicine of University of Southern California, Los Angeles, California, USA
| | - AS Wahed
- Department of Biostatistics and Epidemiology Data Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - JJ Feld
- Toronto Center for Liver Disease, University of Toronto, Toronto, Ontario, Canada
| | - SL Cooper
- San Francisco Center for Liver Disease, California Pacific Medical & Research Institute, San Francisco, California, USA
| | - MG Ghany
- Liver Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - M Lisker-Melman
- Washington University School of Medicine and John Cochran VA Medical Center, St. Louis, Missouri, USA
| | - R Perrillo
- Baylor University Medical Center, Dallas, Texas, USA
| | - RK Sterling
- Section of Hepatology, Virginia Commonwealth University, Richmond, Virginia, USA
| | - M Khalili
- Department of Medicine, University of California San Francisco, San Francisco, California, USA
| | - RT Chung
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - P Rosenthal
- Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | - RJ Fontana
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - A Sarowar
- Toronto Center for Liver Disease, University of Toronto, Toronto, Ontario, Canada
| | - DTY Lau
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA
| | - J Wang
- Department of Biostatistics and Epidemiology Data Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - AS Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - HLA Janssen
- Toronto Center for Liver Disease, University of Toronto, Toronto, Ontario, Canada
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28
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Lee HW, Park SY, Lee YR, Lee H, Lee JS, Kim SU, Park JY, Kim DY, Ahn SH, Kim BK. Episodic Detectable Viremia Does Not Affect Prognosis in Untreated Compensated Cirrhosis With Serum Hepatitis B Virus DNA <2,000 IU/mL. Am J Gastroenterol 2022; 117:288-294. [PMID: 34506308 DOI: 10.14309/ajg.0000000000001497] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 07/19/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION The necessity of antiviral therapy (AVT) for hepatitis B virus (HBV)-infected compensated cirrhosis with low-level viremia (LLV) is controversial. Herein, we evaluated its natural history. METHODS From 3 tertiary hospitals, we enrolled untreated patients with compensated cirrhosis with persistent serum HBV-DNA levels <2,000 IU/mL; LLV was defined as having at least 1 detectable serum HBV-DNA (20-2,000 IU/mL) episode, whereas maintained virological response (MVR) was defined as having persistently undetectable serum HBV-DNA (<20 IU/mL). When serum HBV-DNA was ≥2,000 IU/mL during follow-up, AVT was administered according to guidelines. Study end points were development of cirrhotic complication event (CCE) or hepatocellular carcinoma (HCC). RESULTS Among 567 patients analyzed, cumulative HCC risk at 3, 5, and 7 years was comparable between LLV (n = 391) vs MVR (n = 176) groups (5.7%, 10.7%, and 17.3% vs 7.2%, 15.5%, and 19.4%, respectively [P = 0.390]). CCE risk was also comparable between 2 groups (7.5%, 12.8%, and 13.7% vs 7.8%, 12.3%, and 14.6%, respectively [P = 0.880]). By multivariate analysis, LLV (vs MVR) was not associated with HCC or CCE risks, with adjusted hazard ratios of 1.422 (95% confidence interval [CI] 0.694-2.913; P = 0.336) and 1.816 (95% CI: 0.843-3.911; P = 0.128), respectively. Inverse probability of treatment weighting analysis yielded comparable outcomes between 2 groups, regarding HCC and CCE risks with hazard ratios of 0.903 (95% CI: 0.528-1.546; P = 0.711) and 1.192 (95% CI: 0.675-2.105; P = 0.545), respectively. DISCUSSION Episodic LLV among untreated patients with compensated cirrhosis does not increase the risk of disease progression compared with MVR status. Thus, the benefits of AVT for episodic LLV should be re-evaluated.
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Affiliation(s)
- Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Soo Young Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daege, Republic of Korea
| | - Yu Rim Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daege, Republic of Korea
| | - Hyein Lee
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Jae Seung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
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Hatooka H, Shimomura Y, Imamura M, Teraoka Y, Morio K, Fujino H, Ono A, Nakahara T, Murakami E, Yamauchi M, Kawaoka T, Makokha GN, Miki D, Tsuge M, Hiramatsu A, Abe-Chayama H, Hayes CN, Aikata H, Tanaka S, Chayama K. Construction of an anti-hepatitis B virus preS1 antibody and usefulness of preS1 measurement for chronic hepatitis B patients: Anti-HBV PreS1 antibody. J Infect 2021; 84:391-399. [PMID: 34953905 DOI: 10.1016/j.jinf.2021.12.025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 12/06/2021] [Accepted: 12/13/2021] [Indexed: 11/30/2022]
Abstract
OBJECTIVES The preS1 region plays an essential role in hepatitis B virus (HBV) infection. We construct an antibody that binds to preS1 and a measurement system for serum preS1 in chronic HBV-infected patients. METHODS Hybridoma clones that produce anti-preS1 antibodies were obtained by the iliac lymph node method. Epitope mapping was conducted, and an enzyme-linked immunosorbent assay (ELISA)-based method was developed. Using this ELISA system, serum preS1 levels were measured in 200 chronic HBV-infected patients. RESULTS Eight types of hybridomas were obtained, of which antibody 3-55 using amino acids 38-47 as the epitope showed high binding affinity to preS1. Serum preS1 levels measured by ELISA using 3-55 antibody were correlated with HBsAg, HBcrAg and HBV DNA levels. Among HBeAg-negative patients without antiviral therapeutic objective (HBV DNA <3.3 log IU/mL or alanine aminotransferase ≤30 U/L), preS1 was significantly higher in subjects who had progressed to the point of requiring antiviral therapy compared to subjects who had maintained their status for the preceding three years (p<0.01). CONCLUSIONS We constructed an antibody against preS1 and an ELISA system capable of measuring serum preS1 levels. PreS1 may serve as a novel tool to predict the need for antiviral therapy in HBeAg-negative HBV-infected patients.
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Affiliation(s)
- Haruna Hatooka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Yumi Shimomura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Grace Naswa Makokha
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hiromi Abe-Chayama
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; Center for Medical Specialist Graduate Education and Research, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Shinji Tanaka
- Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan
| | - Kazuaki Chayama
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; Collaborative Research Laboratory of Medical Innovation, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan; Institute of Physical and Chemical Research (RIKEN) Center for Integrative Medical Sciences, Yokohama, Japan.
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Controversies in Treating Chronic Hepatitis B virus: The Role of Hepatitis B Virus DNA and Surface Antigen Titer. Clin Liver Dis 2021; 25:763-784. [PMID: 34593152 DOI: 10.1016/j.cld.2021.06.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Controversial areas in chronic hepatitis B (CHB) are those where there is uncertainty, or differences of opinion in management, or where evidence may be insufficient. Areas of controversy include whether patients with high viral load but normal liver function tests should be treated to prevent hepatocellular carcinoma (HCC) or liver disease progression to cirrhosis. Another area is whether quantitative hepatitis B surface antigen (qHBsAg) can be used to better characterize phases of CHB and prognosticate. Finally, the utility of qHBsAg in the management of patients on antiviral therapy such as interferon and nucleoside analogues could improve management practices.
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Joo EJ, Cheong HS, Kwon MJ, Sohn W, Kim HN, Cho YK. Relationship between gut microbiome diversity and hepatitis B viral load in patients with chronic hepatitis B. Gut Pathog 2021; 13:65. [PMID: 34717727 PMCID: PMC8557478 DOI: 10.1186/s13099-021-00461-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 10/19/2021] [Indexed: 12/21/2022] Open
Abstract
Background Hepatitis B virus (HBV) infection is associated with a reduced risk of developing dyslipidemia and non-alcoholic fatty liver diseases. Given that the gut microbiota plays a significant role in cholesterol metabolism, we compared the differences in gut microbial diversity and composition between HBV-infected and uninfected subjects. Results A prospective case–control study was designed comprising healthy controls (group A) and HBV-infected individuals (group B) in a 1:1 ratio (57 participants each; total = 114). The patients in group B were divided into two subgroups according to their HBV DNA loads: B1 < 2000 IU/mL (N = 40) and B2 ≥ 2000 IU/mL (N = 17). In a pairwise comparison of HBV-infected individuals and controls, higher alpha diversity was noted in group B, and the difference was significant only in patients in group B1. Alloprevotella and Eubacterium coprostanoligenes were predominant in group B1 compared to the control, whereas the abundance of Bacteroides fragilis and Prevotella 2 was lower. Conclusions The gut microbiome in HBV-infected individuals with a low viral load is highly diverse and is dominated by specific taxa involved in fatty acid and lipid metabolism. To our knowledge, this is the first demonstration of a correlation between the presence of certain bacterial taxa and chronic HBV infection depending on the load of HBV DNA. Supplementary Information The online version contains supplementary material available at 10.1186/s13099-021-00461-1.
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Affiliation(s)
- Eun-Jeong Joo
- Division of Infectious Diseases, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea
| | - Hae Suk Cheong
- Division of Infectious Diseases, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea
| | - Min-Jung Kwon
- Department of Laboratory Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Won Sohn
- Division of Gastroenterology and Hepatology, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Han-Na Kim
- Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul, 03181, Republic of Korea. .,Department of Clinical Research Design & Evaluation, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
| | - Yong Kyun Cho
- Division of Infectious Diseases, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea. .,Division of Gastroenterology and Hepatology, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul, 03181, Republic of Korea.
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Wang G, Duan Z. Guidelines for Prevention and Treatment of Chronic Hepatitis B. J Clin Transl Hepatol 2021; 9:769-791. [PMID: 34722192 PMCID: PMC8516840 DOI: 10.14218/jcth.2021.00209] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 07/20/2021] [Accepted: 08/03/2021] [Indexed: 12/12/2022] Open
Abstract
To achieve the goal of the World Health Organization to eliminate viral hepatitis as a major public health threat by 2030, the Chinese Society of Infectious Diseases and the Chinese Society of Hepatology convened an expert panel in 2019 to update the guidelines for the prevention and treatment of chronic hepatitis B (CHB). The current guidelines cover recent advances in basic, clinical, and preventive studies of CHB infection and consider the actual situation in China. These guidelines are intended to provide support for the prevention, diagnosis, and treatment of CHB.
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Affiliation(s)
- Guiqiang Wang
- Center for Liver Diseases, Department of Infectious Diseases, Peking University First Hospital; Department of Infectious and Liver Diseases, Peking University International Hospital, Beijing, China
| | - Zhongping Duan
- Center for Difficult and Complicated Liver Diseases and Artificial Liver, Beijing YouAn Hospital, Capital Medical University, Beijing, China
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Lee HW, Cho YY, Lee H, Lee JS, Kim SU, Park JY, Kim DY, Ahn SH, Kim BK, Park SY. Impact of tenofovir alafenamide vs. entecavir on hepatocellular carcinoma risk in patients with chronic hepatitis B. Hepatol Int 2021; 15:1083-1092. [PMID: 34402025 DOI: 10.1007/s12072-021-10234-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 07/04/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Whether entecavir (ETV) or tenofovir alafenamide (TAF) is better at preventing hepatocellular carcinoma (HCC) development among patients with chronic hepatitis B (CHB) remains unclear. The present study was conducted to explore the ability of these two antivirals to prevent HCC. METHODS From 2012 to 2019, treatment-naïve CHB patients undergoing ETV or TAF therapy were recruited at three academic teaching hospitals. The TAF group comprised patients starting TAF as first-line antiviral and those switching antivirals from tenofovir disoproxil fumarate to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded from the analysis. Cumulative probabilities of HCC were assessed using the Kaplan-Meier method. RESULTS In total, 1810 patients (1525 and 285 in ETV and TAF groups, respectively) were recruited. The annual HCC incidence was statistically not different between the ETV and TAF groups (1.67 vs. 1.19 per 100 person-years, respectively) with an adjusted hazard ratio (HR) of 0.681 (p = 0.255), as determined by multivariate analysis. Male, hypertension, liver cirrhosis, FIB-4 index, and albumin were independent prognostic factors for HCC development. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results, with non-statistically different HCC incidence between the ETV and TAF groups (1.07 vs. 1.19 per 100 person-years (HR = 0.973; p = 0.953) and 1.67 vs. 1.89 per 100 person-years, respectively (HR = 0.949; p = 0.743). CONCLUSIONS These findings suggest that ETV- and TAF-treated CHB patients have similar risk of developing HCC. Further studies with the larger sample size and longer follow-up are needed to validate these results.
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Affiliation(s)
- Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Young Youn Cho
- Department of Internal Medicine, Chung Ang University College of Medicine, Seoul, Korea
| | - Hyein Lee
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Jae Seung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea.
| | - Soo Young Park
- Department of Internal Medicine, Kyungpook National University School of Medicine, 130 Dongdeok-ro, Jung-gu, Daegu, 41944, Republic of Korea.
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Jeng WJ, Lok AS. Should Treatment Indications for Chronic Hepatitis B Be Expanded? Clin Gastroenterol Hepatol 2021; 19:2006-2014. [PMID: 32434068 DOI: 10.1016/j.cgh.2020.04.091] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/20/2020] [Accepted: 04/24/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIM Antiviral therapy has greatly improved the outcomes of patients with chronic hepatitis B virus (HBV) infection and active liver disease or advanced fibrosis/cirrhosis. However, current treatment does not eradicate HBV and long-term treatment is needed in most patients to maintain clinical benefit. Thus, professional society guidelines do not recommend treatment of all patients with chronic HBV infection. This review article will examine evidence for and against expansion of treatment to patients in whom treatment is not recommended based on current guidelines. RESULTS Available data support expanding treatment to immune tolerant patients and patients in the grey zones who have evidence of active/advanced liver disease based on liver biopsy or non-invasive tests and those who remain in the immune tolerant phase after age 40. Evidence supporting treatment expansion to confirmed inactive carriers and other immune tolerant patients is lacking. CONCLUSIONS HBV treatment indications can be more liberal when new therapies that can achieve HBsAg loss safely in a high percentage of patients after a finite course of treatment are available.
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Affiliation(s)
- Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch, Taiwan; Chang Gung University College of Medicine, Taiwan
| | - Anna S Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan.
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Wu F, Lu R, Liu Y, Wang Y, Tian Y, Li Y, Li M, Wang W, Zhang X, Jia X, Dang S. Efficacy and safety of peginterferon alpha monotherapy in Chinese inactive chronic hepatitis B virus carriers. Liver Int 2021; 41:2032-2045. [PMID: 33896094 DOI: 10.1111/liv.14897] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 02/27/2021] [Accepted: 03/31/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS The effectiveness and safety of peginterferon alpha (peg-IFN-α) monotherapy in inactive hepatitis B virus (HBV) carriers (IHCs) have not been fully evaluated. METHODS This observational study prospectively enrolled 298 IHCs in China from 2015 to 2019. Participants were given the right to choose to either receive peg-IFN-α monotherapy (treatment group, n = 142) or be monitored without treatment (control group, n = 156) according to their wishes. The scheduled treatment duration was 48 weeks. All participants were followed up to 72 weeks. The main efficacy endpoint was hepatitis B surface antigen (HBsAg) clearance at 72 weeks. RESULTS Baseline characteristics were similar between both groups. At 72 weeks, intention-to-treat analysis showed that the rates of HBsAg clearance and seroconversion of the treatment group were 47.9% (68/142) and 36.6% (52/142), respectively, which were significantly higher than the HBsAg clearance rate of 1.9% (3/156) and the seroconversion rate of 0.6% (1/156) in the control group (both P < .001). Baseline HBV DNA < 20 IU/mL, lower HBsAg levels at baseline, 12 and 24 weeks, alanine aminotransferase elevation at 12 weeks, and greater HBsAg reduction from baseline to 12 and 24 weeks were independent predictors of HBsAg clearance. Generally, the therapy was well tolerated. Only five participants discontinued therapy as a result of peg-IFNα-related adverse events. CONCLUSIONS Peg-IFN-α monotherapy results in high rates of HBsAg clearance and seroconversion and the treatment is safe for IHCs.
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Affiliation(s)
- Fengping Wu
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Rui Lu
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yixin Liu
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yikai Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yan Tian
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yaping Li
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Mei Li
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wenjun Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xin Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaoli Jia
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shuangsuo Dang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Post G, Howell J, Sow A, Ndow G, Chemin I, Lo G, Cessay A, Cohen D, Njie R, Toure S, Diop M, Sombie R, Nana J, Leroy V, Lacombe K, Bojang L, Tacke F, Toure-Kane C, Ka M, Mendy M, Mboup S, Thursz M, Shimakawa Y, Ingiliz P, Lemoine M. Clinical utility of quantifying hepatitis B surface antigen in African patients with chronic hepatitis B. J Viral Hepat 2021; 28:1003-1010. [PMID: 33749097 DOI: 10.1111/jvh.13499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 03/11/2021] [Indexed: 12/20/2022]
Abstract
The clinical utility of quantifying hepatitis B surface antigen (qHBsAg) levels in African subjects with chronic hepatitis B virus (HBV) infection has been poorly documented. From a multicentre cohort of 944 HBV-infected African patients, we aimed to assess whether qHBsAg alone can accurately identify i) those in a HBeAg-negative chronic HBV infection phase at low risk of liver disease progression and ii) those in need of antiviral therapy according to the 2017 EASL guidelines. We analysed 770 HBV mono-infected treatment-naïve patients, mainly males (61%) from West Africa (92%), median age 35 years (IQR: 30-44), median HBV DNA: 95.6 IU/ml (10.0-1,300.0), median qHBsAg 5,498 IU/ml (1,171-13,000) and HBeAg-pos 38 (5%). A total of 464/770 (60.2%) patients were classified as HBeAg-negative chronic infection (median age 36 years (31-46), median ALT 23 IU/l (18-28), median HBV-DNA 33.5 IU/ml (3.8-154.1), median LSM 4.8 kPa (4.1-5.8)) and qHBsAg levels had poor accuracy to identify these subjects with an AUROC at 0.58 (95%CI: 0.54-0.62), sensitivity 55.0% and specificity 55.6%; 118/770 (15.3%) patients were eligible for treatment according to the 2017 EASL criteria. qHBsAg correlated poorly with HBV DNA and had poor accuracy to select patients for antiviral therapy with an AUROC at 0.54 (0.49-0.60), sensitivity 46.6% and specificity 46.9%. In African treatment-naïve HBV-infected subjects, the clinical utility of qHBsAg to identify subjects in HBeAg-negative infection phase or subjects eligible for antiviral therapy seems futile. Whether qHBsAg levels can be used as a predictor of long-term liver complications in Africa needs to be further investigated.
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Affiliation(s)
- Gerrit Post
- Department of Gastroenterology and Hepatology, Charité University Medical Center, Berlin, Germany
- Center for Infectiology, Berlin, Germany
| | - Jess Howell
- Disease Elimination, Burnet Institute, Department of Gastroenterology, St. Vincent's Hospital, Department of Epidemiology and Preventive Medicine, Monash University Melbourne, Victoria, Australia
| | - Amina Sow
- Laboratoire de Bactériologie & Virologie, CHNU Dalal Jamm Guediawaye, IRESSEF Diamnoadio Dakar, Senegal
| | - Gibril Ndow
- Medical Research Council the Gambia unit (MRCG, London School of Hygiene and Tropical Medicine, Viral hepatitis Unit, Fajara, The Gambia
| | - Isabelle Chemin
- INSERM U1052, CNRS 5286, Univ Lyon, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Gora Lo
- Laboratoire de Bactériologie & Virologie, CHNU Dalal Jamm Guediawaye, IRESSEF Diamnoadio Dakar, Senegal
| | - Amie Cessay
- Medical Research Council the Gambia unit (MRCG, London School of Hygiene and Tropical Medicine, Viral hepatitis Unit, Fajara, The Gambia
| | - Damien Cohen
- INSERM U1052, CNRS 5286, Univ Lyon, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Ramou Njie
- International Agency for Research on Cancer (IARC, Lyon, France
| | - Souleymane Toure
- Unite de Formation et de Recherche (UFR) des sciences de la santé de l'Universite de Thies, Senegal
| | - Madoky Diop
- Unite de Formation et de Recherche (UFR) des sciences de la santé de l'Universite de Thies, Senegal
| | - Roger Sombie
- Service d'hépatogastro-entérologie, Centre Hospitalier Universitaire Yalgado Ouédraogo, Université Joseph Ki-Zerbo, Ouagadougou, Burkina Faso
| | - Jean Nana
- Department of Hepatology & Gastroenterology, Université Grenoble Alpes, Grenoble, France
| | - Vincent Leroy
- Department of Hepatology & Gastroenterology, Université Grenoble Alpes, Grenoble, France
| | - Karine Lacombe
- Department of infectious diseases and tropical medicine, hôpital Saint-Antoine, SorbonneUniversité, Inserm IPLESP, APHP, Sorbonne, France
| | - Lamin Bojang
- Medical Research Council the Gambia unit (MRCG, London School of Hygiene and Tropical Medicine, Viral hepatitis Unit, Fajara, The Gambia
| | - Frank Tacke
- Department of Gastroenterology and Hepatology, Charité University Medical Center, Berlin, Germany
| | - Coumba Toure-Kane
- Laboratoire de Bactériologie & Virologie, CHNU Dalal Jamm Guediawaye, IRESSEF Diamnoadio Dakar, Senegal
| | - Mourtalla Ka
- Unite de Formation et de Recherche (UFR) des sciences de la santé de l'Universite de Thies, Senegal
| | - Maimuna Mendy
- International Agency for Research on Cancer (IARC, Lyon, France
| | - Souleymane Mboup
- Laboratoire de Bactériologie & Virologie, CHNU Dalal Jamm Guediawaye, IRESSEF Diamnoadio Dakar, Senegal
| | - Mark Thursz
- Department of Metabolism, Digestion and Reproduction, Division of Digestive Diseases, Hepatology Section, Imperial College London, St Mary's campus, London, UK
| | - Yusuke Shimakawa
- Unité d'Épidémiologie des Maladies Émergentes, Institut Pasteur, Paris, France
| | - Patrick Ingiliz
- Department of Gastroenterology and Hepatology, Charité University Medical Center, Berlin, Germany
- Center for Infectiology, Berlin, Germany
| | - Maud Lemoine
- Department of Metabolism, Digestion and Reproduction, Division of Digestive Diseases, Hepatology Section, Imperial College London, St Mary's campus, London, UK
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Tan M, Ren F, Yang X. Anti-HBV therapeutic potential of small molecule 3,5,6,7,3',4'-Hexamethoxyflavone in vitro and in vivo. Virology 2021; 560:66-75. [PMID: 34051476 DOI: 10.1016/j.virol.2021.05.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 05/08/2021] [Accepted: 05/18/2021] [Indexed: 10/21/2022]
Abstract
Current treatment methods for hepatitis B are mainly antiviral drug therapy and immunotherapy, in which antiviral drugs are mainly nucleoside analogue and interferon. They can significantly reduce the viral load but rarely achieve hepatitis B surface antigen (HBsAg) loss. 3,5,6,7,3',4'-Hexamethoxyflavone was screened out from a small molecule compound library for its lower cytotoxic effect and greater HBsAg inhibition activity. Meanwhile, we further performed experiments in HepG2.2.15, HepG2-NTCP cells, PHHs and HBV transgenic mouse model to evaluate the anti-HBV effects of 3,5,6,7,3',4'-Hexamethoxyflavone. Our study found that 3,5,6,7,3',4'-Hexamethoxyflavone can significantly reduce the level of HBV RNAs, HBV DNA and HBsAg, in addition, the activity of four HBV promoters and the ratio of total RNAs/cccDNA and 3.5 kb RNA/cccDNA were decreased by 3,5,6,7,3',4'-Hexamethoxyflavone. Mechanistically, we found HNF3α plays important roles in Hex mediated HBV transcription inhibition. Our study indicated Hex was a potential anti-HBV therapeutic drug.
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Affiliation(s)
- Ming Tan
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Fang Ren
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Xiao Yang
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
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Li M, Zhang L, Lu Y, Chen Q, Lu H, Sun F, Zeng Z, Wan G, Zhao L, Xie Y. Early Serum HBsAg Kinetics as Predictor of HBsAg Loss in Patients with HBeAg-Negative Chronic Hepatitis B after Treatment with Pegylated Interferonα-2a. Virol Sin 2021; 36:311-320. [PMID: 32975731 PMCID: PMC8087759 DOI: 10.1007/s12250-020-00290-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 07/16/2020] [Indexed: 01/05/2023] Open
Abstract
Hepatitis B surface antigen (HBsAg) loss is an ideal treatment endpoint for patients with chronic hepatitis B (CHB). We investigated the predictive value of on-treatment HBsAg levels for HBsAg loss in hepatitis B e antigen (HBeAg)-negative CHB patients who received 120-week PEG-IFNα-2a treatment. Serum HBV DNA, HBsAg, and anti-HBs levels were assayed at baseline and every 3 months during the treatment. Of 81 patients, 12 achieved HBsAg loss, 20 achieved HBsAg < 100 IU/mL, and 49 maintained HBsAg ≥ 100 IU/mL. HBsAg loss rate was only 3.7% at 48 weeks, while it reached to 11.1% and 14.8% after treatment of 96 weeks and 120 weeks. The cutoff HBsAg levels at 12 weeks predicting HBsAg loss at 96 weeks and 120 weeks of treatment were 400 IU/mL and 750 IU/mL, with AUC 0.725 and 0.722, positive predictive value (PPV) 29.41% and 30.56%, and negative predictive value (NPV) 93.75% and 97.78%, respectively. The cutoff HBsAg levels at 24 weeks predicting HBsAg loss at 96 weeks and 120 weeks of treatment were 174 IU/mL and 236 IU/mL respectively, with AUC 0.925 and 0.922, PPV 40.0% and 46.15%, and both NPV 100%. The predictive ability of the cutoff HBsAg levels at 24 weeks was better than that at 12 weeks for HBsAg loss at either 96 or 120 weeks (χ2 = 3.880, P = 0.049 and χ2 = 4.412, P = 0.036). These results indicate that extended therapy is critical to HBsAg loss in HBeAg-negative CHB patients during PEG-IFN treatment, and the HBsAg level at 24 weeks can be used to predict HBsAg loss during tailoring PEG-IFN therapy.
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Affiliation(s)
- Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, 100015, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Qiqi Chen
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, 100015, China
| | - Huihui Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Fangfang Sun
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Zhan Zeng
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, 100015, China
| | - Gang Wan
- Department of Biostatistics, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Linqing Zhao
- Laboratory of Virology Capital Institute of Pediatrics, Beijing, 100020, China.
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, 100015, China.
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Wu JW, Kao JH, Tseng TC. Three Heads are Better than Two: HBcrAg as a New Predictor of HBV-related HCC. Clin Mol Hepatol 2021; 27:524-534. [PMID: 33618507 PMCID: PMC8524074 DOI: 10.3350/cmh.2021.0012] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 02/21/2021] [Indexed: 01/13/2023] Open
Abstract
Patients with chronic hepatitis B virus (HBV) infection are at risk of developing hepatocellular carcinoma (HCC), and serum markers reflecting viral replication are potential predictors for HCC development. Besides the levels of serum HBV DNA and hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) quantification is an emerging serological marker for viral replication. Unlike HBV DNA and HBsAg, HBcrAg is a covalently closed circular DNA-derived protein marker, consisting of hepatitis B e antigen (HBeAg), p22cr, and hepatitis B core antigen. In treatment-naïve HBV patients, higher HBcrAg levels are shown to be associated with an increased risk of HCC in several studies. More importantly, HBcrAg may complement HBV DNA level to predict HCC development. For example, an Asian treatment-naïve cohort study’s data showed that HBcrAg level of 4 log U/mL was effective to stratify HCC risk in HBeAg-negative patients with intermediate viral loads, who may not need antiviral therapy because of the low to moderate risk of HCC. In patients receiving prolonged nucleos(t)ide analogue with profound viral suppression, most data indicated that HBV DNA and HBsAg levels no longer serve as HCC predictors. However, several studies suggested on-treatment HBcrAg levels may remain as an HCC predictor. In summary, HBcrAg level can be a useful biomarker for treatment-naïve patients, but its value in on-treatment patients needs validation. The next challenge is how to combine HBcrAg with the other viral markers to construct a better HCC prediction model, optimizing the management of HBV patients.
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Affiliation(s)
- Jer-Wei Wu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, 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
| | - 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
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40
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Yang HC, Su TH. Viral and Host Factors Affecting Disease Progression of Hepatitis B Virus Infection. HEPATITIS B VIRUS AND LIVER DISEASE 2021:205-230. [DOI: 10.1007/978-981-16-3615-8_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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41
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Baklouti R, Gueddiche A, Ben Abdelwahed M, Aissaoui F, Zakhama M, Bouhlel W, Sriha A, Kooli I, Sallem OK, Argoubi A, Hichem LM, Ben Chaabane N, Safer L. The role of quantitative HBsAg in the natural history of e antigen-negative chronic hepatitis B: A Tunisian prospective study. Infect Dis Now 2020; 51:464-469. [PMID: 34366082 DOI: 10.1016/j.idnow.2020.10.004] [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: 08/01/2020] [Revised: 10/06/2020] [Accepted: 10/29/2020] [Indexed: 11/20/2022]
Abstract
BACKGROUND/AIMS During the natural course of Chronic Hepatitis B (CHB) infection, differentiation between inactive carrier (IC) and HBeAg negative CHB is a subject of ongoing debate. We studied the role of hepatitis B surface antigen (HBsAg) level as a means of differentiating between CHB and IC in a group of untreated chronic HBeAg-negative HBV-infected patients. STUDY A total of 115 HBeAg negative carriers were enrolled and followed up for>12 months; 78 as inactive carriers (IC), and 37 as active carriers (AC). Among ACs, patients were categorized according to the highest rate of viral load: AC1 (n=23), active carriers with persistent HBV-DNA<20,000 IU/mL; AC2 (n=14), active carriers with HBV-DNA>20,000 IU/mL. RESULTS HBsAg levels were higher in AC compared to IC patients (1607 IU/ml vs. 225 IU/ml respectively, P=0.001). Among the AC group, the 23 AC1 cases had HBsAg levels significantly lower than the 14 AC2 patients (1756 IU/mL vs. 3327 IU/mL respectively; P<10-3). HBsAg showed weak correlation with HBV-DNA in the whole cohort (r=0.44, P<0.01). The suggested cutoff value of HBsAg titer to differentiate between the two groups was 938 IU/mL. Combined single-point quantification of HBsAg (938 IU/mL) and HBV DNA (2000 IU/mL) identified IC with 87.2% specificity and 91.7% positive predictive value. CONCLUSION This study confirms the predictability of a one-time combined HBsAg and HBV DNA measurement for true inactive carriers requiring neither strict follow-up nor antiviral treatment.
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Affiliation(s)
- Raoua Baklouti
- Faculty of medicine of Monastir, Department of gastroenterology, Fattouma Bourguiba Hospital, Monastir, Tunisia.
| | - Arwa Gueddiche
- Faculty of medicine of Monastir, Department of gastroenterology, Fattouma Bourguiba Hospital, Monastir, Tunisia
| | - Mehdi Ben Abdelwahed
- Faculty of medicine of Monastir, Department of gastroenterology, Fattouma Bourguiba Hospital, Monastir, Tunisia
| | - Firas Aissaoui
- Faculty of medicine of Monastir, Department of gastroenterology, Fattouma Bourguiba Hospital, Monastir, Tunisia
| | - Majda Zakhama
- Faculty of medicine of Monastir, Department of gastroenterology, Fattouma Bourguiba Hospital, Monastir, Tunisia
| | - Wided Bouhlel
- Faculty of medicine of Monastir, Department of gastroenterology, Fattouma Bourguiba Hospital, Monastir, Tunisia
| | - Asma Sriha
- Faculty of medicine of Monastir, Department of community medicine, Fattouma Bourguiba Hospital, Monastir, Tunisia
| | - Ikbel Kooli
- Faculty of medicine of Monastir, Department of infectiology, Fattouma Bourguiba Hospital, Monastir, Tunisia
| | - Om Kalthoum Sallem
- Faculty of medicine of Monastir, Department of gastroenterology, Fattouma Bourguiba Hospital, Monastir, Tunisia
| | - Aida Argoubi
- Faculty of medicine of Monastir, Department of virology, Fattouma Bourguiba Hospital, Monastir, Tunisia
| | - Loghmeri Mohamed Hichem
- Faculty of medicine of Monastir, Department of gastroenterology, Fattouma Bourguiba Hospital, Monastir, Tunisia
| | - Nabil Ben Chaabane
- Faculty of medicine of Monastir, Department of gastroenterology, Fattouma Bourguiba Hospital, Monastir, Tunisia
| | - Leila Safer
- Faculty of medicine of Monastir, Department of gastroenterology, Fattouma Bourguiba Hospital, Monastir, Tunisia
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Peiffer KH, Spengler C, Basic M, Jiang B, Kuhnhenn L, Obermann W, Zahn T, Glitscher M, Loglio A, Facchetti F, Carra G, Kubesch A, Vermehren J, Knop V, Graf C, Dietz J, Finkelmeier F, Herrmann E, Trebicka J, Grünweller A, Zeuzem S, Sarrazin C, Lampertico P, Hildt E. Quadruple mutation GCAC1809-1812TTCT acts as a biomarker in healthy European HBV carriers. JCI Insight 2020; 5:135833. [PMID: 33055418 PMCID: PMC7710305 DOI: 10.1172/jci.insight.135833] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 10/07/2020] [Indexed: 12/14/2022] Open
Abstract
Many mutation analyses of the HBV genome have been performed in the search for new prognostic markers. However, the Kozak sequence preceding precore was covered only infrequently in these analyses. In this study, the HBV core promoter/precore region was sequenced in serum samples from European inactive HBV carriers. Quadruple mutation GCAC1809-1812TTCT was found with a high prevalence of 42% in the Kozak sequence preceding precore among all HBV genotypes. GCAC1809-1812TTCT was strongly associated with coexistence of basal core promoter (BCP) double mutation A1762T/G1764A and lower HBV DNA levels. In vitro GCAC1809-1812TTCT lead to drastically diminished synthesis of pregenomic RNA (pgRNA), precore mRNA, core, HBsAg, and HBeAg. Calculation of the pgRNA secondary structure suggests a destabilization of the pgRNA structure by A1762T/G1764A that was compensated by GCAC1809-1812TTCT. In 125 patients with HBV-related cirrhosis, GCAC1809-1812TTCT was not detected. While a strong association of GCAC1809-1812TTCT with inactive carrier status was observed, BCP double mutation was strongly correlated with cirrhosis, but this was only observed in absence of GCAC1809-1812TTCT. In conclusion, our data reveal that GCAC1809-1812TTCT is highly prevalent in inactive carriers and acts as a compensatory mutation for BCP double mutation. GCAC1809-1812TTCT seems to be a biomarker of good prognosis in HBV infection. HBV core promoter/precore region was sequenced in serum samples of European inactive HBV carriers, revealing that GCAC1809-1812TTCT mutation is highly prevalent in inactive carriers.
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Affiliation(s)
- Kai-Henrik Peiffer
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany.,Paul Ehrlich Institute, Division of Virology, Langen, Germany
| | | | - Michael Basic
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany.,Paul Ehrlich Institute, Division of Virology, Langen, Germany
| | - Bingfu Jiang
- Paul Ehrlich Institute, Division of Virology, Langen, Germany
| | - Lisa Kuhnhenn
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - Wiebke Obermann
- Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany
| | - Tobias Zahn
- Paul Ehrlich Institute, Division of Virology, Langen, Germany
| | - Mirco Glitscher
- Paul Ehrlich Institute, Division of Virology, Langen, Germany
| | - Alessandro Loglio
- A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Maggiore Hospital, University of Milan, Milan, Italy
| | - Floriana Facchetti
- A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Maggiore Hospital, University of Milan, Milan, Italy
| | - Gert Carra
- Paul Ehrlich Institute, Division of Virology, Langen, Germany
| | - Alica Kubesch
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - Johannes Vermehren
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - Viola Knop
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - Christiana Graf
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - Julia Dietz
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - Fabian Finkelmeier
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - Eva Herrmann
- Department of Medicine, Institute of Biostatistics and Mathematical Modeling, J.W. Goethe University, Frankfurt, Germany
| | - Jonel Trebicka
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - Arnold Grünweller
- Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany
| | - Stefan Zeuzem
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - Christoph Sarrazin
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany.,Department of Gastroenterology, St. Josefs Hospital, Wiesbaden, Germany
| | - Pietro Lampertico
- A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Maggiore Hospital, University of Milan, Milan, Italy
| | - Eberhard Hildt
- Paul Ehrlich Institute, Division of Virology, Langen, Germany.,German Center for Infection Research (DZIF), Gießen-Marburg-Langen, Germany
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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.
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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
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Chang KC, Lee CY, Chang TS, Hung CH, Chen WM, Chen MY, Huang TJ, Chiu WN, Hu JH, Lin YC, Huang WC, Hsu NT, Lu SN. Usefulness of quantitative hepatitis B surface antigen testing in hepatitis B community-based screening. J Formos Med Assoc 2020; 120:847-853. [PMID: 32896456 DOI: 10.1016/j.jfma.2020.08.031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 08/15/2020] [Accepted: 08/21/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/PURPOSE Low viral load (LVL) of hepatitis B virus (HBV) is a predictor of chronic HBV infection. However, the usefulness of quantitative hepatitis B surface antigen (qHBsAg) in predicting LVL in community-based screening has not been well studied. We aimed to measure the prevalence of LVL in HBV carriers and validate the efficacy of qHBsAg in predicting LVL. METHODS This community-based screening study was conducted in Taiwan. HBV DNA was assayed in HBsAg carriers. Participants were randomized to training and validation sets to determine the ability of qHBsAg to predict LVL. Receiver operating characteristic curves were used to identify the best cutoff values in the training set. RESULTS Among the 2919 participants, 359 (12.2%) were HBsAg carriers. There were 132 and 137 carriers in the training and validation sets, respectively. Significant correlations were found between qHBsAg and HBV DNA in both training and validation sets. Thirty and 29 participants with qHBsAg <8 IU/mL in the training and validation sets, respectively, had LVL. Using 8 IU/mL as the cutoff, negative predictive value (NPV) of qHBsAg for HBV DNA levels >2000 IU/mL was 100%. The best cutoff level of qHBsAg to predict HBV LVL was 200 IU/mL, with a sensitivity, specificity, and accuracy of 75.0%, 76.1%, and 75.8%, respectively, in the training set. The positive predictive value and NPV were 70.0% and 77.9%, respectively, in the validation set. CONCLUSION Approximately 60% of HBsAg carriers had HBV LVL, and qHBsAg <8 IU/mL accurately predicts LVL. This quantitative test provides additional information for community-based screening.
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Affiliation(s)
- Kao-Chi Chang
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Chih-Yi Lee
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Te-Sheng Chang
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan; Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Yunlin, Taiwan; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chao-Hung Hung
- Department of Internal Medicine, Division of Hepato-Gastroenterology, Kaohsiung Chang Gung Memorial Hospital, Taiwan
| | - Wei-Ming Chen
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Mei-Yen Chen
- College of Nursing, Chang Gung University of Science and Technology, Chiayi, Taiwan
| | - Tung-Jung Huang
- Division of Thoracic Medicine, Chang Gung Memorial Hospital, Yunlin, Taiwan
| | - Wen-Nan Chiu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Yunlin, Taiwan
| | - Jing-Hong Hu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Yunlin, Taiwan
| | - Yu-Chih Lin
- Division of Family Medicine, Chang Gung Memorial Hospital, Yunlin, Taiwan
| | - Wei-Cheng Huang
- Department of Geriatric, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Nien-Tzu Hsu
- Biostatistics and Bioinformatics Center of Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Department of Internal Medicine, Division of Hepato-Gastroenterology, Kaohsiung Chang Gung Memorial Hospital, Taiwan; Biostatistics and Bioinformatics Center of Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
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Taniguchi H, Iwasaki Y, Aimi M, Shimazaki G, Moriya A. Clinical features of chronic hepatitis B patients with low hepatitis B surface antigen levels and determinants of hepatitis B surface antigen seroclearance. JGH Open 2020; 4:698-706. [PMID: 32782959 PMCID: PMC7411555 DOI: 10.1002/jgh3.12321] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 02/22/2020] [Accepted: 02/25/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM A low hepatitis B surface antigen (HBsAg) level is reported to be predictive of future HBsAg seroclearance. A hospital-based cohort study was conducted to clarify the clinical features of patients with low HBsAg levels and to demonstrate the usefulness of low HBsAg levels for predicting HBsAg seroclearance. METHODS A total of 1459 patients with chronic hepatitis B were included in the study. Of these, 587 had repeated measurements for HBsAg levels and two or more records of HBsAg-positive results. HBsAg levels were measured with a commercially available HBsAg assay. Based on a cut-off index (COI) of 2000, a high HBsAg level was defined as HBsAg ≥2000 COI, and a low HBsAg level was defined as HBsAg <2000 COI. RESULTS The proportion of patients with low HBsAg levels at baseline tended to increase with age. Patients with low HBsAg levels at baseline had significantly older age, lower transaminase levels, and lower hepatitis B virus (HBV) DNA levels than those with high HBsAg levels. The annual HBsAg seroclearance rate was 1.30%/year. The cumulative incidences of HBsAg seroclearance differed significantly by HBsAg level at baseline (<2000 vs ≥2000 COI), age (≥50 vs <50 years), and HBV DNA level (<4.0 vs ≥4.0 log copies/mL). Cox proportional hazards regression analyses showed that low HBsAg level (<2000 COI) and low HBV DNA level (<4.0 log copies/mL) were significantly associated with HBsAg seroclearance. CONCLUSION Aging was one of the factors affecting HBsAg level. HBsAg seroclearance was significantly associated with low HBsAg level and low HBV DNA level at baseline.
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Affiliation(s)
| | | | - Masahito Aimi
- Internal MedicineTottori Municipal HospitalTottoriJapan
| | | | - Akio Moriya
- GastroenterologyMitoyo General HospitalJapan
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Cavallone D, Ricco G, Oliveri F, Colombatto P, Moriconi F, Coco B, Romagnoli V, Salvati A, Surace L, Bonino F, Brunetto MR. Do the circulating Pre-S/S quasispecies influence hepatitis B virus surface antigen levels in the HBeAg negative phase of HBV infection? Aliment Pharmacol Ther 2020; 51:1406-1416. [PMID: 32390175 DOI: 10.1111/apt.15753] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/19/2019] [Accepted: 04/06/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Virus, host factors and their interplay influence Hepatitis B surface Antigen serum levels during Hepatitis B Virus (HBV) infection course and treatment. AIM To study the Pre-S/S circulating quasispecies in a cohort of untreated, HBeAg negative, genotype-D, HBsAg carriers. METHODS We studied 260 carriers: 71 with HBeAg negative infection (ENI; HBV-DNA ≤2000 IU/mL); 42 Grey Zone (GZ; HBV-DNA ≤20 000 IU/mL); 82 chronic hepatitis (CH) and 65 cirrhosis (CI) (HBV-DNA > 20 000 IU/mL). Population sequencing was applied to identify Pre-S/S gene mutations responsible for any amino acid substitution or potential biological/antigenic implications (M-muts) on HBsAg. RESULTS HBsAg serum levels were lower in ENI + GZ than in CH + CI (2.61 [-1.10/4.06] vs 3.62 [2.41/4.92] log10 IU/mL, P < 0.001) and in CI than CH (3.48 [2.41/4.38] vs 3.66 [2.57/4.92] log10 IU/mL, P < 0.001). M-muts were found in 73 (28.1%) cases: 5 (7.0%) ENI, 3 (7.1%) GZ, 26 (31.7%) CH, 39 (60.0%) CI (P < 0.001) and mostly in Pre-S2 (17.6%) than Pre-S1 (5.8%) and Small-S (10.8%; P < 0.001). Overall HBsAg serum levels were higher in carriers with M-muts (3.56 [0.95/4.38] vs 3.17 [-1.10/4.92] log10 IU/mL, P < 0.001), but comparable in carriers with or without M-mut when considering separately ENI + GZ (2.84 [0.95/3.89] vs 2.61 [-1.10/4.06] log10 IU/mL, P = 0.330] and CH + CI (3.57 [2.67/4.38] vs 3.63 [2.41/4.92] log10 IU/mL, P = 0.37). Infection phase (β: 0.422, P < 0.001), age (β: -0.260, P < 0.001), ALT (β: -0.103, P = 0.045), liver stiffness (β: -0.118, P = 0.039) and HBV-DNA (β: 0.384, P < 0.001), but not M-mut were independently associated with HBsAg serum levels. CONCLUSIONS In HBeAg negative, genotype-D, carriers Pre-S/S heterogeneity increases with severity of liver disease, but does not influence HBsAg serum levels, that in low viraemic carriers are associated with an effective control of HBV.
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Affiliation(s)
- Daniela Cavallone
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Gabriele Ricco
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Filippo Oliveri
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Piero Colombatto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Francesco Moriconi
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Barbara Coco
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Veronica Romagnoli
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Antonio Salvati
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Lidia Surace
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
| | - Ferruccio Bonino
- Biostructure and Bio-imaging Institute of National Research Council of Italy, Naples, Italy
| | - Maurizia Rossana Brunetto
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy
- Biostructure and Bio-imaging Institute of National Research Council of Italy, Naples, Italy
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Yang R, Cui L, Liu Y, Cong X, Fei R, Wu S, Wei L. A hook-effect-free homogeneous light-initiated chemiluminescence assay: is it reliable for screening and the quantification of the hepatitis B surface antigen? ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:606. [PMID: 32566632 PMCID: PMC7290535 DOI: 10.21037/atm.2020.02.59] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background Hepatitis B virus (HBV) infection remains a threat to global public health. As a hallmark of HBV infection, hepatitis B surface antigen (HBsAg) has been used to screen for HBV infection for decades, and quantitative assays are also being clinically rejuvenated to predict the disease outcome and monitor the antiviral response. Herein, we developed and evaluated a hook-effect-free homogeneous quantitative HBsAg assay based on the light-initiated chemiluminescence immunoassay (LICA). Methods A hook-effect-free LICA algorithm was established by measuring the relative light units (RLUs) of two time points during the immunoreaction. The precision was assessed using low- and high-level controls. Consecutive clinical serum samples were tested using the LICA and Abbott Architect assay; samples producing inconsistent results were retested using supplementary assays including the HBsAg neutralization, HBV DNA, and Roche Elecsys HBsAg assays for further confirmation. The consistency, sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were calculated. For the quantitative results, the correlation was analyzed. The coverage of different genotypes and mutations by the LICA was evaluated. Moreover, serial on-treatment and follow-up samples from chronic hepatitis B patients were also measured using the two assays. Results The LICA had better within-run and within-laboratory precisions than the Architect assay. In total, 5,176 clinical samples were tested. The two assays showed a consistency of 99.63%. The LICA showed greater specificity (99.95% vs. 99.77%) and PPV (99.75% vs. 98.77%) than the Architect assay, whereas the Architect assay showed greater sensitivity (100.00% vs. 99.01%) and NPV (100.00% vs. 99.82%). The two assays displayed an excellent correlation independent of genotypes and mutations. The LICA hook-free algorithm recognized 100% of the underestimated results. Furthermore, similar HBsAg dynamics were demonstrated using the LICA and Architect HBsAg assay. Conclusions The hook-free LICA provides a reliable tool for screening for HBV infection and quantifying HBsAg.
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Affiliation(s)
- Ruifeng Yang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing 100044, China
| | - Liyan Cui
- Department of Clinical Laboratory, Peking University Third Hospital, Beijing 100191, China
| | - Yan Liu
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing 100044, China
| | - Xu Cong
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing 100044, China
| | - Ran Fei
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing 100044, China
| | - Shuping Wu
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing 100044, China
| | - Lai Wei
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing 100044, China
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48
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Buti M, Riveiro‐Barciela M, Esteban R. Rethinking the inactive carrier state: management of patients with low‐replicative HBeAg‐negative chronic hepatitis B and normal liver enzymes. CLINICAL DILEMMAS IN VIRAL LIVER DISEASE 2020:150-155. [DOI: 10.1002/9781119533481.ch26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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49
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Kim JH, Ghosh A, Ayithan N, Romani S, Khanam A, Park JJ, Rijnbrand R, Tang L, Sofia MJ, Kottilil S, Moore CB, Poonia B. Circulating serum HBsAg level is a biomarker for HBV-specific T and B cell responses in chronic hepatitis B patients. Sci Rep 2020; 10:1835. [PMID: 32020034 PMCID: PMC7000714 DOI: 10.1038/s41598-020-58870-2] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 01/16/2020] [Indexed: 11/08/2022] Open
Abstract
Chronic hepatitis B (CHB) infection functional cure is defined as sustained loss of HBsAg and several therapeutic strategies are in clinical development designed to pharmacologically reduce serum HBsAg, break immune tolerance, and increase functional cure rates. However, little is known about pre-treatment HBsAg levels as an indicator of HBV immune potential. Here, we compared the phenotypes and HBV-specific response of lymphocytes in CHB patients stratified by serum HBsAg levels <500 (HBslo) or >50,000 IU/ml (HBshi) using immunological assays (flow cytometry, ICS, ELISPOT). HBshi patients had significantly higher expression of inhibitory PD-1 on CD4+ T cells, particularly among TEMRA subset, and higher FcRL5 expression on B cells. Upon HBcAg(core) or HBsAg(env)-stimulation, 85% and 60% of HBslo patients had IFNγ+TNFα+ and IFNγ+ IL2+ CD4+ T cell responses respectively, in comparison to 33% and 13% of HBshi patients. Checkpoint blockade with αPD-1 improved HBV-specific CD4+ T cell function only in HBslo patients. HBsAg-specific antibody-secreting cells (ASCs) response was not different between these groups, yet αPD-1 treatment resulted in significantly higher fold change in ASCs among patients with HBsAg <100 IU/ml compared to patients with HBsAg >5,000 IU/ml. Thus, serum HBsAg correlates with inhibitory receptor expression, HBV-specific CD4+ T cell responses, and augmentation by checkpoint blockade.
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Affiliation(s)
- Jin Hyang Kim
- Arbutus Biopharma Corporation, 701 Veterans Circle, Warminster, Pennsylvania, 18974, United States
| | - Alip Ghosh
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, 21201, United States
| | - Natarajan Ayithan
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, 21201, United States
| | - Sara Romani
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, 21201, United States
| | - Arshi Khanam
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, 21201, United States
| | - Jang-June Park
- Arbutus Biopharma Corporation, 701 Veterans Circle, Warminster, Pennsylvania, 18974, United States
| | - Rene Rijnbrand
- Arbutus Biopharma Corporation, 701 Veterans Circle, Warminster, Pennsylvania, 18974, United States
| | - Lydia Tang
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, 21201, United States
| | - Michael J Sofia
- Arbutus Biopharma Corporation, 701 Veterans Circle, Warminster, Pennsylvania, 18974, United States
| | - Shyam Kottilil
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, 21201, United States
| | - Chris B Moore
- Arbutus Biopharma Corporation, 701 Veterans Circle, Warminster, Pennsylvania, 18974, United States
| | - Bhawna Poonia
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, 21201, United States.
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50
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Dusheiko G. Will we need novel combinations to cure HBV infection? Liver Int 2020; 40 Suppl 1:35-42. [PMID: 32077595 DOI: 10.1111/liv.14371] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 01/22/2020] [Accepted: 12/31/2019] [Indexed: 12/15/2022]
Abstract
Chronic hepatitis B is a numerically important cause of cirrhosis and hepatocellular carcinoma. Nucleoside analogue therapy may modify the risk. However, maintenance suppressive therapy is required, as a functional cure (generally defined as loss of HBsAg off treatment) is an uncommon outcome of antiviral treatment. Chronic hepatitis B is a numerically important cause of cirrhosis and hepatocellular carcinoma. Nucleoside analogue therapy may modify the risk. However, maintenance suppressive therapy is required, as a functional cure (generally defined as loss of HBsAg off treatment) is an uncommon outcome of antiviral treatment. Currently numerous investigational agents being developed to either interfere with specific steps in HBV replication or as host cellular targeting agents, that inhibit viral replication, and deplete or inactivate cccDNA, or as immune modulators. Synergistic mechanisms will be needed to incorporate a decrease in HBV transcription, impairment of transcription from HBV genomes, loss of cccDNA or altered epigenetic regulation of cccDNA transcription, and immune modulation or immunologically stimulated hepatocyte cell turnover. Nucleoside analogue suppressed patients are being included in many current trials. Trials are progressing to combination therapy as additive or synergistic effects are sought. These trials will provide important insights into the biology of HBV and perturbations of the immune response, required to effect HBsAg loss at different stages of the disease. The prospect of cures of hepatitis B would ensure that a wide range of patients could be deemed candidates for treatment with new compounds if these were highly effective, finite and safe. Withdrawal of therapy in short-term trials is challenging because short-term therapies may risk severe hepatitis flares, and hepatic decompensation. The limited clinical trial data to date suggest that combination therapy is inevitable.
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Affiliation(s)
- Geoffrey Dusheiko
- Kings College Hospital, London, UK.,University College London Medical School, London, UK
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