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Li W, Huang R, Wang J, Zhang B, Wang Q, Feng J, Xing T. Development and validation of a new predictive model for the immune tolerance stage of chronic HBV infection based on the liver histopathological changes. BMC Gastroenterol 2025; 25:408. [PMID: 40426052 PMCID: PMC12107786 DOI: 10.1186/s12876-025-03999-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 05/15/2025] [Indexed: 05/29/2025] Open
Abstract
OBJECTIVE To identify clinical and viral indicators for the development of a new model to accurately differentiate the stages of chronic hepatitis B virus (HBV) infection based on histopathological changes in the liver. METHODS Clinical and liver pathology data from chronic hepatitis B (CHB) patients who underwent liver biopsy were retrospectively collected. The patients were allocated into test and validation groups. The area under the receiver operating characteristic (ROC) curve (AUC) was calculated to idneitfy the optimal diagnostic value for differentiating the stages of chronic HBV infection. RESULTS A total of 118 patients and 73 patients who met the diagnostic and inclusion criteria were selected as the test group and validation group, respectively. Multivariate analysis revealed that HBeAg was independently correlated with the IT and IC stages. The cutoff value of HBeAg used to quantitatively differentiate between IT and IC was 1335 S/CO. The AUC values were 0.921 (95% confidence interval (CI): 0.836-0.971) and 0.846 (95% CI: 0.726-0.967) in the test and validation groups, respectively. A new prediction model of the IT stage was established by using three indicators, namely, HBeAg, HBsAg and HBV DNA. The AUC values were 0.923 (95% CI: 0.864-0.982, p < 0.001) and 0.89 (95% CI: 0.787-0.994, p < 0.01) in the test and validation groups, respectively, when this prediction model was used. For the new model, CMA guidelines (2019 version), EASL guidelines (2017 version) and AASLD guidelines (2018 version), the error rates in the test group were 4.65%, 11.62%, 23.26%, and 46.51%, respectively, while the errors rates in the validation group were 20.0%, 25.0%, 40.0%, and 45.0%, respectively. CONCLUSIONS High levels of HBeAg, rather than HBeAg positivity, may serve as a predictor of the IT stage. A predictive model for the immune tolerance stage was established by combining three indicators. Compared with the recommended standards from multiple current guidelines, the new prediction model has a significantly lower error rate.
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Affiliation(s)
- Wentao Li
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, China
| | - Rui Huang
- Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
| | - Jian Wang
- Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
| | - Binhao Zhang
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, China
| | | | - Jiang Feng
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, China
| | - Tongjing Xing
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, China.
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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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Giovane RA, deWeber K, Sauceda U, Bianchi D. Blood-Borne Infection Prevention in Combat Sports: Position Statement of the Association of Ringside Physicians. Clin J Sport Med 2025:00042752-990000000-00320. [PMID: 40197438 DOI: 10.1097/jsm.0000000000001350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 02/22/2025] [Indexed: 04/10/2025]
Abstract
ABSTRACT The Association of Ringside Physicians (ARP) emphasizes the importance of screening combat sports athletes for blood-borne infections, including hepatitis B, HIV, and hepatitis C, to mitigate transmission risks and ensure participant safety. Although transmission of hepatitis B and C and HIV in combat sports is rare, protecting athletes is of utmost importance. It is the recommendation of the ARP that all fighters participating in combat sports, in which the presence of blood is a common occurrence and is allowed during competition, should undergo testing for HIV, hepatitis B (HBV), and hepatitis C (HCV). Testing should be conducted using serum samples, because rapid tests are not considered acceptable for accurate results. Testing for HBV, HCV, and HIV should optimally be done within 3 months of competition, but within 6 months is acceptable. Athletes whose tests suggest active HBV, HCV, or HIV infection should be disqualified from competition in sports where blood is common and allowed. Athletes with cured prior HCV infection may be cleared for competition in all combat sports. Athletes with prior HBV infection and no detectable HBV DNA in blood can be cleared for competition in all combat sports. Athletes with latent HBV infection with detectable HBV DNA in blood have a small risk of disease reactivation, so they should not be cleared.
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Affiliation(s)
- Richard A Giovane
- Department of Family Medicine, University of Alabama, Tuscaloosa, Alabama
| | - Kevin deWeber
- SW Washington Sports Medicine Fellowship, Vancouver, Washington
- Oregon Health and Science University, Portland, Oregon
| | - Uziel Sauceda
- RUHS/UCR Sports Medicine Fellowship, Moreno Valley California
- Riverside University Health System/University of California Riverside, Moreno Valley California
| | - Davide Bianchi
- Chief Medical Officer SwissBoxing, Verbandarzt SwissBoxing, Switzerland
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Pak K, Sachar R, Saab S. Projected Mitigation of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B in the Gray Zone and the Immune-Tolerant Phase in the United States. Dig Dis Sci 2025; 70:1547-1554. [PMID: 39979574 DOI: 10.1007/s10620-025-08909-z] [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: 11/23/2024] [Accepted: 02/02/2025] [Indexed: 02/22/2025]
Abstract
PURPOSE Based on current practice guidelines, there are a substantial number of individuals who do not meet criteria for chronic hepatitis B (CHB) treatment eligibility but may be at risk of developing HCC. We sought to determine the estimated number of untreated patients with CHB in the Gray Zone or immune-tolerant phase who would develop HCC. METHODS US epidemiologic data were obtained from the US Department of HHS. The literature was reviewed for studies that analyzed the distribution of phases of CHB patients including the Gray Zone and studies that determined the cumulative incidence of HCC over a set period unique to both the Gray Zone and the immune-tolerant phase populations. We modeled the projected number of patients in each group who would develop HCC in a period of 5 and 10 years. RESULTS There are about 880,000 to 1.89 million people living with CHB in the US. Based on our model, we estimated 1224-4146 patients and 6662-22,574 patients will likely develop HCC in 5 years and 10 years, respectively, if left untreated in the high viral load and normal liver enzyme Gray Zone. An estimated 356-1537 patients and 873-3774 patients will develop HCC in 5 years and 10 years, respectively, if left untreated in the immune-tolerant phase of CHB. Among patients who develop cirrhosis in the Gray Zone, approximately, 1615-5471 patients will develop HCC. CONCLUSION Current guidelines do not recommend hepatitis B antiviral therapy in patients in the Gray Zone and the immune-tolerant phase. Patients who fall into these categories are still at risk for HCC. By the numbers, the projected number of patients to develop HCC among these populations is in the order of thousands. Future guidelines should explore increasing treatment eligibility for potential mitigation of HCC burden in the US.
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Affiliation(s)
- Kevin Pak
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Ryan Sachar
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Sammy Saab
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
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5
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Jia Y, Qi X, Yu X, Dong M, Wu J, Li J, He J, Ma Z, Zhang X, Xie Y, Guo Y, Mao R, Huang Y, Li F, Zhu H, Zhang J. Accuracy of International Guidelines in Identifying Normal Liver Histology in Chinese Patients With HBeAg-Positive Chronic HBV Infection. J Viral Hepat 2025; 32:e14024. [PMID: 39535479 DOI: 10.1111/jvh.14024] [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: 07/25/2024] [Revised: 09/25/2024] [Accepted: 09/29/2024] [Indexed: 11/16/2024]
Abstract
We evaluated the diagnostic accuracy of various international guideline criteria for identifying HBeAg-positive chronic HBV infection patients with no significant liver disease. A total of 1108 HBeAg-positive CHB patients were retrospectively enrolled. The guidelines assessed included those from the European Association for the Study of the Liver (EASL) 2017, the American Association for the Study of the Liver Disease (AASLD) 2018, the Asian Pacific Association for the Study of the Liver (APASL) 2015 and the Chinese Society of Hepatology (CSH) 2022. The CSH criteria demonstrated a higher proportion of patients with G0-1 and S0-1 (82.9%) compared to the EASL (75.9%), AASLD (75.3%) and APASL groups (58.8%). Additionally, the CSH criteria exhibited a significantly higher predictive value (AUC 0.782, 95% CI 0.754-0.809) than the EASL (AUC 0.765, 95% CI 0.737-0.793), AASLD (AUC 0.749, 95% CI 0.720-0.778) and APASL (AUC 0.720, 95% CI 0.690-0.750) criteria for identifying G0-1 and S0-1. Adding quantitative HBsAg levels (> 104 IU/mL) to the EASL, AASLD and APASL criteria improved diagnostic performance. Consequently, the CSH guideline thresholds showed higher accuracy in identifying Chinese HBeAg-positive patients with no significant liver disease compared to EASL, AASLD and APASL criteria, emphasising the importance of considering quantitative HBsAg in the evaluation of HBeAg-positive chronic HBV infection.
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Affiliation(s)
- Yidi Jia
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Xun Qi
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xueping Yu
- Department of Infectious Diseases, The First Hospital of Quanzhou, Fujian Medical University, Fujian, China
| | - Minhui Dong
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jingwen Wu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jing Li
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jingjing He
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhenxuan Ma
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Xueyun Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yiran Xie
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yue Guo
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Richeng Mao
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yuxian Huang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Fahong Li
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Haoxiang Zhu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University, Shanghai, China
- Department of Infectious Diseases, Jing' An Branch of Huashan Hospital, Fudan University, Shanghai, China
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Liang H, Wang H, Liang M, Zhang X, Dai M, Li H, Li X, Yin X, Liu X, Yao J, Guan Z, Qiu Y. The prognosis and immune repertoire characteristics of HBsAg and anti-HBs double positive chronic hepatitis B patients. Clin Exp Med 2025; 25:32. [PMID: 39775320 PMCID: PMC11711149 DOI: 10.1007/s10238-024-01537-3] [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: 08/14/2024] [Accepted: 12/07/2024] [Indexed: 01/11/2025]
Abstract
Coexistence of hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) has been observed in some chronic hepatitis B (CHB) patients (DP patients), but the clinical outcomes and comprehensive characterization of immune micro-environmental changes for this specific population remain inconclusive. In this study, we retrospectively analyze the prognosis of 305 patients in Foshan City, Guangdong Province, China, and also investigated the molecular immunology changes in HBsAg and anti-HBs double positive CHB patients (DP group), CHB patients who had recovered from IFN-ɑ treatment (RP group), and healthy controls (HC group) using T cell receptor (TCR) and B cell receptor (BCR) immune repertoire sequencing. Our findings revealed that 22.30% of DP patients were diagnosed with severe liver disease. Immune repertoire sequencing revealed significant skewing in the diversities of T cell receptor β-chain (TRB) and immunoglobulin heavy chain (IGH) in the DP group compared to the RP group. Unique V(D)J gene combinations, such as IGHV1-18/IGHD3-22/IGHJ5, IGHV1-8/IGHD6-13/IGHJ3, and IGHV1-8/IGHD6-19/IGHJ3, as well as TRBV12-3/TRBD1/TRBJ1-5 and TRBV11-2/TRBD2/TRBJ2-1, exhibited distinct utilization patterns in the DP group. Moreover, the top ten most utilized amino acid motifs in the complementarity determining region 3 (CDR3) of TRB in the DP group showed significant differences from those in the RP group. Notably, motifs such as "xxxYDSSGYx" and "AREx" in the IGH CDR3s were selectively prevalent in the DP group. These findings are expected to provide evidence supporting the poor clinical prognosis of DP patients and offer new insights into the distinct immune micro-environmental changes of this group.
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Affiliation(s)
- Huijun Liang
- The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, 528225, China
| | - Haifang Wang
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Minfeng Liang
- Department of Infectious Diseases, The First People's Hospital of Foshan, Foshan, 528000, China
| | - Xiaobin Zhang
- The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, 528225, China
| | - Meifen Dai
- The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, 528225, China
| | - Haixia Li
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xin Li
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xiaofeng Yin
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xinyao Liu
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jiaqi Yao
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ziyun Guan
- The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, 528225, China.
| | - Yurong Qiu
- Guangzhou Huayin Health Medical Group Co., Ltd, Guangzhou, 510515, China.
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Xing T. Existing problems and new advice on stage criteria of natural history for chronic hepatitis B. BMC Infect Dis 2025; 25:17. [PMID: 39754052 PMCID: PMC11699759 DOI: 10.1186/s12879-024-10408-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Accepted: 12/24/2024] [Indexed: 01/06/2025] Open
Abstract
The natural stages of chronic hepatitis B can be divided into four stages according to changes in virology, biochemistry, and pathology. However, there have been significant differences in the recommended stage criteria in the several major guidelines for chronic hepatitis B, especially regarding the immune tolerance phase. Inconsistent standards of indicators for different stages resulted in some problems, such as incorrect stage, uncertain stages and poor comparation of related studies. We propose suggestions for revisions to the stage criteria for CHB based on recent researches, including three stages: immune tolerance stage, immune clearance stage, and immune control stage. These revision suggestions rationalize some of the existing problems with the stage criteria for CHB and can significantly reduce the number of patients in the "uncertain stage" or "gray zone," which is particularly valuable in guiding clinical practice. However, further clinical studies with large samples are needed to confirm these suggestions.
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Affiliation(s)
- Tongjing Xing
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, China.
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Zhang J, Yu S, Zhu K, Li S, Huang Y. Probability analysis of hepatocellular carcinoma in hepatitis patients in the gray zone. Front Med (Lausanne) 2024; 11:1464981. [PMID: 39776842 PMCID: PMC11703914 DOI: 10.3389/fmed.2024.1464981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Objective To investigate the probability of hepatocellular carcinoma (HCC) in a large number of gray-zone (GZ) patients with chronic hepatitis B (CHB) in clinical practice. Methods The patients with CHB who were diagnosed and treated in our hospital from January 2013 to January 2023 were analyzed retrospectively. Results According to the different levels of HBeAg, ALT and HBV DNA, GZ patients were divided into four categories: (1) Gray zone A (GZ-A): HBeAg positive, normal ALT level, HBV DNA ≤ 106 IU/ml; (2) Gray zone B (GZ-B): HBeAg positive, ALT>ULN, HBV DNA ≤ 2 × 104 IU/ml; (3) Gray zone C (GZ-C): HBeAg negative, normal ALT level, HBV DNA ≥ 2 × 103 IU/ml; and (4) Gray zone D (GZ-D): HBeAg negative, ALT > ULN, serum HBV DNA ≤ 2 × 103 IU/ml. This observational study showed that after adjustment using inverse probability of treatment weighting (IPTW), the probability of developing HCC in the GZ group was similar to that in the immune-tolerant, HBeAg-positive immune active, and inactive groups. The IPTW-adjusted analysis revealed that the probability of developing HCC in the GZ-B subgroup was similar to that in the immune-active and HBeAg-negative immune-active groups. Conclusion The GZ group and GZ-B subgroup have a higher risk of HCC. Anti-hepatitis B virus therapy should be considered as early as possible for patients in the GZ group, especially in the GZ-B subgroup.
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Affiliation(s)
- Jianna Zhang
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Sijie Yu
- Department of Infectious Diseases, Zhoushan Hospital, Wenzhou Medical University, Zhoushan, China
| | - Kailu Zhu
- Department of Infectious Diseases, Taizhou First People's Hospital, Taizhou, China
| | - Shibo Li
- Department of Infectious Diseases, Zhoushan Hospital, Wenzhou Medical University, Zhoushan, China
| | - Yu Huang
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Li J, Liu S, Zang Q, Yang R, Zhao Y, He Y. Current trends and advances in antiviral therapy for chronic hepatitis B. Chin Med J (Engl) 2024; 137:2821-2832. [PMID: 38945693 PMCID: PMC11649291 DOI: 10.1097/cm9.0000000000003178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Indexed: 07/02/2024] Open
Abstract
ABSTRACT Chronic hepatitis B virus (HBV) infection is a global public health concern. Existing antiviral drugs, including nucleos(t)ide analogs and interferon-α, can suppress HBV replication and improve the prognosis. However, the persistence of covalently closed circular DNA (cccDNA), the integration of HBV-DNA into the host genome, and compromised immune responses impede the successful treatment of hepatitis B. While achieving a functional cure of HBV remains elusive with the current treatment methods, this is the goal of new therapeutic approaches. Therefore, developing novel antiviral drugs is necessary for achieving a functional or complete cure for chronic hepatitis B. In recent years, substantial progress has been made in drug discovery and development for HBV infection. Direct-acting antiviral agents such as entry inhibitors, capsid assembly modulators, subviral particle release inhibitors, cccDNA silencers, and RNA interference molecules have entered clinical trials. In addition, several immunomodulatory agents, including toll-like receptor agonists, therapeutic vaccines, checkpoint inhibitors, and monoclonal antibodies, are also making their way toward clinical use. In this review, we summarize the recent progress and limitations of chronic hepatitis B treatment and discuss perspectives on approaches to achieving functional cure. Although it will take some time for these new antiviral drugs to be widely used in clinical practice, combination therapy may become a preferable treatment option in the future.
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Affiliation(s)
- Juan Li
- Department of Infectious Diseases, First Affiliated Teaching Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
- Institution of Hepatology, First Affiliated Teaching Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
| | - Siyi Liu
- Department of Infectious Diseases, First Affiliated Teaching Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
| | - Qijuan Zang
- Department of Infectious Diseases, First Affiliated Teaching Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
| | - Ruijie Yang
- Institution of Hepatology, First Affiliated Teaching Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
| | - Yingren Zhao
- Department of Infectious Diseases, First Affiliated Teaching Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
- Institution of Hepatology, First Affiliated Teaching Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
- Shaanxi Clinical Research Center of Infectious Diseases, Xi’an, Shaanxi 710061, China
- Clinical Research Center for Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
| | - Yingli He
- Department of Infectious Diseases, First Affiliated Teaching Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
- Institution of Hepatology, First Affiliated Teaching Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
- Shaanxi Clinical Research Center of Infectious Diseases, Xi’an, Shaanxi 710061, China
- Clinical Research Center for Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
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10
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Li Y, Zhu Y, Gao D, Pan Y, Wang J, Zhang S, Yan X, Zhu L, Zhu C, Liu X, Zhang Z, Li J, Chen Y, Huang R, Wu C. HBeAg-positive CHB patients with indeterminate phase associated with a high risk of significant fibrosis. Virol J 2024; 21:287. [PMID: 39538258 PMCID: PMC11562367 DOI: 10.1186/s12985-024-02561-1] [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: 09/18/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND The risk of liver fibrosis in HBeAg-positive chronic hepatitis B (CHB) patients with indeterminate phase is not well characterized. We aimed to compare the presence of liver fibrosis in HBeAg-positive CHB patients between indeterminate phase and immune-tolerant phase. METHODS This multi-center, retrospective cohort study included 719 treatment-naïve HBeAg-positive CHB patients with normal alanine aminotransferase (ALT). Patients with HBV DNA > 106 IU/mL were categorized into immune-tolerant phase, whereas those with HBV DNA ≤ 106 IU/mL were classified into indeterminate phase. Significant liver fibrosis and cirrhosis were determined by APRI, FIB-4, transient elastography, or liver biopsy. RESULTS The median age of patients was 33.0 years and 59.8% of patients were male. 81.5% and 18.5% of patients were in the immune-tolerant phase and indeterminate phase, respectively. The APRI (0.33 vs. 0.27, P < 0.001), FIB-4 (1.07 vs. 0.72, P < 0.001), and liver stiffness values (7.80 kPa vs. 5.65 kPa, P = 0.011) were higher in patients with indeterminate phase than those with immune-tolerant phase. Patients in the indeterminate phase had significantly higher proportions of significant fibrosis (27.1% vs. 11.3%, P < 0.001) and cirrhosis (14.3% vs. 3.2%, P < 0.001) compared to those in the immune-tolerant phase. In the multivariate analysis, indeterminate phase (OR 2.138, 95% CI 1.253, 3.649, P = 0.005) was associated with a higher risk of significant fibrosis, especially for patients aged ≥ 30 years. CONCLUSION HBeAg-positive CHB patients in the indeterminate phase had more severe liver fibrosis compared to those in the immune-tolerant phase.
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Affiliation(s)
- Yuanyuan Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yijia Zhu
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dongmei Gao
- Department of Public Health, Huai'an No. 4 People's Hospital, Huai'an, Jiangsu, China
| | - Yifan Pan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jian Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Shaoqiu Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Xiaomin Yan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Li Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Chuanwu Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xingxiang Liu
- Department of Clinical Laboratory, Huai'an No. 4 People's Hospital, Huai'an, Jiangsu, China
| | - Zhaoping Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Yuxin Chen
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China.
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China.
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China.
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11
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Ismael NY, Usmael SA, Belay NB, Mekonen HD, Johannessen A, Orlien SM. Chronic hepatitis B virus infection in Eastern Ethiopia: Clinical characteristics and determinants of cirrhosis. World J Hepatol 2024; 16:995-1008. [PMID: 39086536 PMCID: PMC11287608 DOI: 10.4254/wjh.v16.i7.995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 06/14/2024] [Accepted: 07/05/2024] [Indexed: 07/26/2024] Open
Abstract
BACKGROUND Chronic hepatitis B (CHB) virus infection is a major cause of liver-associated morbidity and mortality, particularly in low-income countries. A better understanding of the epidemiological, clinical, and virological characteristics of CHB will guide appropriate treatment strategies and improve the control and management of CHB in Ethiopia. AIM To investigate the characteristics of CHB in Eastern Ethiopia and assess the efficacy and safety of antiviral treatment. METHODS This cohort study included 193 adults who were human immunodeficiency virus-negative with CHB between June 2016 and December 2019. Baseline assessments included chemistry, serologic, and viral markers. χ 2 tests, Mann-Whitney U tests, and logistic regression analyses were used to identify the determinants of cirrhosis. Tenofovir disoproxil fumarate (TDF) was initiated using treatment criteria from the Ethiopian CHB pilot program. RESULTS A total of 132 patients (68.4%) were men, with a median age of 30 years [interquartile range (IQR): 24-38]. At enrollment, 60 (31.1%) patients had cirrhosis, of whom 35 (58.3%) had decompensated cirrhosis. Khat use, hepatitis B envelope antigen positivity, and a high viral load were independently associated with cirrhosis. Additionally, 66 patients (33.4%) fulfilled the treatment criteria and 59 (30.6%) started TDF. Among 29 patients who completed 24 months of treatment, the median aspartate aminotransferase to platelet ratio index declined from 1.54 (IQR: 0.66-2.91) to 1.10 (IQR: 0.75-2.53) (P = 0.002), and viral suppression was achieved in 80.9% and 100% of patients after 12 months and 24 months of treatment, respectively. Among the treated patients, 12 (20.3%) died within the first 6 months of treatment, of whom 8 had decompensated cirrhosis. CONCLUSION This study highlights the high prevalence of cirrhosis, initial mortality, and the efficacy of TDF treatment. Scaling up measures to prevent and control CHB infections in Ethiopia is crucial.
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Affiliation(s)
- Nejib Y Ismael
- Department of Internal Medicine, Haramaya University, College of Health and Medical Sciences, Harar 252, Ethiopia
| | - Semir A Usmael
- Department of Internal Medicine, Haramaya University, College of Health and Medical Sciences, Harar 252, Ethiopia.
| | - Nega B Belay
- Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa 1000, Ethiopia
- Regional Centre for Imported and Tropical Diseases, Oslo University Hospital, Oslo 0450, Ullevål, Norway
| | - Hailemichael Desalegn Mekonen
- Internal Medicine, Gastroenterology and Hepatology Unit, Saint Paul's Hospital Millennium Medical College, Addis Ababa 1000, Ethiopia
- Department of Infectious Disease, Vestfold Hospital Trust, Tønsberg 3103, Norway
| | - Asgeir Johannessen
- Regional Centre for Imported and Tropical Diseases, Oslo University Hospital, Oslo 0450, Ullevål, Norway
- Department of Infectious Disease, Vestfold Hospital Trust, Tønsberg 3103, Norway
- Institute of Clinical Medicine, Oslo University, Oslo 0318, Norway
| | - Stian Ms Orlien
- Regional Centre for Imported and Tropical Diseases, Oslo University Hospital, Oslo 0450, Ullevål, Norway
- Department of Infectious Disease, Vestfold Hospital Trust, Tønsberg 3103, Norway
- Department of Pediatrics, Oslo University, Oslo 0450, Ullevål, Norway
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12
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Duan M, Xiao H, Shi M, Xie Y, Zhao P, Li S, Chi X, Liu X, Zhuang H. Significant liver histological change is common in HBeAg-positive chronic hepatitis B with normal ALT. BMC Infect Dis 2024; 24:723. [PMID: 39044129 PMCID: PMC11264461 DOI: 10.1186/s12879-024-09617-1] [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: 08/31/2023] [Accepted: 07/15/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND AND AIMS Numerous HBeAg-positive chronic hepatitis B (CHB) patients with persistently normal ALT have significant liver histopathology. It is imperative to identify true "immune tolerant" patients. We aimed to evaluate the liver histopathology features of HBeAg-positive CHB patients with normal ALT and the incidence of liver cirrhosis and HCC in CHB patients during follow-up. METHODS 179 HBeAg-positive CHB patients with normal ALT who performed liver biopsy from 2009 to 2018 were retrospectively analyzed. Liver necroinflammation ≥ G2 and/or liver fibrosis ≥ S2 was defined as significant liver histopathological change. RESULTS 57.5% patients were in the indeterminate phase with significant liver histological changes. The proportion of the patients with evident liver necroinflammation was higher in the high-normal ALT group (21-40U/L) when compared with the low-normal ALT group (≤ 20 U/L) (51.3% vs. 30.0%, p < 0.05), and patients aged ≥ 40 years had a higher proportion of significant fibrosis than those aged < 40 years (64.5% vs. 39.9%, p < 0.05). The percentages of patients with ≥ S2 and ≥ G2/S2 in the HBV DNA < 107 IU/mL group were higher than those in the HBV DNA ≥ 107 IU/mL group (72.7% vs. 40.1%, p < 0.01; 81.8% vs. 54.1%, p < 0.05). During follow-up, two of immune tolerant patients and four of indeterminate patients developed into cirrhosis, and one of immune tolerant patients and one of indeterminate patients developed into HCC, respectively. CONCLUSIONS HBeAg-positive CHB patients with high-normal ALT or HBV DNA < 107 IU/mL were tend to be indeterminate. Liver biopsy or noninvasive approaches are recommended to evaluate liver histopathology, and antiviral therapy is recommended for patients with significant liver histopathology.
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Affiliation(s)
- Menghui Duan
- Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China
- The Clinical Laboratory of Tianjin Chest Hospital, Tianjin, China
| | - Huanming Xiao
- Hepatology Department, Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Guangzhou, Guangdong Province, 510120, China
| | - Meijie Shi
- Hepatology Department, Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Guangzhou, Guangdong Province, 510120, China
| | - Yubao Xie
- Hepatology Department, Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Guangzhou, Guangdong Province, 510120, China
| | - Pengtao Zhao
- Hepatology Department, Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Guangzhou, Guangdong Province, 510120, China
| | - Sheng Li
- Hepatology Department, Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Guangzhou, Guangdong Province, 510120, China
| | - Xiaoling Chi
- Hepatology Department, Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Guangzhou, Guangdong Province, 510120, China.
| | - Xueen Liu
- Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China.
| | - Hui Zhuang
- Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China.
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Liu M, Zhao T, Zhang J, Bu B, Zhang R, Xia X, Geng J. Estimating the key outcomes and hepatocellular carcinoma risk in patients in immune-tolerant phase of chronic hepatitis B virus infection: A systematic review and meta-analysis. Rev Med Virol 2024; 34:e2570. [PMID: 38964866 DOI: 10.1002/rmv.2570] [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: 03/02/2024] [Revised: 06/10/2024] [Accepted: 06/26/2024] [Indexed: 07/06/2024]
Abstract
The question of whether patients in the immune-tolerant (IT) phase of chronic hepatitis B virus (HBV) infection should undergo antiviral therapy and determine the optimal regimen remains unclear. A comprehensive search of PubMed, Embase, MEDLINE, Cochrane Library, and Wanfang Data from inception to 5 December 2023, was conducted. Studies reporting on key outcomes such as HBV DNA undetectability, HBeAg loss or seroconversion, HBsAg loss or seroconversion, and hepatocellular carcinoma (HCC) incidence in patients in the IT phase of chronic HBV infection were included. In total, 23 studies were incorporated. Approximately 4% of patients in the IT phase achieved spontaneous HBeAg loss over 48 weeks of follow-up. Antiviral therapy demonstrated a favourable impact on HBV DNA negative conversion (Children: risk ratios [RR] = 6.83, 95% CI: 2.90-16.05; Adults: RR = 25.84, 95% CI: 6.47-103.31) and HBsAg loss rates (Children: RR = 9.49, 95% CI: 1.74-51.76; Adults: RR = 7.35, 95% CI: 1.41-38.27) for patients in the IT phase. Subgroup analysis revealed that in adult patients in the IT phase, interferon plus nucleos(t)ide analogues (NA)-treated patients exhibited a higher pooled rate of HBsAg loss or seroconversion than those treated with NA monotherapy (9% vs. 0%). Additionally, the pooled annual HCC incidence for patients in the IT phase was 3.03 cases per 1000 person-years (95% CI: 0.99-5.88). Adult patients in the IT phase had a significantly lower HCC incidence risk than HBeAg-positive indeterminate phase patients (RR = 0.46, 95% CI: 0.32-0.66), with no significant differences observed between IT and immune-active phases. Presently, there is insufficient evidence solely based on reducing the risk of HCC incidence, to recommend treating patients in the IT phase of chronic HBV infection. However, both adult and paediatric patients in the IT phase responded well to antiviral therapy, showing favourable rates of HBsAg loss or seroconversion.
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Affiliation(s)
- Min Liu
- Department of Infectious Disease and Hepatic Disease, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Taixue Zhao
- Medical School of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Jinyang Zhang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Bing Bu
- Department of Infectious Disease and Hepatic Disease, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Ruyi Zhang
- Department of Infectious Disease and Hepatic Disease, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Xueshan Xia
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, China
- Kunming Medical University, Kunming, Yunnan, China
| | - Jiawei Geng
- Department of Infectious Disease and Hepatic Disease, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
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Huang D, Lai H, Zhu Z, Yu H, Peng J, Chen Y, Liao X, Chen J. Inverse relationship between HBV DNA levels and liver histopathological changes in immune-tolerant CHB patients. J Viral Hepat 2024; 31:363-371. [PMID: 38581159 DOI: 10.1111/jvh.13940] [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: 01/29/2024] [Revised: 03/21/2024] [Accepted: 03/23/2024] [Indexed: 04/08/2024]
Abstract
Limited data exist regarding the association between hepatitis B virus (HBV) DNA levels and liver histopathological changes in patients with chronic hepatitis B (CHB) during the immune tolerant (IT) phase. In this study, we retrospectively analysed liver biopsy results from 150 adult IT-CHB patients. The liver tissue necroinflammation and fibrosis were evaluated by the Scheuer scoring system. Multivariate logistic regression, smooth curve fitting, and segmented regression models were used to examine the association between HBV DNA levels and liver histopathological changes. A total of 26%, 30.67% and 42% of IT patients had significant necroinflammation (≥G2), significant fibrosis (≥S2) and significant histopathological changes (≥G2 and/or ≥S2), respectively. HBV DNA levels were independently and non-linear inversely associated with significant necroinflammation and histopathological changes in IT-CHB patients. Patients with HBV DNA levels <107 IU/mL had a higher risk of significant histopathological changes compared to those with levels >107 IU/mL. The findings were further confirmed by smooth curve fitting analyses, subgroup and sensitivity analyses. In segmented regression model analyses, the optimal DNA value for the lowest odds ratio of significant histopathological changes was 7.26 log10 IU/mL. A non-linear inverse association between HBV DNA levels and significant histopathological changes in IT-CHB patients. DNA 7.26 log10 IU/mL may serve as a potential cut-off point to define a 'true immune tolerant phase' with minimal liver histopathological changes.
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Affiliation(s)
- Deliang Huang
- Department of Liver Diseases, The Third People's Hospital of Shenzhen, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Huiyi Lai
- Department of Liver Diseases, The Third People's Hospital of Shenzhen, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Zhibin Zhu
- Department of Liver Diseases, The Third People's Hospital of Shenzhen, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Hong Yu
- Department of Pathology, The Third People's Hospital of Shenzhen, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Jinghan Peng
- Department of Liver Diseases, The Third People's Hospital of Shenzhen, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Yuanyuan Chen
- Department of Liver Diseases, The Third People's Hospital of Shenzhen, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Xuejiao Liao
- Department of Liver Diseases, The Third People's Hospital of Shenzhen, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Jun Chen
- Department of Liver Diseases, The Third People's Hospital of Shenzhen, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
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15
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Wang J, Zhu L, Zhang Z, Zhang S, Pan Y, Li Y, Cao F, Jiang C, Fan T, Xiong Y, Liu J, Chen Y, Yin S, Tong X, Zhu C, Liu X, Li J, Wu C, Huang R. Lower HBV DNA level is associated with more severe liver fibrosis in HBeAg-positive chronic hepatitis B with normal alanine transaminase. Virol J 2024; 21:127. [PMID: 38835029 PMCID: PMC11151594 DOI: 10.1186/s12985-024-02368-0] [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: 01/12/2024] [Accepted: 04/16/2024] [Indexed: 06/06/2024] Open
Abstract
BACKGROUND The association of hepatitis B virus (HBV) DNA levels and liver fibrosis in chronic hepatitis B (CHB) patients with immune-tolerant phase remains unclear. We explored the association between liver fibrosis and HBV DNA levels in HBeAg-positive CHB patients with normal alanine transaminase (ALT) with relatively high HBV DNA. METHODS Six hundred and twenty-two HBeAg-positive CHB patients with normal ALT were included. Patients were divided into three categories: low (6 log10 IU/mL ≤ HBV DNA < 7 log10 IU/mL), moderate (7 log10 IU/mL ≤ HBV DNA < 8 log10 IU/mL), and high (HBV DNA ≥ 8 log10 IU/mL). APRI, FIB-4, transient elastography, or liver biopsy were used to assess liver fibrosis. RESULTS The median age of patients was 33.0 years and 57.9% patients were male. 18.8%, 52.1%, and 29.1% of patients had low, moderate, and high HBV DNA levels, respectively. The APRI (0.33 vs. 0.26 vs. 0.26, P < 0.001), FIB-4 (1.03 vs. 0.71 vs. 0.68, P < 0.001), and LSM values (7.6 kPa vs. 5.6 kPa vs. 5.5 kPa, P = 0.086) were higher in low HBV DNA group than other two groups. Low HBV DNA group had higher proportions of significant fibrosis (24.8% vs. 9.9% vs. 3.3%, P < 0.001) and cirrhosis (7.7% vs. 2.5% vs. 1.1%, P = 0.004) than moderate and high HBV DNA groups. Moderate (OR 3.095, P = 0.023) and low (OR 4.968, P = 0.003) HBV DNA were independent risk factors of significant fibrosis. CONCLUSION Lower HBV DNA level was associated with more severe liver fibrosis in HBeAg-positive CHB patients with ALT.
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Affiliation(s)
- Jian Wang
- Department of Infectious Diseases, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Li Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Zhiyi Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Shaoqiu Zhang
- Department of Infectious Diseases, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China
| | - Yifan Pan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuanyuan Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Fei Cao
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Chao Jiang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, Jiangsu, China
| | - Tao Fan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Ye Xiong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jiacheng Liu
- Department of Infectious Diseases, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China
| | - Yuxin Chen
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Xin Tong
- Department of Infectious Diseases, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Chuanwu Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xingxiang Liu
- Department of Clinical Laboratory, Huai'an No. 4 People's Hospital, Huai'an, Jiangsu, China
| | - Jie Li
- Department of Infectious Diseases, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China.
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China.
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
| | - Chao Wu
- Department of Infectious Diseases, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China.
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China.
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
| | - Rui Huang
- Department of Infectious Diseases, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China.
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China.
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China.
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, Jiangsu, China.
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Tang J, Zhang J, Zhang G, Peng W, Ling N, Zhou Y, Xu H, Ren H, Chen M. Stat3 activation-triggered transcriptional networks govern the early stage of HBV-induced hepatic inflammation. mBio 2024; 15:e0306823. [PMID: 38440978 PMCID: PMC11005361 DOI: 10.1128/mbio.03068-23] [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: 11/17/2023] [Accepted: 02/01/2024] [Indexed: 03/06/2024] Open
Abstract
The chronic carrier state of the hepatitis B virus (HBV) often leads to the development of liver inflammation as carriers age. However, the exact mechanisms that trigger this hepatic inflammation remain poorly defined. We analyzed the sequential processes during the onset of liver inflammation based on time-course transcriptome and transcriptional regulatory networks in an HBV transgenic (HBV-Tg) mice model and chronic HBV-infected (CHB) patients (data from GSE83148). The key transcriptional factor (TF) responsible for hepatic inflammation occurrence was identified and then validated both in HBV-Tg mice and liver specimens from young CHB patients. By time-course analysis, an early stage of hepatic inflammation was demonstrated in 3-month-old HBV-Tg mice: a marked upregulation of genes related to inflammation (Saa1/2, S100a8/9/11, or Il1β), innate immunity (Tlr2, Tlr7, or Tlr8), and cells chemotaxis (Ccr2, Cxcl1, Cxcl13, or Cxcl14). Within CHB samples, a unique early stage of inflammation activation was discriminated from immune tolerance and immune activation groups based on distinct gene expression patterns. Enhanced activation of TF Stat3 was strongly associated with increased inflammatory gene expression in this early stage of inflammation. Expression of phosphorylated Stat3 was higher in liver specimens from young CHB patients with relatively higher alanine aminotransferase levels. Specific inhibition of Stat3 activation significantly attenuated the degree of liver inflammation, the expression of inflammation-related genes, and the inflammatory monocytes and macrophages in 3-month-old HBV-Tg mice. Stat3 activation is essential for hepatic inflammation occurrence and is a novel indicator of early-stage immune activation in chronic HBV carriers. IMPORTANCE Until now, it remains a mystery that chronic hepatitis B virus (HBV)-infected patients in the "immune tolerance phase" will transition to the "immune activation phase" as they age. In this study, we reveal that Stat3 activation-triggered hepatic transcriptional alterations are distinctive characteristics of the early stage of immune/inflammation activation in chronic HBV infection. For the first time, we discover a mechanism that might trigger the transition from immune tolerance to immune activation in chronic HBV carriers.
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Affiliation(s)
- Jinglin Tang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Transfusion Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Jiaxuan Zhang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Laboratory Medicine, Bishan Hospital of Chongqing Medical University, Bishan Hospital of Chongqing, Chongqing, China
| | - Gaoli Zhang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenhui Peng
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ning Ling
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yingzhi Zhou
- Department of Infection, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Hongmei Xu
- Department of Infection, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Ren
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Min Chen
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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He J, Miao R, Chen Y, Wang H, Liu M. The dual role of regulatory T cells in hepatitis B virus infection and related hepatocellular carcinoma. Immunology 2024; 171:445-463. [PMID: 38093705 DOI: 10.1111/imm.13738] [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: 08/07/2023] [Accepted: 11/27/2023] [Indexed: 03/09/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a major contributor to cancer-related deaths worldwide. Hepatitis B virus (HBV) infection is a major etiologic factor leading to HCC. While there have been significant advancements in controlling HBV replication, achieving a complete cure for HBV-related HCC (HBV-HCC) remains an intricate challenge. HBV persistence is attributed to a myriad of mechanisms, encompassing both innate and adaptive immune responses. Regulatory T cells (Tregs) are pivotal in upholding immune tolerance and modulating excessive immune activation. During HBV infection, Tregs mediate specific T cell suppression, thereby contributing to both persistent infection and the mitigation of liver inflammatory responses. Studies have demonstrated an augmented expression of circulating and intrahepatic Tregs in HBV-HCC, which correlates with impaired CD8+ T cell function. Consequently, Tregs play a dual role in the context of HBV infection and the progression of HBV-HCC. In this comprehensive review, we discuss pertinent studies concerning Tregs in HBV infection, HBV-related cirrhosis and HCC. Furthermore, we summarize Treg responses to antiviral therapy and provide Treg-targeted therapies specific to HBV and HCC.
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Affiliation(s)
- Jinan He
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Rui Miao
- Guangzhou Women and Children Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yao Chen
- Department of Internal Medicine, Northeast Yunnan Regional Central Hospital, Zhaotong, Yunan, China
| | - Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mei Liu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Wei S, Xie Q, Liao G, Chen H, Hu M, Lin X, Li H, Peng J. Patients with chronic hepatitis B who have persistently normal alanine aminotransferase or aged < 30 years may exhibit significant histologic damage. BMC Gastroenterol 2024; 24:120. [PMID: 38532310 DOI: 10.1186/s12876-024-03208-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 03/18/2024] [Indexed: 03/28/2024] Open
Abstract
BACKGROUND The timing of antiviral therapy for chronic hepatitis B (CHB) patients with normal alanine transaminase (ALT) or aged < 30 years is still undetermined. We aimed to elucidate the correlation between liver histology, age, and ALT level in CHB patients and analyze the histological characteristics of the liver among patients with persistently normal ALT or aged < 30 years. METHODS A retrospective analysis was conducted on 697 treatment-naive CHB patients. Liver biopsies were performed, and significant histological damage was defined as the grade of liver inflammation ≥ G2 and/or fibrosis ≥ S2 based on the Scheuer scoring system. RESULTS The liver inflammation grades and fibrosis stages correlated positively with age, ALT, AST, GGT levels and negatively with the counts of PLT (all p < 0.050) in HBeAg-positive patients. Higher ALT levels and lower PLT counts were independently associated with significant liver inflammation and fibrosis in both HBeAg-positive and HBeAg-negative patients. Furthermore, among those with persistently normal ALT levels, the incidence of significant liver inflammation and fibrosis were 66.1% and 53.7% in HBeAg-positive groups, and 63.0% and 55.5% in HBeAg-negative groups. Moreover, there was no significant difference in the prevalence of significant liver damage between patients aged < 30 years and those aged ≥ 30 years, in both HBeAg-positive (≥ G2 or ≥ S2: 63.8% vs. 75.8%, p = 0.276) and HBeAg-negative (≥ G2 or ≥ S2: 65.9% vs. 72.5%, p = 0.504) groups, among patients with persistently normal ALT levels. CONCLUSIONS A considerable proportion of CHB patients with persistently normal ALT, including those below the age of 30 years, exhibited significant histological damage. This highlights the importance of initiating early antiviral therapy for HBV-infected individuals, even in the absence of elevated ALT levels.
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Affiliation(s)
- Sufang Wei
- Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Foshan, 528308, China
- Department of Infectious Diseases, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, 510080, China
| | - Qiuli Xie
- Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Foshan, 528308, China
| | - Guichan Liao
- Department of Infectious Diseases, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, 510080, China
| | - Hongjie Chen
- Department of Infectious Diseases, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, 510080, China
| | - Meixin Hu
- Department of Infectious Diseases, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, 510080, China
| | - Xiaoli Lin
- Department of Infectious Diseases, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, 510080, China
| | - Hong Li
- Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Foshan, 528308, China
| | - Jie Peng
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510080, China.
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Varghese N, Majeed A, Nyalakonda S, Boortalary T, Halegoua-DeMarzio D, Hann HW. Review of Related Factors for Persistent Risk of Hepatitis B Virus-Associated Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:777. [PMID: 38398168 PMCID: PMC10887172 DOI: 10.3390/cancers16040777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 01/30/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Chronic hepatitis B virus (HBV) infection is the largest global cause of hepatocellular carcinoma (HCC). Current HBV treatment options include pegylated interferon-alpha and nucleos(t)ide analogues (NAs), which have been shown to be effective in reducing HBV DNA levels to become undetectable. However, the literature has shown that some patients have persistent risk of developing HCC. The mechanism in which this occurs has not been fully elucidated. However, it has been discovered that HBV's covalently closed circular DNA (cccDNA) integrates into the critical HCC driver genes in hepatocytes upon initial infection; additionally, these are not targets of current NA therapies. Some studies suggest that HBV undergoes compartmentalization in peripheral blood mononuclear cells that serve as a sanctuary for replication during antiviral therapy. The aim of this review is to expand on how patients with HBV may develop HCC despite years of HBV viral suppression and carry worse prognosis than treatment-naive HBV patients who develop HCC. Furthermore, HCC recurrence after initial surgical or locoregional treatment in this setting may cause carcinogenic cells to behave more aggressively during treatment. Curative novel therapies which target the life cycle of HBV, modulate host immune response, and inhibit HBV RNA translation are being investigated.
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Affiliation(s)
- Nevin Varghese
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Amry Majeed
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Suraj Nyalakonda
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Tina Boortalary
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Hie-Won Hann
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
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20
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Liu YC, Jeng WJ. Should Indications for Antiviral Therapy for Hepatitis B Be Broadened to Include Immune-Tolerant Patients, Inactive Carriers, or Patients in the “Gray Zone”? CURRENT HEPATOLOGY REPORTS 2024; 23:11-21. [DOI: 10.1007/s11901-024-00635-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/04/2024] [Indexed: 01/04/2025]
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21
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Huang R, Liu J, Wang J, Qiu Y, Zhu L, Li Y, Liu Y, Zhan J, Xue R, Jiang S, Geng Y, Wan Y, Li M, Mao M, Gao D, Gu Y, Zhang Y, Yin S, Tong X, Xia J, Yan X, Ding W, Chen Y, Li J, Zhu C, Wu C. Histological features of chronic hepatitis B patients with normal alanine aminotransferase according to different criteria. Hepatol Commun 2024; 8:e0357. [PMID: 38206209 PMCID: PMC10786593 DOI: 10.1097/hc9.0000000000000357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 10/28/2023] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND The upper limits of normal (ULNs) for alanine aminotransferase (ALT) are different among international guidelines for chronic hepatitis B (CHB). We aimed to investigate the proportion of significant histological disease in Asian patients with CHB with detectable hepatitis B virus (HBV) DNA under diverse ALT ULNs. METHODS Consecutive patients with CHB and detectable HBV DNA who underwent liver biopsy were retrospectively included from four tertiary hospitals. Above grade 2 inflammation and stage 2 fibrosis were defined as significant inflammation and significant fibrosis, respectively. Significant histological disease was defined as above grade 2 inflammation or stage 2 fibrosis. RESULTS Among the 414 patients with detectable HBV DNA and normal ALT, the proportion of those with significant histological disease was lower (59.7%) according to the ULN for ALT at 30/19 U/L (male/female), while the corresponding proportions were 66.7% and 62.3% according to the ULNs of 40 U/L and 35/25 U/L (male/female), respectively. In patients with detectable HBV DNA and normal ALT levels without significant fibrosis, the proportions of significant inflammation were comparable among different ULNs of ALT at 40 U/L (30.7%), 35/25 U/L (27.3%) and 30/19 U/L (25.0%). The proportion of significant histological disease was significantly lower in patients with normal ALT for 2 determinations at least 6 months apart compared to patients with normal ALT once. CONCLUSIONS Although a more stringent ALT ULN may reduce the risk of the presence of significant histological disease in patients with detectable HBV DNA, the rates of significant histological disease remain high. Persistently normal ALT levels are more important for excluding patients with CHB with a high probability of significant histological disease.
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Affiliation(s)
- Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jiacheng Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Jian Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Yuanwang Qiu
- Department of Infectious Diseases, The Fifth People’s Hospital of Wuxi, Wuxi, Jiangsu, China
| | - Li Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yiguang Li
- Department of Infectious Diseases, The Fifth People’s Hospital of Wuxi, Wuxi, Jiangsu, China
| | - Yilin Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jie Zhan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ruifei Xue
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Suling Jiang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yu Geng
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yawen Wan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, Nanjing, Jiangsu, China
| | - Ming Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Minxin Mao
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Dongmei Gao
- Department of Hepatology, Huai’an No. 4 People’s Hospital, Huai’an, Jiangsu, China
| | - Yan Gu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yao Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Xin Tong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Juan Xia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Xiaomin Yan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Weimao Ding
- Department of Hepatology, Huai’an No. 4 People’s Hospital, Huai’an, Jiangsu, China
| | - Yuxin Chen
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Chuanwu Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
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You H, Wang F, Li T, Xu X, Sun Y, Nan Y, Wang G, Hou J, Duan Z, Wei L, Jia J, Zhuang H. Guidelines for the Prevention and Treatment of Chronic Hepatitis B (version 2022). J Clin Transl Hepatol 2023; 11:1425-1442. [PMID: 37719965 PMCID: PMC10500285 DOI: 10.14218/jcth.2023.00320] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 08/02/2023] [Accepted: 08/03/2023] [Indexed: 09/19/2023] Open
Abstract
To facilitate the achieving of the goal of "eliminating viral hepatitis as a major public health threat by 2030" set by the World Health Organization, the Chinese Society of Hepatology together with the Chinese Society of Infectious Diseases (both are branches of the Chinese Medical Association) organized a panel of experts and updated the guidelines for prevention and treatment of chronic hepatitis B in China (version 2022). With the support of available evidence, this revision of the guidelines focuses on active prevention, large scale testing, and expansion of therapeutic indication of chronic hepatitis B with the aim of reducing the hepatitis B related disease burden.
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Affiliation(s)
- Hong You
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Fusheng Wang
- The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Taisheng Li
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiaoyuan Xu
- Peking University First Hospital, Beijing, China
| | - Yameng Sun
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yuemin Nan
- Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | | | - Jinlin Hou
- Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhongping Duan
- Beijing You-An Hospital, Capital Medical University, Beijing, China
| | - Lai Wei
- Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hui Zhuang
- Peking University Health Science Center, Beijing, China
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23
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Su F, Jacobson IM. Chronic Hepatitis B: Treat all Who Are Viremic? Clin Liver Dis 2023; 27:791-808. [PMID: 37778770 DOI: 10.1016/j.cld.2023.06.001] [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] [Indexed: 10/03/2023]
Abstract
The main aim of antiviral therapy in patients with chronic hepatitis B (CHB) is to prevent disease progression and reduce the risk of hepatocellular carcinoma (HCC). In general, treatment is recommended for select patient groups viewed as being at higher risk of developing adverse outcomes from CHB. However, patients who do not meet treatment criteria under current international guidelines may still benefit from antiviral therapy to reduce CHB-related complications. Moreover, well-tolerated antiviral drugs that are highly effective at suppressing viral replication are now widely available, and withholding therapy from patients with viremia is increasingly controversial. In this article, we review traditional treatment paradigms and argue the merits of expanding treatment eligibility to patients with CHB who do not meet current treatment criteria.
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Affiliation(s)
- Feng Su
- Department of Medicine, New York University Grossman School of Medicine, 150 East 32nd Street, Suite 101, New York, NY 10016, USA; New York University Langone Transplant Institute, 317 East 34th Street, 8th Floor, New York, NY 10016, USA.
| | - Ira M Jacobson
- Department of Medicine, New York University Grossman School of Medicine, 150 East 32nd Street, Suite 101, New York, NY 10016, USA
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24
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Patel A, Dossaji Z, Gupta K, Roma K, Chandler TM, Minacapelli CD, Catalano K, Gish R, Rustgi V. The Epidemiology, Transmission, Genotypes, Replication, Serologic and Nucleic Acid Testing, Immunotolerance, and Reactivation of Hepatitis B Virus. GASTRO HEP ADVANCES 2023; 3:139-150. [PMID: 39129942 PMCID: PMC11307719 DOI: 10.1016/j.gastha.2023.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 10/18/2023] [Indexed: 08/13/2024]
Abstract
The epidemiology of Hepatitis B virus (HBV) has drastically changed in recent decades due to public health initiatives, including universal infant vaccination programs,urbanization driving global travel, and migration patterns. Despite screening of pregnant women and newborns significantly reducing the rate of perinatal transmission in certain parts of the world, other, perhaps more uncommon, routes (e.g., parenteral) have led to outbreaks in specific areas affected by the opioid epidemic and injection drug use. Although our current understanding of the effect of genetic variants of HBV is lacking, we review current knowledge and patterns of genetic variants with geographical predominance, pathophysiology, and clinical manifestations. Serologic and molecular markers are used to screen, identify phase and activity of infection, and monitor response to antivirals and/or reactivation. This review will provide the most up-to-date summary of the epidemiology, transmission, genotype, replication, and current methods of screening to follow the various phases of HBV, including immunotolerance and reactivation.
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Affiliation(s)
- Ankoor Patel
- Internal Medicine, Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences (RBHS), Rutgers University, New Brunswick, New Jersey
- Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Zahra Dossaji
- Internal Medicine, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas, Nevada
| | - Kapil Gupta
- Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Katerina Roma
- Internal Medicine, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas, Nevada
| | - Toni-Marie Chandler
- Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Carlos D. Minacapelli
- Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
- Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Kaitlyn Catalano
- Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Robert Gish
- Hepatitis B Foundation, Doylestown, Pennsylvania
| | - Vinod Rustgi
- Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
- Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
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25
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Zhang X, Wan Z, Lin M, Li Y, Wu X, Jiang J, Lin S, Chi X. Immunoglobulin A and complement C4 are involved in the progression of liver fibrosis in patients with chronic hepatitis B. Int Immunopharmacol 2023; 122:110604. [PMID: 37451022 DOI: 10.1016/j.intimp.2023.110604] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 06/28/2023] [Accepted: 07/02/2023] [Indexed: 07/18/2023]
Abstract
OBJECTIVE To explore the relationship between immunoglobulin A (IgA), complement C4, and liver fibrosis (L.F.) progression (LFP) in patients with chronic hepatitis B (CHB). METHODS This is a retrospective cohort study of CHB patients who received liver biopsies. Relevant data, including demographics, clinical serum markers, and immunological results obtained during liver biopsies, were collected and analyzed to assess and verify the relationship between IgA, C4, and LFP. RESULTS This study included 1,938 CHB patients, of whom 132 received two liver biopsies (group 1). Thirty (22.7%) of these patients were diagnosed with LFP (increase in L.F. stage (Scheuer score F ≥ 1)). IgA (C-IgA) and C4 (C-C4) change values between the first and second biopsies were independent risk factors for LFP. IgA levels increased, and C4 levels decreased during the second liver puncture. The remaining 1,806 patients received one liver puncture (group 2). They were divided into the following subgroups: A (F ≤ 1), B (1 < F ≤ 3), and C (F > 3) to verify whether the same trend was observed by cross-sectional study. IgA levels were highest, and C4 levels were lowest in group C (IgA: C > B > A, p < 0.05; C4: C < B < A, p < 0.05). CONCLUSIONS The findings of this study suggest that serum IgA and C4 levels are independent risk factors for LFP that could serve as future targets for L.F. management and treatment.
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Affiliation(s)
- Xiujuan Zhang
- The Second Clinical College of Guangzhou University of Chinese Medicine, 510120, Guangzhou, PR China; Department of Hepatology Diseases, Guangdong Provincial Hospital of Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 510120, Guangzhou, PR China
| | - Zemin Wan
- Department of Laboratory Medicine, Guangdong Provincial Hospital of Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 510120, Guangzhou, PR China
| | - Ming Lin
- Department of Hepatology Diseases, Guangdong Provincial Hospital of Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 510120, Guangzhou, PR China
| | - Yingxian Li
- Department of Medical Education, Guangdong Provincial Hospital of Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 510120, Guangzhou, PR China
| | - Xiaoju Wu
- Department of Hepatology Diseases, Guangdong Provincial Hospital of Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 510120, Guangzhou, PR China
| | - Junmin Jiang
- Department of Hepatology Diseases, Guangdong Provincial Hospital of Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 510120, Guangzhou, PR China
| | - Shanshan Lin
- Department of Hepatology Diseases, Guangdong Provincial Hospital of Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 510120, Guangzhou, PR China
| | - Xiaoling Chi
- Department of Hepatology Diseases, Guangdong Provincial Hospital of Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 510120, Guangzhou, PR China.
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26
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Zongo SV, Djigma FW, Yonli AT, Sorgho PA, Nagalo BM, Traore L, Somda D, Amegnona LJ, Languie E, Some CCB, Sia LMJ, Sourabie IB, Sombie RA, Serme AK, Obiri-Yeboah D, Simpore J. Association of DRB1*11 and DRB1*12 alleles of the HLA system with the evolution of the Hepatitis B virus infection in Burkina Faso. Mol Biol Rep 2023; 50:5039-5047. [PMID: 37101005 DOI: 10.1007/s11033-023-08353-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 02/22/2023] [Indexed: 04/28/2023]
Abstract
BACKGROUND Hepatitis B Virus (HBV) infection affect all social strata of humanity and in the absence of any management, this infection has a different outcome from one infected person to another. This suggests that there are specific individual factors that influence the outcome of the pathology. Sex, immunogenetics and age of contraction of the virus have been cited as factors that influence the evolution of the pathology. In this study, we looked at two alleles of the Human Leucocyte Antigen (HLA) system to measure their possible involvement in the evolution of HBV infection. METHOD AND RESULTS We conducted a cohort study involving 144 individuals spread over 04 distinct stages of infection and then compared allelic frequencies in these populations. A multiplex PCR was conducted and the data obtained was analyzed using R and SPSS software. Our study revealed a predominance of HLA-DRB1*12 in our study population without, however, showing a significant difference between HLA-DRB1*11 and HLA-DRB1*12. The HLA-DRB1*12 proportion was significantly higher in chronic hepatitis B (CHB) and resolved hepatitis B (RHB) compared to cirrhosis and hepatocellular carcinoma (HCC) (p-value = 0,002). Carrying HLA-DRB1*12 has been associated with a low risk of complication of infection (CHB → cirrhosis; OR 0,33 p-value 0,017; RHB → HCC OR 0,13; p-value = 0,00,045) whereas the presence of HLA-DRB1*11 in the absence of HLA-DRB1*12 increased the risk of developing severe liver disease. However, a strong interaction of these alleles with the environment could modulate the infection. CONCLUSION Our study shown that HLA-DRB1*12 is the most frequent and it's carriage may be protective in the development of infection.
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Affiliation(s)
- Sidnooma Véronique Zongo
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Florencia Wendkuuni Djigma
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso.
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso.
| | - Albert Théophane Yonli
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
| | - Pegdwendé Abel Sorgho
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
| | - Bolni Marius Nagalo
- Division of Hematology and Oncology, Mayo Clinic, Arizona, 13400 E. Shea Blvd. , Scottsdale, AZ, 85259, USA
| | - Lassina Traore
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Dogfounianalo Somda
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
| | - Lanyo Jospin Amegnona
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Eugène Languie
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Couna Christiane Bere Some
- Centre Hospitalier Universitaire Yalgado Ouedraogo (CHU-YO), P.O. Box: 03 BP 7022, Ouagadougou 03, Burkina Faso
| | | | - Issa Boaffi Sourabie
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
| | - Roger Arsène Sombie
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Abdel Karim Serme
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Dorcas Obiri-Yeboah
- Department of Microbiology and Immunology, School of Medical Sciences, University of Cape Coast, PMB, Cape Coast, Cape Coast, Ghana
| | - Jacques Simpore
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
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Li S, Li Z, Du H, Zao X, Gan D, Yang X, Li X, Xing Y, Ye Y. Identification of pseudo-immune tolerance for chronic hepatitis B patients: Development and validation of a non-invasive prediction model. Front Public Health 2023; 11:1137738. [PMID: 37089512 PMCID: PMC10113541 DOI: 10.3389/fpubh.2023.1137738] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 03/17/2023] [Indexed: 04/07/2023] Open
Abstract
Background and aimsPatients with chronic hepatitis B (CHB) in the immune tolerant (IT) phase were previously thought to have no or slight inflammation or fibrosis in the liver. In fact, some CHB patients with normal ALT levels still experience liver fibrosis. This study aimed to develop and validate a non-invasive model for identifying pseudo-immune tolerance (pseudo-IT) of CHB by predicting significant liver fibrosis.MethodsThis multi-center study enrolled a total of 445 IT-phase patients who had undergone liver biopsy for the training cohort (n = 289) and validation cohort (n = 156) during different time periods. A risk model (IT-3) for predicting significant liver fibrosis (Ishak score ≥ 3) was developed using high-risk factors which were identified using multivariate stepwise logistic regression. Next, an online dynamic nomogram was created for the clinical usage. The receiver operating characteristic (ROC) curve, net reclassification improvement and integrated discrimination improvement were used to assess the discrimination of the IT-3 model. Calibration curves were used to evaluate the models’ calibration. The clinical practicability of the model was evaluated using decision curve analysis and clinical impact curves.Results8.8% (39 of 445) patients presented with significant liver fibrosis in this study. Aspartate aminotransferase (AST), hepatitis B e-antigen (HBeAg), and platelet (PLT) were included in the prediction model (IT-3). The IT-3 model showed good calibration and discrimination both in the training and validation cohorts (AUC = 0.888 and 0.833, respectively). The continuous NRI and IDI showed that the IT-3 model had better predictive accuracy than GPR, APRI, and FIB-4 (p < 0.001). Decision curve analysis and clinical impact curves were used to demonstrate the clinical usefulness. At a cut-off value of 106 points, the sensitivity and specificity were 91.7 and 70.2%, respectively.ConclusionThe IT-3 model proved an accurate non-invasive method in identifying pseudo-IT of CHB, which can help to formulate more appropriate treatment strategies.
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Affiliation(s)
- Shuo Li
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Zhiguo Li
- Department of Gastroenterology, Beijing Fengtai Hospital of Integrated Traditional and Western Medicine, Beijing, China
| | - Hongbo Du
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaobin Zao
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Da’nan Gan
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Xianzhao Yang
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoke Li
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Xiaoke Li,
| | - Yufeng Xing
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
- Yufeng Xing,
| | - Yong’an Ye
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
- Yong’an Ye,
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Jeng WJ, Wong GLH. The truth of the matter: will immune-tolerant chronic hepatitis B patients benefit from antiviral treatment? Hepatol Commun 2023; 7:e0060. [PMID: 36790353 PMCID: PMC9931031 DOI: 10.1097/hc9.0000000000000060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 01/04/2023] [Indexed: 02/16/2023] Open
Affiliation(s)
- Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Grace Lai-Hung Wong
- Medical Data Analytics Centre (MDAC), Department of Medicine and Therapeutics, and State Key Lab of Digestive Diseases, The Chinese University of Hong Kong, Hong Kong
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Wang J, Yan X, Zhu L, Liu J, Qiu Y, Li Y, Liu Y, Xue R, Zhan J, Jiang S, Geng Y, Wan Y, Li M, Mao M, Gao D, Yin S, Tong X, Xia J, Ding W, Chen Y, Li J, Zhu C, Huang R, Wu C. Significant histological disease of patients with chronic hepatitis B virus infection in the grey zone. Aliment Pharmacol Ther 2023; 57:464-474. [PMID: 36324235 DOI: 10.1111/apt.17272] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/08/2022] [Accepted: 10/15/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND Many patients with chronic hepatitis B (CHB) do not meet the definitions of the traditional natural phases and are classified as being in the grey zone (GZ). AIMS To investigate liver histology, and to establish a management strategy for patients with CHB in the GZ. METHODS This study included 1043 patients with CHB who underwent liver biopsy. Phases of natural history were determined according to the AASLD 2018 hepatitis B guidance. CHB patients in the GZ were divided into HBeAg-positive, normal ALT and HBV DNA ≤106 IU/ml (GZ-A); HBeAg-positive, elevated ALT and HBV DNA ≤2 × 104 IU/ml (GZ-B); HBeAg-negative, normal ALT and HBV DNA ≥2 × 103 IU/ml (GZ-C) and HBeAg-negative, elevated ALT and HBV DNA ≤2 × 103 IU/ml (GZ-D). Significant histological disease was defined as liver inflammation ≥G2 and/or liver fibrosis ≥S2. RESULTS Two hundred and forty two (23.2%) patients were in the GZ. Approximately 72.7% had significant histological disease. HBeAg-positive GZ CHB patients had a higher proportion of significant histological disease than HBeAg-negative GZ patients (91.1% vs. 68.5%, p = 0.002). GZ-D (42.6%) was the dominant category, followed by GZ-C (38.8%), GZ-A (10.3%) and GZ-B (8.3%). The highest proportion of significant histological disease was observed patients in GZ-B (100.0%), followed by GZ-A (84.0%), GZ-D (69.9%) and GZ-C (67.0%). Prothrombin time (PT) was an independent risk factor of significant histological disease in the HBeAg-negative GZ. CONCLUSIONS Over 70% of GZ CHB patients had significant histological disease. We recommend antiviral treatment for HBeAg-positive and HBeAg-negative GZ CHB patients with high PT.
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Affiliation(s)
- Jian Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Xiaomin Yan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Li Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jiacheng Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yuanwang Qiu
- Department of Infectious Diseases, The Fifth People's Hospital of Wuxi, Wuxi, Jiangsu, China
| | - Yiguang Li
- Department of Infectious Diseases, The Fifth People's Hospital of Wuxi, Wuxi, Jiangsu, China
| | - Yilin Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Ruifei Xue
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jie Zhan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Suling Jiang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yu Geng
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yawen Wan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, Nanjing, Jiangsu, China
| | - Ming Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Minxin Mao
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Dongmei Gao
- Department of Hepatology, Huai'an No. 4 People's Hospital, Huai'an, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Xin Tong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Juan Xia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Weimao Ding
- Department of Hepatology, Huai'an No. 4 People's Hospital, Huai'an, Jiangsu, China
| | - Yuxin Chen
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China.,Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Chuanwu Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China.,Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China.,Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
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Lee HA, Kim SU, Seo YS, Ahn SH, Rim CH. Comparable outcomes between immune-tolerant and active phases in noncirrhotic chronic hepatitis B: a meta-analysis. Hepatol Commun 2023; 7:e0011. [PMID: 36691962 PMCID: PMC9851695 DOI: 10.1097/hc9.0000000000000011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 10/10/2022] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Antiviral therapy is not indicated for patients with chronic hepatitis B (CHB) in the immune-tolerant (IT) phase. We compared the outcomes between the untreated IT phase and the treated immune-active (IA) phase in noncirrhotic HBeAg-positive CHB patients. METHODS We systematically searched 4 databases, including PubMed, Medline, Embase, and Cochrane, until August 2021. The pooled incidence rates of HCC and mortality in the IT and IA cohorts and phase change in the IT cohort were investigated. Studies that included patients with liver cirrhosis were excluded. RESULTS Thirteen studies involving 11,903 patients were included. The overall median of the median follow-up period was 62.4 months. The pooled 5-year and 10-year incidence rates of HCC were statistically similar between the IT and IA cohorts (1.1%, 95% CI: 0.4%-2.8% vs. 1.1%, 95% CI: 0.5%-2.3%, and 2.7%, 95% CI: 1.0%-7.3% vs. 3.6%, 95% CI: 2.4%-5.5%, respectively, all p>0.05). The pooled 5-year odds ratio of HCC between IT and IA cohorts was 1.05 (95% CI: 0.32-3.45; p=0.941). The pooled 5-year incidence rate of mortality was statistically similar between the IT and IA cohorts (1.9%, 95% CI: 1.1%-3.4% vs. 1.0%, 95% CI: 0.3%-2.9%, p=0.285). Finally, the pooled 5-year incidence rate of phase change in the IT cohort was 36.1% (95% CI: 29.5%-43.2%). CONCLUSION The pooled incidence rates of HCC and mortality were comparable between the untreated IT and the treated IA phases in noncirrhotic HBeAg-positive CHB patients.
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Affiliation(s)
- Han Ah Lee
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Yeon Seok Seo
- Departments of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Chai Hong Rim
- Department of Radiation Oncology, Korea University College of Medicine, Seoul, Korea
- Department of Radiation Oncology, Korea University Ansan Hospital, Gyeonggi-do, Korea
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Li Z, Yang D, Ge Y, Song S, Lv Q, Ye Y. Histologic changes in immune-tolerant patients with chronic hepatitis B: a systematic review and meta-analysis. Sci Rep 2023; 13:469. [PMID: 36627364 PMCID: PMC9831999 DOI: 10.1038/s41598-023-27545-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
The serological diagnostic criteria for the immune-tolerant (IT) phase have not been strictly defined and it is hard to determine an accurate rate for significant histologic changes among IT patients. The aim of this study was to establish a baseline rate of significant histologic changes and to determine the main characteristics of IT patients. We systematically searched PubMed, Embase, and Web of Science. Studies reporting liver biopsy results (inflammation grade or fibrosis stage) for adults with chronic hepatitis B virus (HBV) infection in the IT phase diagnosed by serological criterion were included to pool the rate of significant histologic changes. Studies that enrolled subjects with confirmed chronic HBV infection in the IT phase diagnosed by serological and liver biopsy criteria (dual criteria) were included to pool the mean values of main characteristics among IT patients. Of 319 studies screened, 15 were eventually included in the meta-analysis. The pooled rates of significant liver fibrosis and inflammatory activity for 10 studies were 10% (95% confidence interval [CI] 0.06-0.18) and 16% (95% CI 0.07-0.31), respectively. The pooled mean values of age, alanine aminotransferase level, HBV DNA level, and HBsAg level for another 5 studies with IT patients diagnosed by dual criteria were 30.7 years (95% CI 27.31-34.09), 26.64 IU/mL (95% CI 24.45-28.83), 8.41 log10 cp/mL (95% CI 7.59-9.23), and 4.24 log10 IU/mL (95% CI 3.67-4.82), respectively. Significant histologic changes were not rare events among IT patients. Strictly defined serological diagnostic criteria for the IT phase are warranted.
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Affiliation(s)
- Zhiguo Li
- Department of Gastroenterology, Beijing Fengtai Hospital of Integrated Traditional and Western Medicine, Beijing, 100072, China.
| | - Dongliang Yang
- Department of Math, Cangzhou Medical College, Cangzhou, Hebei China
| | - Yue Ge
- grid.459359.70000 0004 1763 3154Department of Gastroenterology, Beijing Fengtai Hospital of Integrated Traditional and Western Medicine, Beijing, 100072 China
| | - Shu Song
- grid.459359.70000 0004 1763 3154Department of Gastroenterology, Beijing Fengtai Hospital of Integrated Traditional and Western Medicine, Beijing, 100072 China
| | - Qin Lv
- grid.459359.70000 0004 1763 3154Department of Gastroenterology, Beijing Fengtai Hospital of Integrated Traditional and Western Medicine, Beijing, 100072 China
| | - Yong’an Ye
- grid.24695.3c0000 0001 1431 9176Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
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Harris AM, Schillie S. Hepatitis B and Hepatitis D Viruses. PRINCIPLES AND PRACTICE OF PEDIATRIC INFECTIOUS DISEASES 2023:1125-1133.e4. [DOI: 10.1016/b978-0-323-75608-2.00213-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Yardeni D, Chang KM, Ghany MG. Current Best Practice in Hepatitis B Management and Understanding Long-term Prospects for Cure. Gastroenterology 2023; 164:42-60.e6. [PMID: 36243037 PMCID: PMC9772068 DOI: 10.1053/j.gastro.2022.10.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 09/25/2022] [Accepted: 10/04/2022] [Indexed: 02/03/2023]
Abstract
The hepatitis B virus (HBV) is a major cause of cirrhosis and hepatocellular carcinoma worldwide. Despite an effective vaccine, the prevalence of chronic infection remains high. Current therapy is effective at achieving on-treatment, but not off-treatment, viral suppression. Loss of hepatitis B surface antigen, the best surrogate marker of off-treatment viral suppression, is associated with improved clinical outcomes. Unfortunately, this end point is rarely achieved with current therapy because of their lack of effect on covalently closed circular DNA, the template of viral transcription and genome replication. Major advancements in our understanding of HBV virology along with better understanding of immunopathogenesis have led to the development of a multitude of novel therapeutic approaches with the prospect of achieving functional cure (hepatitis B surface antigen loss) and perhaps complete cure (clearance of covalently closed circular DNA and integrated HBV DNA). This review will cover current best practice for managing chronic HBV infection and emerging novel therapies for HBV infection and their prospect for cure.
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Affiliation(s)
- David Yardeni
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Kyong-Mi Chang
- Medical Research, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania; Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Marc G Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
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Qian Z, Hu M, Wu H, Chen H, Liao G, Kang Z, Lin X, Peng J. The Efficacy of Antiviral Treatment for Chronic Hepatitis B Patients with Normal ALT Levels: A Systematic Review and Meta-analysis. HEPATITIS MONTHLY 2022; 22. [DOI: 10.5812/hepatmon-129836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 10/03/2022] [Accepted: 10/06/2022] [Indexed: 01/04/2025]
Abstract
Context: When nucleos(t)ide analogues (NAs) were applied clinically to manage chronic hepatitis B virus infection, the prognosis of chronic hepatitis B (CHB) patients greatly improved. However, certain CHB patients with normal alanine aminotransferase (ALT) levels were not used to be considered as the population with the need for antiviral treatment. Objectives: This systematic review and meta-analysis collected and analyzed data from clinical trials to assess and compare the efficacy of antiviral treatment among patients with elevated and normal ALT levels. Methods: A systematic search was performed to gather studies published from 1990.01 to 2022.08 in PubMed and Web of Science databases. The quality of the literature was assessed, and 16 studies were included for further analysis. Basic information on included studies and study populations was collected. A meta-analysis was carried out to evaluate three major outcomes of viral response, hepatitis B envelope antigen (HBeAg) loss, and HBeAg seroconversion after NAs treatment based on data extracted from these studies. Odds ratios (ORs) with 95% confidence intervals (CIs) for all outcomes were calculated using fixed-effects models. Results: In the 16 relevant studies, 5,345 patients met the inclusion criteria, including 3,687 patients receiving NAs treatment. All patients were grouped into one with elevated ALT and another with normal ALT based on whether their pretreatment ALT levels > 1*upper limit of normal (ULN). For patients receiving lamivudine, the viral response showed no significant difference between the groups with elevated and normal ALT levels (pooled log OR: 0.51 [-0.23 - 1.26], P = 0.79); the pooled log OR for HBeAg loss was 1.19 (0.63 - 1.76, P = 0.03) and pooled log OR for HBeAg seroconversion was 2.19 (0.91 - 3.47, P = 0.40). For patients receiving first-line therapy with tenofovir disoproxil fumarate (TDF) and entecavir (ETV), the viral response showed no significant difference between the two groups: Pooled log OR (0.38 [-0.22 - 0.97], P = 0.10). The pooled log OR for HBeAg loss and HBeAg seroconversion was (-0.07 [-0.81 - 0.67], P = 0.68) and (0.40 [-0.84 - 1.63], P = 0.88), respectively. Conclusions: The efficacies of first-line therapy with TDF and ETV treatments were similar in groups with elevated and normal ALT levels for the outcomes of viral response and HBeAg loss. These findings may support further treatment of CHB patients with normal ALT levels.
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35
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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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36
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Xu X, Wu C, Jiang L, Peng C, Pan L, Zhang X, Shen W, Chen L, Lou Z, Xu K, Li L, Dong Y, Ruan B. Cost-Effectiveness of Hepatitis B Mass Screening and Management in High-Prevalent Rural China: A Model Study From 2020 to 2049. Int J Health Policy Manag 2022; 11:2115-2123. [PMID: 34664496 PMCID: PMC9808295 DOI: 10.34172/ijhpm.2021.126] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 09/04/2021] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Chronic hepatitis B (CHB) is highly prevalent among adults in rural China and better management of those populations is of vital importance for viral hepatitis elimination. Adult immunization has been the subject of much controversy in previous studies. This study estimates the cost-effectiveness of population-based hepatitis B screening, treatment, and immunization strategy (comprehensive strategy) in rural areas with high prevalence under the national policy of sharp-drop drug prices. METHODS We constructed a Markov model comparing 4 strategies in a 30-year horizon from the healthcare payer perspective: (1) the conventional pattern; (2) screening and treating infected (treatment); (3) screening and immunizing susceptible individuals (immunization); and (4) the comprehensive strategy. Screening intensity ranged from 50% to 100%. Outcomes were measured by costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and clinical outcomes. RESULTS The costs for the conventional pattern, treatment strategy, immunization strategy, and comprehensive strategy were US$ 341, 351, 318, and 323, respectively. In addition, effects were 17.45, 17.57, 17.46, and 17.58 QALYs, respectively. The ICER of the comprehensive strategy was US$ 35/QALY gained at 50% screening intensity and 420 US$/QALY gained at 100%. The net monetary benefit increased with increasing screening intensity and declined after 90%, with the highest value of US$40 693. All new infections and 52.5% mortality could be avoided from 2020 to 2049 if all patients were properly treated and all susceptible individuals were immunized. The results were stable within a wide range of parameters. CONCLUSION It was cost-effective to implement the mass hepatitis B screening, treatment, and immunization strategy in areas of rural China with high prevalence, and the strategy gained the most net monetary benefit at a screening intensity of 90%. Although it was impractical to fulfill 100% coverage, efforts should be made to obtain more people screened.
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Affiliation(s)
- Xiaolan Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Chensi Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lushun Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Chunting Peng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Liya Pan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xue Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Wei Shen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lin Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhuoqi Lou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Kaijin Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yin Dong
- People’s Hospital Medical Community of Yuhuan County, Taizhou, China
| | - Bing Ruan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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37
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Nguyen HH, Lee SS. Fluctuating hepatitis B viremia: Full of sound and fury, signifying nothing? Saudi J Gastroenterol 2022; 28:319-321. [PMID: 35946260 PMCID: PMC9752534 DOI: 10.4103/sjg.sjg_307_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Henry H. Nguyen
- Liver Unit, University of Calgary Cumming School of Medicine, Canada
| | - Samuel S. Lee
- Liver Unit, University of Calgary Cumming School of Medicine, Canada
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38
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Yoon EL, Jun DW. Precision medicine in the era of potent antiviral therapy for chronic hepatitis B. J Gastroenterol Hepatol 2022; 37:1191-1196. [PMID: 35430754 DOI: 10.1111/jgh.15856] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 04/04/2022] [Indexed: 12/09/2022]
Abstract
With the wide use of potent and safe nucloes(t-)ide analogues (NAs) treatment, patient-centered care is getting important. Intensive care for comorbidity has gain utmost importance in care of aging chronic hepatitis B (CHB) patients with life-long antiviral treatment. Linkage to care of patients with CHB is essential for the goal of hepatitis B virus (HBV) eradication. As long-term suppression of HBV DNA replication does not prevent hepatocellular carcinoma (HCC), prevention of HCC is another challenge for NAs treatment. There is a possibility of hepatocarcinogenesis in the immune-tolerant phase and risk of loss of patients during active monitoring seeking the time point for antiviral treatment initiation. Initiation of NAs treatment from the immune-tolerant phase would improve the linkage to care. However, universal recommendation is premature and evidence for cost-effectiveness needs to be accumulated. Early initiation of NAs in the evidence of significant disease progression, either HBV associated or comorbidity associated, would be a better strategy to reduce the risk of HCC in patients located in the gray zone.
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Affiliation(s)
- Eileen L Yoon
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
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39
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Lin MH, Li HQ, Zhu L, Su HY, Peng LS, Wang CY, He CP, Liang XE, Wang Y. Liver Fibrosis in the Natural Course of Chronic Hepatitis B Viral Infection: A Systematic Review with Meta-Analysis. Dig Dis Sci 2022; 67:2608-2626. [PMID: 34008117 DOI: 10.1007/s10620-021-07009-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 04/14/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Quantitative data are limited on the natural course of liver fibrosis in patients with chronic HBV infection (CHB). AIMS To estimate the prevalence of fibrosis status including non-fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis throughout the natural course of CHB. METHODS We searched Cochrane library, EMBASE, PubMed, SCOPUS, Web of Science, and ScienceDirect from January 1993 to November 2019 for studies with histologic data on liver fibrosis in CHB natural course. CHB course was defined based on current criteria for identifying infection phases as recommended by international clinical practice guidelines, including the HBeAg-positive immune-tolerant, HBeAg-positive immune-active, HBeAg-negative immune-inactive, HBeAg-negative immune-reactive, and HBsAg-negative phases. Pooled prevalence rate of fibrosis status at each phase was obtained from random-effect meta-analyses. RESULTS Thirty-three studies with 9,377 adult participants (23.8-49.0 age years; 45.5-88.6% males) were eligible and finally included. The estimated prevalence of non-fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis was, for HBeAg-positive immune-tolerant phase: 31.2% (95%CI 15.6-46.7), 16.9% (95%CI 7.8-26.1), 5.4% (95%CI 0.0-11.2), and 0.0% (95%CI 0.0-1.5); HBeAg-positive immune-active phase: 6.9% (95%CI 3.6-10.2), 50.6% (95%CI 39.2-61.9), 32.1% (95%CI 24.2-40.0), and 12.8% (95%CI 8.6-17.0); HBeAg-negative immune-inactive phase: 32.4% (95%CI 0.0-100.0), 24.8% (95%CI 4.5-45.1), 3.0% (95%CI 0.0-8.3), and 0.0% (95%CI 0.0-1.0); and HBeAg-negative immune-reactive phase: 6.3% (95%CI 3.5-9.2), 50.3% (95%CI 38.9-61.7), 30.3% (95%CI 20.9-39.6), and 10.0% (95%CI 6.6-13.5), respectively. There was only one study for HBsAg-negative phase, thus not allowing further meta-analyses. CONCLUSIONS Fibrosis risk persists through CHB natural course. These data can support risk estimation in clinical practice and provide reference for noninvasive investigation.
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Affiliation(s)
- Mei-Hong Lin
- Department of Infectious Disease and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.,The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Hai-Qiong Li
- Department of Infectious Disease and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.,The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Lin Zhu
- Department of Infectious Disease and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.,The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Hai-Ying Su
- Department of Infectious Disease and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.,The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Li-Shan Peng
- Department of Infectious Disease and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.,The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Chuang-Yuan Wang
- Department of Infectious Disease and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.,The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Cai-Ping He
- Biomedical Research Center, Southern Medical University, Guangzhou, China.,School of Pharmaceutical Science, Southern Medical University, Guangzhou, China
| | - Xie-Er Liang
- Department of Infectious Disease and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yan Wang
- Department of Infectious Disease and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China. .,Biomedical Research Center, Southern Medical University, Guangzhou, China.
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40
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Borkakoty B, Sarmah MD, Majumdar T, Bhattacharjee CK, Baruah PJ, Biswas D, Kaur H. Role of Innate Immune Regulatory Genes, FOXP3 and FOS in Chronic Hepatitis B Infection. Viral Immunol 2022; 35:338-344. [PMID: 35580072 DOI: 10.1089/vim.2021.0145] [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: 11/13/2022] Open
Abstract
Persistence of hepatitis B virus (HBV) infection leading to chronic infection and its sequalae is responsible for over half a million deaths worldwide. The reason for persistence of chronic hepatitis B (CHB) infection is still not clearly understood. An attempt was made to understand the role of immune regulatory genes in CHB in comparison to spontaneously cleared HBV infection. Relative gene expression of 26 genes involved in innate immunity were studied using Real-Time Polymerase Chain Reaction Array. A total of 679 subjects from three different geographical regions of Northeast India (Assam, Arunachal Pradesh, and Tripura) were included in this case-control study. The cases were subdivided into CHB cases with HBeAg(+)(72), CHB with HBeAg(-)(278), spontaneously cleared controls (88), and healthy controls (228). Overall, 28.3% of the subjects had previous exposure with HBV, while 28.6% had protective antibodies IgG/IgM against HBV. There was a statistically higher number of CHB in men (66.4%) compared to women (33.6%) (p = 0.0001). Proto-oncogene FOS has been found to be moderately upregulated in CHB with HBeAg +ve (2.3-fold) and significantly upregulated (4.1-fold upregulation) in hepatocellular carcinoma. Further, FOXP3 was found to be significantly upregulated (3.0-fold, p = 0.01) in CHB with HBeAg (+) compared to spontaneously cleared HBV infection. In conclusion, CHB with HBeAg positivity was found to have disrupted immune response with upregulation of FOS and FOXP3. Thus, early induction of HBeAg seroconversion with interferon-based therapy or oral nucleos(t)ide analogs along with FOS inhibitors can have important clinical implications in the management of CHB and preventing cirrhosis and HCC.
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Affiliation(s)
- Biswajyoti Borkakoty
- Regional VRDL, ICMR-Regional Medical Research Centre, NE Region, Dibrugarh, India
| | - Mandakini Das Sarmah
- Regional VRDL, ICMR-Regional Medical Research Centre, NE Region, Dibrugarh, India
| | - Tapan Majumdar
- Department of Microbiology, Agartala Government Medical College, Agartala, India
| | | | - Pranjal Jyoti Baruah
- Regional VRDL, ICMR-Regional Medical Research Centre, NE Region, Dibrugarh, India
| | - Dipanakr Biswas
- Regional VRDL, ICMR-Regional Medical Research Centre, NE Region, Dibrugarh, India
| | - Harpreet Kaur
- Division of Epidemiology and Communicable Diseases, Indian Council of Medical Research, New Delhi, India
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41
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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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42
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Koffas A, Mak LY, Gill US, Kennedy PTF. Early Treatment Consideration in Patients with Hepatitis B 'e' Antigen-Positive Chronic Infection: Is It Time for a Paradigm Shift? Viruses 2022; 14:v14050900. [PMID: 35632642 PMCID: PMC9143099 DOI: 10.3390/v14050900] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/22/2022] [Accepted: 04/22/2022] [Indexed: 02/04/2023] Open
Abstract
Chronic hepatitis B (CHB) is associated with significant morbidity and mortality, due to the adverse sequelae of cirrhosis and hepatocellular carcinoma (HCC). To date, antiviral therapy has been reserved for patients with ostensibly active liver disease, fibrosis or cirrhosis, and/or increased risk of HCC. Historically, patients with hepatitis B 'e' antigen (HBeAg)-positive chronic infection, were not offered antiviral therapy. Nevertheless, there has been compelling evidence emerging in recent years, demonstrating that this disease phase is in fact not characterized by immunological tolerance. HBV integration into the human genome is a frequent event found in these patients. Additionally, it may well be associated with active inflammation and fibrosis, even in the presence of persistently normal liver enzymes. Likewise, it appears that the mechanisms of hepatocarcinogenesis are already present during this early stage of the disease. This was reflected in the European Association for the Study of the Liver (EASL) guidelines, where treating patients above the age of 30 years with HBeAg-positive chronic infection was proposed. Lowering the treatment threshold to broaden treatment eligibility is likely to slow disease progression and reduce the risk of developing HCC. The current review discusses the reasons to consider early antiviral therapy in HBeAg-positive chronic infection.
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Affiliation(s)
- Apostolos Koffas
- Barts Liver Centre, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (A.K.); (L.-Y.M.); (U.S.G.)
| | - Lung-Yi Mak
- Barts Liver Centre, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (A.K.); (L.-Y.M.); (U.S.G.)
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Upkar S. Gill
- Barts Liver Centre, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (A.K.); (L.-Y.M.); (U.S.G.)
| | - Patrick T. F. Kennedy
- Barts Liver Centre, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (A.K.); (L.-Y.M.); (U.S.G.)
- Correspondence:
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43
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Hong YM, Yoon KT. [Definition and Management of the Immune Tolerance Phase in Chronic Hepatitis B]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2022; 79:156-160. [PMID: 35473773 DOI: 10.4166/kjg.2022.049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/09/2022] [Accepted: 04/11/2022] [Indexed: 11/03/2022]
Abstract
In the natural course of chronic hepatitis B, the immune tolerance phase is characterized by HBeAg positivity, very high levels of HBV DNA, and persistent normal alanine aminotransferase. The international guideline recommendation for patients in this phase is observation without antiviral treatment because of the low risk of disease progression and the lack of effective antiviral agents. However, recent retrospective studies have shown that progression to hepatic fibrosis and hepatocellular carcinoma may occur in patients who are in the immune tolerance phase. Despite the conceptual definition and clinical diagnostic criteria for this phase, it is difficult to accurately diagnose the true immune tolerance phase. Therefore, we should pay attention to the clinical evaluation and interpretation of the immune tolerance phase and understand the clinical situations in which antiviral treatments should be considered.
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Affiliation(s)
- Young Mi Hong
- Department of Internal Medicine, Pusan National University College of Medicine, Yangsan, Korea.,Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea.,Liver Center, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Ki Tae Yoon
- Department of Internal Medicine, Pusan National University College of Medicine, Yangsan, Korea.,Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea.,Liver Center, Pusan National University Yangsan Hospital, Yangsan, Korea
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44
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The Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2022; 28:276-331. [PMID: 35430783 PMCID: PMC9013624 DOI: 10.3350/cmh.2022.0084] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 01/10/2023] Open
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45
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Lee HA, Lee HW, Park Y, Kim HS, Seo YS. Hepatitis B Core-Related Antigen Is Useful for Predicting Phase and Prognosis of Hepatitis B e Antigen-Positive Patients. J Clin Med 2022; 11:jcm11061729. [PMID: 35330053 PMCID: PMC8956075 DOI: 10.3390/jcm11061729] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/15/2022] [Accepted: 03/16/2022] [Indexed: 12/10/2022] Open
Abstract
The role of hepatitis B core-related antigen (HBcrAg) level in defining clinical phase and predicting prognosis of chronic hepatitis B (CHB) has not been fully studied. CHB patients who had undergone liver biopsy in Korea University Medical Center were included. Patients with liver cirrhosis were excluded. The associations of HBcrAg level with CHB phase, and nucleos(t)ide analogue (NA)-induced hepatitis B e antigen (HBeAg) seroconversion were analyzed. In total, 387 patients (median follow-up of 82.4 months) were included. The CHB phases of patients were defined histologically as immune-tolerant (IT, n = 32, 8.3%), HBeAg-positive and immune-active (PIA, n = 211, 54.5%), HBeAg-negative and immune-active (n = 125, 32.3%), and inactive (n = 19, 4.9%), respectively. In HBeAg-positive patients, the mean HBV DNA levels were comparable between the two groups (p = 0.990). However, the mean HBsAg (7.4 log IU/mL and 6.9 log IU/mL, p = 0.002) and HBcrAg levels (8.2 log U/mL vs. 7.6 log U/mL, p < 0.001) of IT patients were significantly higher than that of PIA patients. In multivariate analysis, younger age (odds ratio [OR] 0.949, p = 0.025), lower alanine aminotransferase (OR 0.988, p = 0.002) and higher HBcrAg level (OR = 2.745 p = 0.022) were independent predictors of the IT phase. Of the patients in the PIA phase, 194 received NA after liver biopsy, and 61 (31.4%) had achieved HBeAg seroconversion after antiviral therapy. In Cox regression analysis, the higher HBcrAg level was the only independent predictor of the NA-induced HBeAg seroconversion (hazard ratio 1.285, p = 0.028). The HBcrAg level is useful for predicting clinical phase of CHB and NA-induced HBeAg seroconversion in HBeAg-positive patients.
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Affiliation(s)
- Han Ah Lee
- Departments of Internal Medicine, Ewha Womans University College of Medicine, Seoul 07985, Korea;
| | - Hyun Woong Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 03772, Korea
- Correspondence: (H.W.L.); (Y.S.S.)
| | - Younhee Park
- Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03772, Korea; (Y.P.); (H.-S.K.)
| | - Hyon-Suk Kim
- Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03772, Korea; (Y.P.); (H.-S.K.)
| | - Yeon Seok Seo
- Departments of Internal Medicine, Korea University College of Medicine, Seoul 02841, Korea
- Correspondence: (H.W.L.); (Y.S.S.)
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Chen X, Zhou J, Wu L, Zhu X, Deng H. MAFLD is Associated with the Risk of Liver Fibrosis and Inflammatory Activity in HBeAg-Negative CHB Patients. Diabetes Metab Syndr Obes 2022; 15:673-683. [PMID: 35256849 PMCID: PMC8898022 DOI: 10.2147/dmso.s351492] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 02/15/2022] [Indexed: 04/10/2023] Open
Abstract
PURPOSE Chronic hepatitis B (CHB) and metabolic associated fatty liver disease (MAFLD) are both important public health problems. The effect of concomitant MAFLD on patients with CHB is still unclear. This study aimed to explore the influence of MAFLD on liver fibrosis and inflammation in CHB patients with different hepatitis B e antigen (HBeAg) status. PATIENTS AND METHODS We retrospectively collected the clinical data of 399 treatment-naïve CHB patients who underwent liver biopsy. All patients were divided into two groups (HBeAg± group). Logistic regression analysis was used to identify factors associated with liver inflammatory activity and significant fibrosis in patients with CHB. Multivariable logistic regressions were repeated in subgroups stratified by HBeAg status. RESULTS In patients with CHB, MAFLD was independently associated with a risk of moderate-to-severe liver activity and significant fibrosis (P <0.05). In the HBeAg-negative group, patients with MAFLD had significantly higher levels of alanine aminotransferase (ALT) (P <0.05) and more severe liver inflammatory activity and fibrosis (P <0.05) compared to those without MAFLD. MAFLD was independently associated with a risk of moderate-to-severe liver activity (A ≥3: OR 3.97, 95% CI 1.71-9.22, P =0.001) and significant fibrosis (F ≥2: OR 2.02, 95% CI 1.09-3.73, P =0.026). In the HBeAg-positive group, MAFLD was found to be independently associated with moderate-to-severe liver activity (OR 2.44, 95% CI 1.03-5.79, P =0.044) but not fibrosis (P =0.618). CONCLUSION MAFLD is associated with the risk of liver fibrosis and inflammatory activity in HBeAg-negative CHB patients. Sufficient attention should be paid to the prevention and treatment of MAFLD in patients with CHB, especially in HBeAg-negative patients.
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Affiliation(s)
- Xiaoman Chen
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China
- Infectious Disease Center, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China
| | - Jing Zhou
- Department of Pathology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Lili Wu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Xiang Zhu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Hong Deng
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China
- Correspondence: Hong Deng; Xiang Zhu, Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, People’s Republic of China, Tel +86-2085252506, Fax +86-2085252063, Email ;
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Premkumar M, Chawla YK. Should We Treat Immune Tolerant Chronic Hepatitis B? Lessons from Asia. J Clin Exp Hepatol 2022; 12:144-154. [PMID: 35068795 PMCID: PMC8766700 DOI: 10.1016/j.jceh.2021.08.023] [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: 06/27/2021] [Accepted: 08/22/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Chronic hepatitis B (CHB) remains a public health burden, with more than 257 million persons living with hepatitis B virus globally. Despite the availability of a safe and efficacious vaccine, access to immunization remains poor. As per current estimates, if Asian countries rely only on immunization to reduce the burden of disease, the timelines for HBV elimination will be extended to 2060-2090, a far cry from the World Health Organization's clarion call for viral hepatitis elimination by 2030. METHODS Currently, all practice guidelines lay stress on immunization, prevention of mother-to-child transmission and treatment of immune active disease or cirrhosis. In this review, we critically examine the data from the Asian cohorts, clinical and public health rationale of early treatment, risk of HCC, and assess the need for revision of guidelines. DISCUSSION Patients in the immune tolerant phase (IT) remain untreated till they meet variable age, transaminase, or fibrosis criteria, are often lost to follow up and continue transmitting the infection. With global migration patterns, immunization programmes alone cannot prevent the complications of HBV like cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC). In addition, data from Asian cohorts from Taiwan and Korea suggest that HBV DNA levels are directly associated with increased risk of HCC. Histological evidence of advanced fibrosis or immune reactive T cell subsets in the IT phase also raises doubts about the viability of current guidelines that focus on age, alanine transaminase levels, and liver stiffness as markers of risk of inflammation and fibrosis. Current practice does not take into account the histological subsets with minimal inflammation, HBV genome integration or risk of HCC with high viral loads. CONCLUSION New data from Asian cohorts argue the case of expanding access to care to IT-CHB from public health and clinical perspective.
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Key Words
- ALT, alanine transaminase
- CHB, chronic hepatitis B
- HBV Elimination in India
- HBV RNA
- HBV, hepatitis B virus
- HCC, hepatocellular carcinoma
- HCV, hepatitis C virus
- IA, immune active
- IT, immune tolerant
- MTCT, mother-to-child transmission
- NA, nucleos(t)ide analogs
- PWID, persons who inject drugs
- WHO, World Health Organization
- cccDNA
- chronic hepatitis B
- hepatocellular carcinoma
- immune tolerant phase
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Affiliation(s)
- Madhumita Premkumar
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Yogesh K. Chawla
- Emeritus Kalinga Institute of Medical Sciences (KIMS), Bhubaneshwar, India
- Address for correspondence: Prof. Yogesh K Chawla, Ex-Director (PGIMER), Former Prof, & Head, Department of Hepatology, PGIMER, Chandigarh, 160012, India.
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Age and fibrosis index for the prediction of hepatocellular carcinoma risk in patients with high hepatitis B virus DNA but normal alanine aminotransferase. Eur J Gastroenterol Hepatol 2022; 34:69-75. [PMID: 32925504 DOI: 10.1097/meg.0000000000001915] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
AIM Chronic hepatitis B patients positive for hepatitis B e antigen (HBeAg) with high serum hepatitis B virus (HBV) DNA levels but normal alanine aminotransferase (ALT) levels may develop hepatocellular carcinoma (HCC). However, ways to risk stratify are limited. METHODS A retrospective cohort of 651 HBeAg positive, adult patients with high serum HBV DNA levels (>7 log IU/ml) but normal or mildly elevated ALT levels (<80 U/L) were analyzed. RESULTS Age and FIB-4 index were independent factors associated with HCC development. When stratified, 5- and 10-year cumulative HCC incidence rates were 0 and 2.0% for patients aged <40 years with FIB-4 index <1.45, and were 5.9 and 32.7% for patients aged ≥40 years with FIB-4 index ≥1.45, respectively (P < 0.001). In patients with normal ALT levels (n = 301), the 10-year HCC incidence rate was 0% for patients aged <40 years with FIB-4 index <1.45, while 5- and 10-years HCC incidence rate was 4.5 and 27.1% for patients aged ≥40 years with FIB-4 index ≥1.45, respectively (P < 0.001). CONCLUSION In patients with high HBV DNA but normal ALT levels, age and FIB-4 index could effectively stratify HCC risk, indicating that these parameters may guide management plans for this population.
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Kawanaka M, Nishino K, Kawamoto H, Haruma K. Hepatitis B: Who should be treated?-managing patients with chronic hepatitis B during the immune-tolerant and immunoactive phases. World J Gastroenterol 2021; 27:7497-7508. [PMID: 34887645 PMCID: PMC8613739 DOI: 10.3748/wjg.v27.i43.7497] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 07/31/2021] [Accepted: 10/31/2021] [Indexed: 02/06/2023] Open
Abstract
New hepatitis B virus (HBV) infections are decreasing owing to improved antiviral therapy and increased HBV vaccination worldwide; however, the number of HBV infections remains a major cause of liver carcinogenesis. HBV triggers cytotoxic immunity to eliminate HBV-infected cells. Therefore, the HBV pathophysiology changes in persistently infected individuals depending on host immune responses and HBV DNA proliferation state. To prevent liver cirrhosis and carcinogenesis caused by HBV, it is important to treat HBV infection at an early stage. Active treatment is recommended for the immunoactive hepatitis B surface-antigen-positive and -negative phase, but not during the immune-inactive phase or immune-tolerant phase; instead, follow-up is recommended. However, these patients should be monitored through regular blood tests to accurately diagnose the immune-inactive or -tolerant phases. The treatment regimen should be determined based on the age, sex, family history of liver cancer, and liver fibrosis status of patients. Early treatment is often recommended due to various problems during the immune-tolerant phase. This review compares the four major international practice guidelines, including those from the Japanese Society of Hepatology, and discusses strategies for chronic hepatitis B treatment during the immune-tolerant, immune-inactive, and resolved phases. Finally, recommended hepatitis B antiviral therapy and follow-up protocols are discussed.
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Affiliation(s)
- Miwa Kawanaka
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama 700-8505, Japan
| | - Ken Nishino
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama 700-8505, Japan
| | - Hirofumi Kawamoto
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama 700-8505, Japan
| | - Ken Haruma
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama 700-8505, Japan
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Combination of quantitative hepatitis B core antibody (qHBcAb) and aspartate aminotransferase (AST) can accurately diagnose immune tolerance of chronic hepatitis B virus infection based on liver biopsy. Clin Res Hepatol Gastroenterol 2021; 45:101563. [PMID: 33272888 DOI: 10.1016/j.clinre.2020.10.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 10/14/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Immune tolerance is defined as HBeAg positive, high hepatitis B virus load (HBV), persistent normal alanine aminotransferase (ALT), no or slight inflammation or fibrosis in liver histology. However, it is still unclear the threshold of high hepatitis B virus load and how to predict histology without liver biopsy. The aim of this study was to predict immune tolerance in HBeAg positive, alanine aminotransferase -normal populations with non-invasive indicators. METHODS Two multi-center prospective cohort study recruited 907 treatment-naïve chronic hepatitis B (CHB) patients who had undergone liver biopsy in mainland China from August 2013 to September 2016 and April 2018 to June2019. Quantitative hepatitis B core antibody, AST and HBV DNA were investigated using commercial diagnostic assays and histological grading and staging was assessed by the Ishak scoring system. RESULTS One hundred and thirteen untreated CHB patients with HBeAg-positive, normal alanine aminotransferase (ALT) and high level of HBV DNA (≥5log10 IU/mL) were enrolled in this study. The area under the receiver operating characteristic curves (AUROCs) of qHBcAb, AST, HBV DNA and qHBcAb-AST index were 79.6%, 80.5%, 76.4% and 87.7%. Our novel qHBcAb-AST index, which combined qHBcAb and AST showed better performance with higher sensitivity (88.6% [95% confidence interval (CI) 72.3% - 96.3%]) and negative predictive value (NPV) (93.8% [95% CI 84.2% - 98.0%]). CONCLUSIONS The combination of qHBcAb and AST can more accurately predict the immune tolerance of people with HBeAg-positive, normal alanine aminotransferase (ALT).
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