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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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Maung ST, Decharatanachart P, Chaiteerakij R. Hepatitis B Surface Antigen Seroclearance Rate After Stopping Nucleos(t)ide Analogues in Chronic Hepatitis B-A Systematic Review and Meta-Analysis. J Gastroenterol Hepatol 2025; 40:1079-1104. [PMID: 40041970 DOI: 10.1111/jgh.16920] [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: 10/19/2024] [Revised: 02/12/2025] [Accepted: 02/17/2025] [Indexed: 05/11/2025]
Abstract
AIM To identify factors influencing HBsAg seroclearance rates after stopping nucleos(t)ide analogue (NA) therapy in patients with chronic hepatitis B (CHB). METHODS We conducted a comprehensive literature search in databases from inception to July 2024. Subgroup analyses and meta-regression were performed to determine factors associated with HBsAg seroclearance, including ethnicity, HBV genotype, NA therapy duration, end-of-treatment (EOT) qHBsAg levels, HBeAg status, cirrhosis status, and follow-up duration. RESULTS The meta-analysis included 62 studies (n = 9867) with a pooled HBsAg seroclearance rate of 10% (95%CI: 8%-12%, I2 = 92%) after NA cessation. HBeAg-negative patients showed significantly higher rates than HBeAg-positive patients (11% vs. 5%, p = 0.030). Subgroup analysis revealed higher seroclearance with follow-up of >5 years (18%, p = 0.004), showing significantly higher rates were observed in studies with longer follow-up periods. Caucasians showed a higher rate (12%) than Asians (9%, p = 0.067). Studies adhering to AASLD, EASL, or APASL stopping rules showed no significant differences in rates. Patients with EOT qHBsAg ≤2.0 log IU/mL had higher rates (23%) than those with >2.0 log IU/mL (11%). Re-treated patients had lower seroclearance (6%) compared to those not re-treated (17%, p = 0.178). Meta-regression identified ethnicity, HBeAg status, and follow-up duration as significant contributors to heterogeneity. Egger's test showed no evidence of publication bias (p = 0.1928). CONCLUSION Our meta-analysis highlights the role of ethnicity, EOT qHBsAg levels, HBeAg-status, and follow-up duration in determining HBsAg seroclearance rates. These findings stress the need for personalized NA discontinuation strategies and further research on HBV genotypes and biomarkers to improve treatment outcomes and predict seroclearance more accurately.
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Affiliation(s)
- Soe Thiha Maung
- Division of Gastroenterology, Department of Medicine, King Chulalongkorn Memorial Hospital and Thai Red Cross Society, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Ma Har Myaing Hospital, Yangon, Myanmar
| | - Pakanat Decharatanachart
- Division of Gastroenterology, Department of Medicine, King Chulalongkorn Memorial Hospital and Thai Red Cross Society, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Division of Academic Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Roongruedee Chaiteerakij
- Division of Gastroenterology, Department of Medicine, King Chulalongkorn Memorial Hospital and Thai Red Cross Society, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence for Innovation and Endoscopy in Gastrointestinal Oncology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Chen YC, Hsu CW, Chien RN. Higher HBeAg-reversion virological relapse and lower sustained remission after treatment cessation in tenofovir-treated HBeAg-positive patients. J Med Virol 2023; 95:e29213. [PMID: 37933418 DOI: 10.1002/jmv.29213] [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: 02/04/2023] [Revised: 10/15/2023] [Accepted: 10/21/2023] [Indexed: 11/08/2023]
Abstract
A complete investigation of the clinical outcomes after treatment cessation in HBeAg-positive patients with HBeAg loss is limited. We retrospectively recruited 242 HBeAg-positive patients with HBeAg loss after a median duration of 37.2 months with tenofovir (TDF, n = 77) or entecavir (ETV, n = 165) treatment. There were 77 (31.8%) patients with sustained virological remission (SVR), 85 (35.1%) with HBeAg-reversion virological relapse, 80 (33.1%) with HBeAg-negative virological relapse after treatment cessation, and 23 (9.5%) with HBsAg loss. Clinical data at baseline, on-treatment and during off-treatment follow-up were analyzed. The 3-year cumulative incidences of overall, HBeAg-reversion and HBeAg-negative virological relapse were 70.2%, 54%, and 53.5%, respectively. The common factors associated with HBeAg-reversion and HBeAg-negative virological relapse were tenofovir treatment (hazard ratio [HR] = 5.411, p < 0.001; HR = 2.066, p = 0.006, respectively) and HBsAg at end of treatment (EOT) (HR = 1.461, p = 0.001; HR = 1.303, p = 0.019, respectively). The 5-year cumulative incidence of HBsAg loss in SVR patients was 13.7% and EOT HBsAg was the only associated factor (HR = 0.524, p = 0.024). Compared to that of ETV-treated patients, TDF-treated patients had a significantly higher 3-year cumulative incidence of virological relapse (87.3% vs. 62.8%, p < 0.001), earlier HBeAg-reversion virological relapse (2.9 vs. 7.8 months, p < 0.001), a higher rate of HBeAg-reversion virological relapse (53.2% vs. 26.7%) and a lower SVR rate (15.6% vs. 39.4%) (p < 0.001). In summary, the clinical outcomes after treatment cessation in HBeAg-positive patients with HBeAg loss were composed of HBeAg-reversion virological relapse, HBeAg-negative virological relapse and SVR. TDF was significantly associated with off-treatment virological relapse. EOT HBsAg plays an important role in HBsAg loss among SVR patients and posttreatment virological relapse.
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Affiliation(s)
- Yi-Cheng Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan City, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Chao-Wei Hsu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan City, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan City, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
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Luo M, Zhou B, Hou J, Jiang D. Biomarkers for predicting nucleos(t)ide analogs discontinuation and hepatitis B virus recurrence after drug withdrawal in chronic hepatitis B patients. Hepatol Res 2022; 52:337-351. [PMID: 35089634 DOI: 10.1111/hepr.13749] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/22/2021] [Accepted: 01/20/2022] [Indexed: 12/11/2022]
Abstract
AIM To summarize HBV-related biomarkers predicting nucleos(t)ide analogs (NAs) discontinuation and hepatitis B virus (HBV) recurrence after drug withdrawal in chronic hepatitis B (CHB) patients, providing references for clinical medication, so as to manage CHB patients more scientifically. METHODS Related pieces of literature were retrieved in PubMed and the results were sorted out. We then analyzed and summarized these articles. RESULTS We found that HBV related biomarkers maybe could predict NAs withdrawal safely and the possibility of relapse after treatment cessation, including hepatitis B e antigen (HBeAg), hepatitis B surface antigen (HBsAg), HBV DNA, HBV RNA, pregenomic-RNA (pgRNA), hepatitis B core-related antigen (HBcrAg), hepatitis B core antibody (anti-HBc), and models containing several indicators for predicting the effectiveness of treatment. CONCLUSIONS HBV DNA, HBV RNA, pgRNA, HBcrAg, anti-HBc, as well as the prediction models formed by several biomarkers could predict the safe discontinuation of NAs before HBsAg loss and recurrence.
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Affiliation(s)
- Mengqi Luo
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bin Zhou
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Deke Jiang
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Kaewdech A, Sripongpun P. Challenges in the discontinuation of chronic hepatitis B antiviral agents. World J Hepatol 2021; 13:1042-1057. [PMID: 34630873 PMCID: PMC8473499 DOI: 10.4254/wjh.v13.i9.1042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/07/2021] [Accepted: 07/28/2021] [Indexed: 02/06/2023] Open
Abstract
Long-term antiviral treatment of chronic hepatitis B patients has been proven to be beneficial in reducing liver-related complications. However, lengthy periods of daily administration of medication have some inevitable drawbacks, including decreased medication adherence, increased cost of treatment, and possible long-term side effects. Currently, discontinuation of antiviral agent has become the strategy of interest to many hepatologists, as it might alleviate the aforementioned drawbacks and increase the probability of achieving functional cure. This review focuses on the current evidence of the outcomes following stopping antiviral treatment and the factors associated with subsequent hepatitis B virus relapse, hepatitis B surface antigen clearance, and unmet needs.
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Affiliation(s)
- Apichat Kaewdech
- Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Songkhla, Thailand
| | - Pimsiri Sripongpun
- Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Songkhla, Thailand.
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APASL guidance on stopping nucleos(t)ide analogues in chronic hepatitis B patients. Hepatol Int 2021; 15:833-851. [PMID: 34297329 DOI: 10.1007/s12072-021-10223-5] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 06/21/2021] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is currently incurable. Long-term treatment with potent and safe nucleos(t)ide analogs (NAs) can reduce hepatocellular carcinoma (HCC) and cirrhosis-related complications through profound viral suppression. However, indefinite therapy raises several crucial issues with pros and cons. Because seroclearance of hepatitis B surface (HBsAg) as functional cure is not easily achievable, a finite therapy including sequential 48-week pegylated interferon therapy may provide an opportunity to facilitate HBsAg seroclearance by the rejuvenation of exhausted immune cells. However, the cost of stopping NA is the high incidence of virological relapse and surge of alanine aminotransferase (ALT) levels, which may increase the risk of adverse outcomes (e.g., decompensation, fibrosis progression, HCC, or liver-related mortality). So far, the APASL criteria to stop NA treatment is undetectable HBV DNA levels with normalization of ALT; however, this criterion for cessation of treatment is associated with various incidence rates of virological/clinical relapse and more than 40% of NA-stoppers eventually receive retreatment. A very intensive follow-up strategy and identification of low-risk patients for virological/clinical relapse by different biomarkers are the keys to stop the NA treatment safely. Recent studies suggested that decreasing HBsAg level at the end-of-treatment to < 100-200 IU/mL seems to be a useful marker for deciding when to discontinue NAs therapy. In addition, several viral and host factors have been reviewed for their potential roles in predicting clinical relapse. Finally, the APASL guidance has proposed rules to stop NA and the subsequent follow-up strategy to achieve a better prognosis after stopping NA. In general, for both HBeAg-positive and HBeAg-negative patients who have stopped treatment, these measurements should be done every 1-3 months at the minimum until 12 months.
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Cornberg M, Sandmann L, Protzer U, Niederau C, Tacke F, Berg T, Glebe D, Jilg W, Wedemeyer H, Wirth S, Höner Zu Siederdissen C, Lynen-Jansen P, van Leeuwen P, Petersen J. S3-Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) zur Prophylaxe, Diagnostik und Therapie der Hepatitis-B-Virusinfektion – (AWMF-Register-Nr. 021-11). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 59:691-776. [PMID: 34255317 DOI: 10.1055/a-1498-2512] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Markus Cornberg
- Deutsches Zentrum für Infektionsforschung (DZIF), Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover; Centre for individualised infection Medicine (CiiM), Hannover.,Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Lisa Sandmann
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Ulrike Protzer
- Institut für Virologie, Technische Universität München/Helmholtz Zentrum München, München
| | | | - Frank Tacke
- Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charité Universitätsmedizin Berlin, Berlin
| | - Thomas Berg
- Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig
| | - Dieter Glebe
- Institut für Medizinische Virologie, Nationales Referenzzentrum für Hepatitis-B-Viren und Hepatitis-D-Viren, Justus-Liebig-Universität Gießen, Gießen
| | - Wolfgang Jilg
- Institut für Medizinische Mikrobiologie und Hygiene, Universität Regensberg, Regensburg
| | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Stefan Wirth
- Zentrum für Kinder- und Jugendmedizin, Helios Universitätsklinikum Wuppertal, Wuppertal
| | | | - Petra Lynen-Jansen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin
| | - Pia van Leeuwen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin
| | - Jörg Petersen
- IFI Institut für Interdisziplinäre Medizin an der Asklepios Klinik St. Georg, Hamburg
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Li FC, Li YK, Fan YC. Biomarkers for hepatitis B virus replication: an overview and a look to the future. Expert Rev Gastroenterol Hepatol 2020; 14:1131-1139. [PMID: 32887529 DOI: 10.1080/17474124.2020.1815530] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 08/24/2020] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Hepatitis B virus (HBV) infection is a major public health issue but there are no powerful drugs to eradicate the virus. HBV markers including HBsAg, HBcrAg, HBV RNA, HBcAb, and HBV DNA are becoming promising biomarkers to reflect the natural phases of chronic HBV infection and predict the outcome of anti-HBV treatment. AREAS COVERED The authors summarized the biomarkers of HBV replication and presented the current advances of these biomarkers on predicting the outcome of anti-HBV treatment and identifying the progression of chronic HBV infection. EXPERT OPINION HBsAg, HBcrAg, HBV RNA, HBcAb, and HBV DNA are noninvasive and feasible biomarkers for monitoring the process of anti-HBV therapy and predicting the progress of HBV infection. However, there are still no strong biomarkers with high sensitivity and specificity for clinical application. Combination of two or more HBV biomarkers, new technique for measuring HBV cccDNA, and searching novel HBV biomarkers are essential for anti-HBV treatment in the future.
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Affiliation(s)
- Feng-Cai Li
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University , Jinan, China
| | - Yue-Kai Li
- Department of Nuclear Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University , Jinan, China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University , Jinan, China
- Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University , Jinan, China
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Liu Y, Xue J, Liao W, Yan H, Liang X. Serum HBV RNA Dynamic and Drug Withdrawal Predictor Value in Patients With Chronic HBV Infection on Long-term Nucleos(t)ide Analogue (NA) Therapy. J Clin Gastroenterol 2020; 54:e73-e82. [PMID: 32604147 PMCID: PMC7458089 DOI: 10.1097/mcg.0000000000001376] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 05/10/2020] [Indexed: 02/07/2023]
Abstract
AIMS This study aimed to investigate the dynamic pattern of serum hepatitis B virus (HBV) RNA in chronic hepatitis B (CHB) patients on long-term nucleos(t)ide analogue (NA) therapy and evaluate predictor value of end-of-treatment (EOT) serum HBV RNA status on drug-withdrawal durability. METHODS We carried out a real-life cohort study of 326 CHB patients on NA treatment between February 12, 2016 and February 21, 2018. Thirty of these patients discontinued NA treatment after enrollment, and were included in 2-year off-therapy follow-up. Serum HBV RNA levels were determined using the RNA simultaneous amplification testing method. RESULTS Both serum HBV RNA and DNA levels declined significantly in long-term antiviral progress. When the treatment duration was longer than 3 years, the undetectable rates of HBV RNA and DNA were 55.10% and 97.0%, respectively. The serum HBV RNA-negative rate was 39.5%. The cumulative 2-year off-therapy viral and clinical relapse rate was 40.56%; 95% confidence interval (95% CI), 21.51-59.61 and 31.31%; 95% CI, 11.32-51.29 in all patients, respectively. Patients with EOT hepatitis B surface antigen (HBsAg)≤1000 IU/mL plus HBV RNA negativity had a relatively lower cumulative 2-year off-therapy viral relapse rate (23.01%; 95% CI, 0.17-45.99). EOT HBsAg≤1000 IU/mL plus HBV RNA negativity showed obvious superiority for the EOT HBsAg≤1000 IU/mL single in drug withdrawal durability prediction, with better specificity (18.18% vs. 72.73%, P=0.03), and the positive predictive value and negative predictive value were 76.92% and 47.06%, respectively. CONCLUSIONS In the long-term antiviral process, both serum HBV RNA and DNA levels declined significantly. EOT serum HBV RNA negativity was not an independent drug withdrawal marker, but can complement the HBsAg titer to monitor drug withdrawal in CHB patients on long-term NA therapy.
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Affiliation(s)
| | | | - Wei Liao
- Departments of Infectious Diseases
| | - Hongli Yan
- Reproductive Medicine Center, Changhai Hospital, Second Military Medical University, Shanghai, China
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Li X, Zhang L, Qiu M, Huang Y, Xiao H, Lu B, Jiang Y, Long F, Lin H, He J, Wu Q, Zhang M, Wang L, Zhu X, Gong M, Sun X, Sun J, Sun F, Lu W, Xu W, Chen G, Li Z, Gan D, Yang X, Du H, Ye Y. Chinese herbal medicine combined with entecavir to reduce the off-therapy recurrence risk in HBeAg-positive chronic hepatitis B patients: a multicener, double-blind, randomized controlled trial in China. Trials 2020; 21:708. [PMID: 32787905 PMCID: PMC7422608 DOI: 10.1186/s13063-020-04417-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 05/14/2020] [Indexed: 12/30/2022] Open
Abstract
Background Nucleos(t)ide analogues (NAs) are the first-line option against chronic hepatitis B (CHB). NAs produce potent suppression of viral replication with a small chance of HBsAg seroclearance and a high risk of virological relapse after discontinuation. The combined therapy of NAs plus traditional Chinese medicine (TCM) is widely accepted and has been recognized as a prospective alternative approach in China. Based on preliminary works, this study was designed to observe the therapeutic effect of TCM plus entecavir (ETV) against HBeAg-positive chronic hepatitis B with respect to reducing the recurrence risk after NA withdrawal. Methods/design The study is a nationwide, multicenter, double-blind, randomized, placebo-controlled trial with a duration of 120 weeks. A total of 18 hospitals and 490 eligible Chinese HBeAg-positive CHB patients will be enrolled and randomly allocated into the experimental group and control group in a 1:1 ratio. Patients in the experimental group will be prescribed TCM formulae (Tiaogan-BuXu-Jiedu granules) plus ETV 0.5 mg per day for consolidation therapy for 96 weeks. Patients in the control group will be prescribed TCM granule placebo plus ETV 0.5 mg per day for the same course. After consolidation therapy, all patients will discontinue their trial drugs and be closely monitored over the next 24 weeks. Once clinical recurrence (CR) occurs, ETV treatment will be restarted. The primary outcome is the cumulative rate of CR at the end of this trial. Conclusion This study is the first of its kind to observe therapeutic effects with respect to reducing recurrence after NA withdrawals after unified integrative consolidation therapy in the CHB population. Trial registration Chinese Clinical Trial Registry No. ChiCTR1900021232. Registered on February 2, 2019
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Affiliation(s)
- Xiaoke Li
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Ludan Zhang
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Mei Qiu
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, Guangdong Province, China
| | - Yi Huang
- Department of Hepatology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400021, China
| | - Huanming Xiao
- Department of Hepatology, Guangdong Hospital of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - Bingjiu Lu
- Department of Hepatology, Liaoning Hospital of Traditional Chinese Medicine, Shenyang, 110032, China
| | - Yuyong Jiang
- Department of Hepatology, Beijing Ditan Hospital, Beijing, 100015, China
| | - Fuli Long
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, 530023, China
| | - Hui Lin
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China
| | - Jinyu He
- Department of Hepatology, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an, 710003, China
| | - Qikai Wu
- Department of Hepatology, The Third People's Hospital of Shenzhen, Shenzhen, 518112, Guangdong Province, China
| | - Mingxiang Zhang
- Department of Hepatology, The Sixth People's Hospital of Shenyang, Shenyang, 110006, China
| | - Li Wang
- Department of Hepatology, Public Health Clinical Center of Chengdu, Chengdu, 610066, China
| | - Xiaoning Zhu
- Department of Hepatology, Affiliated traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646699, China
| | - Man Gong
- Department of Hepatology, 302 Military Hospital of China, Beijing, 100039, China
| | - Xuehua Sun
- Department of Hepatology, Shanghai Shuguang Hospital, Shanghai, 200021, China
| | - Jianguang Sun
- Department of Hepatology, Shandong Hospital of Traditional Chinese Medicine, Jinan, 250011, China
| | - Fengxia Sun
- Department of Hepatology, Beijing Chinese Medicine Hospital, Beijing, 100010, China
| | - Wei Lu
- Department of Hepatology, The Second People's Hospital of Tianjin, Tianjin, 300000, China
| | - Weihua Xu
- Department of Gastroenterology, The Second Hospital of Shandong University, Jinan, 250100, China
| | - Guang Chen
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Zhiguo Li
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Danan Gan
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Xianzhao Yang
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Hongbo Du
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China.
| | - Yong'an Ye
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China.
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Michler T, Kosinska AD, Festag J, Bunse T, Su J, Ringelhan M, Imhof H, Grimm D, Steiger K, Mogler C, Heikenwalder M, Michel ML, Guzman CA, Milstein S, Sepp-Lorenzino L, Knolle P, Protzer U. Knockdown of Virus Antigen Expression Increases Therapeutic Vaccine Efficacy in High-Titer Hepatitis B Virus Carrier Mice. Gastroenterology 2020; 158:1762-1775.e9. [PMID: 32001321 DOI: 10.1053/j.gastro.2020.01.032] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 12/28/2019] [Accepted: 01/20/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Hepatitis B virus (HBV) infection persists because the virus-specific immune response is dysfunctional. Therapeutic vaccines might be used to end immune tolerance to the virus in patients with chronic infection, but these have not been effective in patients so far. In patients with chronic HBV infection, high levels of virus antigens might prevent induction of HBV-specific immune responses. We investigated whether knocking down expression levels of HBV antigens in liver might increase the efficacy of HBV vaccines in mice. METHODS We performed studies with male C57BL/6 mice that persistently replicate HBV (genotype D, serotype ayw)-either from a transgene or after infection with an adeno-associated virus that transferred an overlength HBV genome-and expressed HB surface antigen at levels relevant to patients. Small hairpin or small interfering (si)RNAs against the common 3'-end of all HBV transcripts were used to knock down antigen expression in mouse hepatocytes. siRNAs were chemically stabilized and conjugated to N-acetylgalactosamine to increase liver uptake. Control mice were given either entecavir or non-HBV-specific siRNAs and vaccine components. Eight to 12 weeks later, mice were immunized twice with a mixture of adjuvanted HBV S and core antigen, followed by a modified Vaccinia virus Ankara vector to induce HBV-specific B- and T-cell responses. Serum and liver samples were collected and analyzed for HBV-specific immune responses, liver damage, and viral parameters. RESULTS In both models of HBV infection, mice that express hepatocyte-specific small hairpin RNAs or that were given subcutaneous injections of siRNAs had reduced levels of HBV antigens, HBV replication, and viremia (1-3 log10 reduction) compared to mice given control RNAs. Vaccination induced production of HBV-neutralizing antibodies and increased numbers and functionality of HBV-specific, CD8+ T cells in mice with low, but not in mice with high, levels of HBV antigen. Mice with initially high titers of HBV and knockdown of HBV antigen expression, but not mice with reduced viremia after administration of entecavir, developed polyfunctional, HBV-specific CD8+ T cells, and HBV was eliminated. CONCLUSIONS In mice with high levels of HBV replication, knockdown of HBV antigen expression along with a therapeutic vaccination strategy, but not knockdown alone, increased numbers of effector T cells and eliminated the virus. These findings indicate that high titers of virus antigens reduce the efficacy of therapeutic vaccination. Anti-HBV siRNAs and therapeutic vaccines are each being tested in clinical trials-their combination might cure chronic HBV infection.
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Affiliation(s)
- Thomas Michler
- Institute of Virology, Technical University of Münich, Helmholtz Zentrum München, Münich, Germany; German Center for Infection Research, Münich, Heidelberg, Germany
| | - Anna D Kosinska
- Institute of Virology, Technical University of Münich, Helmholtz Zentrum München, Münich, Germany; German Center for Infection Research, Münich, Heidelberg, Germany
| | - Julia Festag
- Institute of Virology, Technical University of Münich, Helmholtz Zentrum München, Münich, Germany
| | - Till Bunse
- Institute of Virology, Technical University of Münich, Helmholtz Zentrum München, Münich, Germany; German Center for Infection Research, Münich, Heidelberg, Germany
| | - Jinpeng Su
- Institute of Virology, Technical University of Münich, Helmholtz Zentrum München, Münich, Germany
| | - Marc Ringelhan
- Institute of Virology, Technical University of Münich, Helmholtz Zentrum München, Münich, Germany; Department of Internal Medicine II, University Hospital rechts der Isar, Technical University of Munich, Münich, Germany
| | - Hortenzia Imhof
- Institute of Virology, Technical University of Münich, Helmholtz Zentrum München, Münich, Germany
| | - Dirk Grimm
- German Center for Infection Research, Münich, Heidelberg, Germany; Department of Infectious Diseases/Virology, Heidelberg University Hospital, BioQuant, Heidelberg, Germany
| | - Katja Steiger
- Institute of Pathology, Technical University of Munich, Münich, Germany
| | - Carolin Mogler
- Institute of Pathology, Technical University of Munich, Münich, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany
| | | | - Carlos A Guzman
- German Center for Infection Research, Münich, Heidelberg, Germany; Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | | | | | - Percy Knolle
- German Center for Infection Research, Münich, Heidelberg, Germany; Institute of Molecular Immunology, University Hospital rechts der Isar, Technical University of Munich, Münich, Germany
| | - Ulrike Protzer
- Institute of Virology, Technical University of Münich, Helmholtz Zentrum München, Münich, Germany; German Center for Infection Research, Münich, Heidelberg, Germany.
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12
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Papatheodoridi M, Papatheodoridis G. Emerging Diagnostic Tools to Decide When to Discontinue Nucleos(t)ide Analogues in Chronic Hepatitis B. Cells 2020; 9:cells9020493. [PMID: 32093411 PMCID: PMC7072769 DOI: 10.3390/cells9020493] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 02/09/2020] [Accepted: 02/15/2020] [Indexed: 12/27/2022] Open
Abstract
The aim of this review is to outline emerging biomarkers that can serve as diagnostic tools to identify non-cirrhotic chronic hepatitis B (CHB) patients who could safely discontinue nucleos(t)ide analogues (NAs) before HBsAg loss. Regarding possible predictors of post-NAs outcomes, a number of studies have evaluated numerous factors, which can be categorised in markers of hepatitis B virus (HBV) activity, markers of host immune response and markers of other patient characteristics. In clinical practice, the most important question for patients who discontinue NAs is to differentiate those who will benefit by achieving HBsAg loss or at least by remaining in remission and those who will relapse requiring retreatment. Most of the discontinuation studies so far came from Asian and only few from European populations and examined the rates and predictors of post-NA virological and/or combined relapses or HBsAg loss. To date, there is still controversy about predictors of post-NA relapses, while only HBsAg serum levels at NA discontinuation seem to be the most robust predictive marker of the probability of subsequent off-treatment HBsAg seroclearance. Newer viral markers such as HBV RNA and hepatitis B core-related antigen seem promising, but further research is required.
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Affiliation(s)
- Margarita Papatheodoridi
- Institute of Liver and Digestive Health, Royal Free Hospital, University College of London, London NW3 2QG, UK;
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, 11527 Athens, Greece
| | - George Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, 11527 Athens, Greece
- Correspondence: ; Tel.: +30-2132061115
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13
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14
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Liu J, Li T, Zhang L, Xu A. The Role of Hepatitis B Surface Antigen in Nucleos(t)ide Analogues Cessation Among Asian Patients With Chronic Hepatitis B: A Systematic Review. Hepatology 2019; 70:1045-1055. [PMID: 30561829 DOI: 10.1002/hep.30474] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 12/11/2018] [Indexed: 02/06/2023]
Abstract
In actual clinical practice, infinite nucleos(t)ide analogues (NAs) treatment for chronic hepatitis B virus (HBV) infection is unrealistic. The most commonly used endpoint is suppression of HBV DNA to undetectable levels with normalization of alanine aminotransferase. However, this criterion for cessation of treatment is associated with various incidences of virological and clinical relapse. Recent studies suggest that decreasing the hepatitis B surface antigen (HBsAg) level at the end of treatment (EOT) to an appropriate cut-off value appears to be a practicable and attainable cessation criterion. We performed a systematic review to explore the optimal cut-off value of HBsAg at EOT for the cessation of NAs treatment. Eleven studies with 1,716 patients were included in this review. When the HBsAg levels at EOT were <100 IU/mL and >100 IU/mL, the respective off-therapy virological relapse rates were 9.1%-19.6% (range) and 31.4%-86.8% (range) at ≥12 months off therapy, regardless of hepatitis B e antigen (HBeAg) status; the respective off-therapy clinical relapse rates were 15.4%-29.4% (range) and 48.1%-63.6% (range) at ≥12 months off therapy, regardless of HBeAg status; and the respective off-therapy HBsAg loss rates were 21.1%-58.8% (range) and 3.3%-7.4% (range) for HBeAg-negative patients at ≥39 months off therapy. Conclusion: Cessation of long-term NAs therapy before HBsAg seroclearance in patients with chronic hepatitis B is a feasible alternative to indefinite treatment. An HBsAg level <100 IU/mL at EOT seems to be a useful marker for deciding when to discontinue NAs therapy. However, regular monitoring is required after the cessation of NAs treatment, and long-term outcomes must be further evaluated.
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Affiliation(s)
- Jiaye Liu
- Academy of Preventive Medicine, Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Infectious Disease Control and Prevention, Shandong Provincial Center for Disease Control and Prevention, Jinan, China
| | - Tao Li
- Department of Infectious Diseases and Hepatology, the Second Hospital of Shandong University, Jinan, China
| | - Li Zhang
- Academy of Preventive Medicine, Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Infectious Disease Control and Prevention, Shandong Provincial Center for Disease Control and Prevention, Jinan, China
| | - Aiqiang Xu
- Academy of Preventive Medicine, Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Infectious Disease Control and Prevention, Shandong Provincial Center for Disease Control and Prevention, Jinan, China
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15
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Wu YL, Shen CL, Chen XY. Antiviral treatment for chronic hepatitis B: Safety, effectiveness, and prognosis. World J Clin Cases 2019; 7:1784-1794. [PMID: 31417924 PMCID: PMC6692272 DOI: 10.12998/wjcc.v7.i14.1784] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 06/02/2019] [Accepted: 06/27/2019] [Indexed: 02/05/2023] Open
Abstract
The goal of chronic hepatitis B (CHB) therapy is to improve the patient prognosis through the sustained inhibition of viral replication. However, due to the uncertainty and potentially unlimited duration of the treatment course, nucleus(t)ide analogue (NA) resistance and safety, financial costs and patient compliance, different endpoints of antiviral treatment have been proposed in CHB prevention and treatment guidelines. Different treatment endpoints are closely associated with the safety of drug withdrawal and improvements in prognosis. Antiviral treatment suppresses HBV DNA replication, drug withdrawal leads to relapse, and long-term treatment causes drug safety and resistance issues. Although hepatitis B e antigen seroconversion based on HBV DNA inhibition is considered as “a satisfactory endpoint”, drug withdrawal still leads to high relapse rates. Hepatitis B surface antigen (HBsAg) clearance is the “ideal endpoint” in terms of the safety of drug withdrawal and improvements in prognosis. However, the HBsAg clearance rate is low using the conventional single drug treatment and fixed course regimens. Recently, the application of an “optimized antiviral treatment strategy” has improved the HBsAg clearance rate, and make an “ideal endpoint” possible. This article reviews the different antiviral treatment endpoints in terms of the safety of drug withdrawal, improvements in prognosis and relevant advances.
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Affiliation(s)
- Ya-Li Wu
- International Medical Department, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Cheng-Li Shen
- Division of Surgical Oncology, James Cancer Hospital, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Xin-Yue Chen
- International Medical Department, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
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16
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Mak LY, Seto WK, Fung J, Yuen MF. Novel developments of hepatitis B: treatment goals, agents and monitoring tools. Expert Rev Clin Pharmacol 2019; 12:109-120. [DOI: 10.1080/17512433.2019.1567327] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - James Fung
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
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17
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Höner Zu Siederdissen C, Maasoumy B, Cornberg M. New viral biomarkers for Hepatitis B: Are we able to change practice? J Viral Hepat 2018; 25:1226-1235. [PMID: 30187603 DOI: 10.1111/jvh.12993] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 08/28/2018] [Indexed: 12/13/2022]
Abstract
The management of chronic hepatitis B virus (HBV) infection is challenged by its varying natural course and its stealthy nature. Not all HBV-infected patients will develop complications of infection; however, it is of utmost importance to identify patients who are at risk and require antiviral treatment and/or close surveillance. Hepatic inflammation and quantification of HBV DNA have guided treatment decisions in the last decade, and these guided interventions have been shown to reduce liver-related complications and death. Data on the quantification of additional HBV markers such as hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) and hepatitis B virus RNA (HBV RNA) have accumulated in recent years. Here, we review the current evidence of how to use these markers and discuss open issues that require additional research.
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Affiliation(s)
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
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18
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Liu F, Liu ZR, Li T, Liu YD, Zhang M, Xue Y, Zhang LX, Ye Q, Fan XP, Wang L. Varying 10-year off-treatment responses to nucleos(t)ide analogues in patients with chronic hepatitis B according to their pretreatment hepatitis B e antigen status. J Dig Dis 2018; 19:561-571. [PMID: 30098114 DOI: 10.1111/1751-2980.12654] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 06/22/2018] [Accepted: 08/07/2018] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To evaluate the long-term durability and efficacy of nucleos(t)ide analogues (NAs) and to determine the related factors for virological relapse in chronic hepatitis B (CHB) patients. METHODS CHB patients who fulfilled the criteria for discontinuing NAs therapy in accordance with the published guidelines were included in the study from December 2001. Virological relapse was defined as serum hepatitis virus B (HBV) DNA >104 copies/mL twice at least 2 weeks apart. RESULTS A total of 223 CHB patients were enrolled at the time their NAs therapy was discontinued. The 10-year cumulative relapse rate (CRR) in hepatitis B e antigen (HBeAg)-positive patients was statistically lower than that in HBeAg-negative patients (30.9% vs 62.3%, P < 0.001). In the HBeAg-positive group, Cox regression analysis showed that age at cessation (hazard ratio [HR] 1.067, P < 0.001), consolidation therapy (HR 0.958, P = 0.021), and time to HBeAg seroconversion (HR 0.943, P = 0.019) were predictors for relapse. In the HBeAg-negative group, age at cessation (HR 1.040, P = 0.004) and time to HBV DNA negativity (HR 1.246, P = 0.010) were potential predictors for virological relapse. CONCLUSIONS The off-treatment responses to NAs differ in CHB patients with different pretreatment HBeAg status. NA withdrawal is generally safe and feasible in young patients with CHB. Long consolidation periods should be preferred in HBeAg-positive patients to achieve better durability. Benefits of cessation of NAs do not last long in HBeAg-negative CHB patients.
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Affiliation(s)
- Feng Liu
- Department of Infectious Diseases and Hepatology, Second Hospital of Shandong University, Jinan, China
| | - Zhi Rong Liu
- Department of Infectious Diseases and Hepatology, Second Hospital of Shandong University, Jinan, China.,Jinan Infectious Disease Hospital, Shandong University School of Medicine, Jinan, China
| | - Tao Li
- Department of Infectious Diseases and Hepatology, Second Hospital of Shandong University, Jinan, China
| | - You De Liu
- Department of Hepatology, Yantai Infectious Disease Hospital, Yantai, China
| | - Meng Zhang
- Jinan Infectious Disease Hospital, Shandong University School of Medicine, Jinan, China
| | - Yan Xue
- Department of Infectious Diseases and Hepatology, Second Hospital of Shandong University, Jinan, China
| | - Li Xin Zhang
- Department of Infectious Diseases and Hepatology, Second Hospital of Shandong University, Jinan, China
| | - Qian Ye
- Department of Infectious Diseases and Hepatology, Second Hospital of Shandong University, Jinan, China
| | - Xiao Ping Fan
- Department of Hepatology, Qingdao Infectious Disease Hospital, Qingdao, Shandong Province, China
| | - Lei Wang
- Department of Infectious Diseases and Hepatology, Second Hospital of Shandong University, Jinan, China
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19
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Moreno-Cubero E, Arco RTSD, Peña-Asensio J, Villalobos ESD, Míquel J, Larrubia JR. Is it possible to stop nucleos(t)ide analogue treatment in chronic hepatitis B patients? World J Gastroenterol 2018; 24:1825-1838. [PMID: 29740199 PMCID: PMC5937201 DOI: 10.3748/wjg.v24.i17.1825] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Revised: 04/21/2018] [Accepted: 04/23/2018] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB) remains a challenging global health problem, with nearly one million related deaths per year. Nucleos(t)ide analogue (NA) treatment suppresses viral replication but does not provide complete cure of the hepatitis B virus (HBV) infection. The accepted endpoint for therapy is the loss of hepatitis B surface antigen (HBsAg), but this is hardly ever achieved. Therefore, indefinite treatment is usually required. Many different studies have evaluated NA therapy discontinuation after several years of NA treatment and before HBsAg loss. The results have indicated that the majority of patients can remain off therapy, with some even reaching HBsAg seroconversion. Fortunately, this strategy has proved to be safe, but it is essential to consider the risk of liver damage and other comorbidities and to ensure a close follow-up of the candidates before considering this strategy. Unanswered questions remain, namely in which patients could this strategy be effective and what is the optimal time point at which to perform it. To solve this enigma, we should keep in mind that the outcome will ultimately depend on the equilibrium between HBV and the host’s immune system. Viral parameters that have been described as good predictors of response in HBeAg(+) cases, have proven useless in HBeAg(-) ones. Since antiviral immunity plays an essential role in the control of HBV infection, we sought to review and explain potential immunological biomarkers to predict safe NA discontinuation in both groups.
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Affiliation(s)
| | - Robert T Sánchez del Arco
- Internal Medicine Service, Guadalajara University Hospital, University of Alcalá, Guadalajara 19002, Spain
| | - Julia Peña-Asensio
- Department of Biology of Systems, University of Alcalá, Alcalá de Henares (Madrid) 28805, Spain
| | | | | | - Juan Ramón Larrubia
- Department of Medicine and Medical Specialties, University of Alcalá, Alcalá de Henares (Madrid) 28805, Spain
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20
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Van Hees S, Bourgeois S, Van Vlierberghe H, Sersté T, Francque S, Michielsen P, Sprengers D, Reynaert H, Henrion J, Negrin Dastis S, Delwaide J, Lasser L, Decaestecker J, Orlent H, Janssens F, Robaeys G, Colle I, Stärkel P, Moreno C, Nevens F, Vanwolleghem T, Belgian NA Stop Study Group, Van Hees S, Bourgeois S, Van Vlierberghe H, Sersté T, Francque S, Michielsen P, Sprengers D, Reynaert H, Henrion J, Negrin‐Dastis S, Delwaide J, Lasser L, Decaestecker J, Orlent H, Janssens F, Robaeys G, Colle I, Stärkel P, Moreno C, Nevens F, Vanwolleghem T. Stopping nucleos(t)ide analogue treatment in Caucasian hepatitis B patients after HBeAg seroconversion is associated with high relapse rates and fatal outcomes. Aliment Pharmacol Ther 2018; 47:1170-1180. [PMID: 29498078 PMCID: PMC5900846 DOI: 10.1111/apt.14560] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 10/05/2017] [Accepted: 01/21/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Stopping nucleos(t)ide analogues (NA) after hepatitis B e antigen (HBeAg) seroconversion is associated with high relapse rates in Asian patients, but data in Caucasian cohorts are scarce. Clinical course, outcomes and immunological aspects of chronic hepatitis B infections differ substantially between distinct ethnicities. AIM The aim of this study was to determine relapse rates, factors predicting relapse and clinical outcomes after nucleos(t)ide analogue cessation in a large, predominantly Caucasian cohort of chronic hepatitis B patients with nucleos(t)ide analogue-induced HBeAg seroconversion. METHODS This is a nationwide observational cohort study including HBeAg positive, mono-infected chronic hepatitis B patients with nucleos(t)ide analogue-induced HBeAg seroconversion from 18 centres in Belgium. RESULTS A total of 98 patients with nucleo(s)tide analogue-induced HBeAg seroconversion were included in the study. Of the 62 patients who stopped treatment after a median consolidation treatment of 8 months, 30 relapsed. Higher gamma-glutamyl transferase levels at both treatment initiation (HR 1.004; P = 0.001 per unit increment) and HBeAg seroconversion (HR 1.006; P = 0.013 per unit increment) were associated with an increased risk of clinically significant relapse in a multivariate Cox regression model. Treatment cessation led to liver-related death in 2 patients, of whom one showed a severe flare. Of the patients who continued treatment after HBeAg seroconversion, none relapsed or developed severe hepatic outcomes. CONCLUSION Treatment withdrawal in Caucasian chronic hepatitis B patients after nucleos(t)ide analogue-induced HBeAg seroconversion results in viral relapses in more than half of patients with potential fatal outcomes. These real-world data further lend support to preferentially continue NA treatment after HBeAg seroconversion until HBsAg loss.
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21
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Tong MJ, Pan CQ, Han SB, Lu DS, Raman S, Hu K, Lim JK, Hann HW, Min AD. An expert consensus for the management of chronic hepatitis B in Asian Americans. Aliment Pharmacol Ther 2018; 47:1181-1200. [PMID: 29479728 PMCID: PMC5900913 DOI: 10.1111/apt.14577] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 10/10/2017] [Accepted: 01/27/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is common with major clinical consequences. In Asian Americans, the HBsAg carrier rate ranges from 2% to 16% which approximates the rates from their countries of origin. Similarly, HBV is the most important cause of cirrhosis, hepatocellular carcinoma (HCC) and liver related deaths in HBsAg positive Asians worldwide. AIM To generate recommendations for the management of Asian Americans infected with HBV. METHODS These guidelines are based on relevant data derived from medical reports on HBV from Asian countries as well as from studies in the HBsAg positive Asian Americans. The guidelines herein differ from other recommendations in the treatment of both HBeAg positive and negative chronic hepatitis B (CHB), in the approach to HCC surveillance, and in the management of HBV in pregnant women. RESULTS Asian American patients, HBeAg positive or negative, with HBV DNA levels >2000 IU/mL (>104 copies/mL) and ALT values above normal are candidates for anti-viral therapy. HBeAg negative patients with HBV DNA >2000 IU/mL and normal ALT levels but who have either serum albumin <3.5 g/dL or platelet count <130 000 mm3 , basal core promoter (BCP) mutations, or who have first-degree relatives with HCC should be offered treatment. Patients with cirrhosis and detectable HBV DNA must receive life-long anti-viral therapy. Indications for treatment include pregnant women with high viraemia, coinfected patients, and those requiring immunosuppressive therapy. In HBsAg positive patients with risk factors, life-long surveillance for HCC with alpha-fetoprotein (AFP) testing and abdominal ultrasound examination at 6-month intervals is required. In CHB patients receiving HCC treatments, repeat imaging with contrast CT scan or MRI at 3-month intervals is strongly recommended. These guidelines have been assigned to a Class (reflecting benefit vs. risk) and a Level (assessing strength or certainty) of evidence. CONCLUSIONS Application of the recommendations made based on a review of the relevant literature and the opinion of a panel of Asian American physicians with expertise in HBV treatment will inform physicians and improve patient outcomes.
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Affiliation(s)
- M. J. Tong
- Pfleger Liver InstituteDivision of Digestive DiseasesDavid Geffen School of Medicine at UCLALos AngelesCAUSA
- Liver CenterHuntington Medical Research InstitutesPasadenaCAUSA
| | - C. Q. Pan
- Division of Gastroenterology and HepatologyNYU Langone Medical CenterNew York University School of MedicineNew YorkNYUSA
| | - S.‐H. B. Han
- Pfleger Liver InstituteDivision of Digestive DiseasesDavid Geffen School of Medicine at UCLALos AngelesCAUSA
| | - D. S.‐K. Lu
- Department of Radiological SciencesDavid Geffen School of Medicine at UCLALos AngelesCAUSA
| | - S. Raman
- Department of Radiological SciencesDavid Geffen School of Medicine at UCLALos AngelesCAUSA
| | - K.‐Q. Hu
- Division of GI/HepatologySchool of MedicineUniversity of California, IrvineOrangeCAUSA
| | - J. K. Lim
- Yale Liver Center and Section of Digestive DiseasesYale University School of MedicineNew HavenCTUSA
| | - H. W. Hann
- Liver Disease Prevention CenterDivision of Gastroenterology and HepatologySidney Kimmel Jefferson Medical College of Thomas Jefferson UniversityPhiladelphiaPAUSA
| | - A. D. Min
- Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNYUSA
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22
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Höner Zu Siederdissen C, Maasoumy B, Cornberg M. What is new on HBsAg and other diagnostic markers in HBV infection? Best Pract Res Clin Gastroenterol 2017; 31:281-289. [PMID: 28774410 DOI: 10.1016/j.bpg.2017.04.009] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 04/28/2017] [Indexed: 01/31/2023]
Abstract
Challenges in the management of chronic hepatitis B virus (HBV) infection involve the prediction of the natural course to identify patients who require antiviral therapy and the prediction of functional cure as ultimate goal of antiviral therapy. HBV DNA as marker for viral replication is important but not sufficient for an adequate management of patients with chronic HBV infection. Data on the quantification of additional HBV marker such as hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) and hepatitis B virus RNA (HBV RNA) have accumulated in recent years. Here we review the current evidence how to use these markers and discuss open issues that require additional research.
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Affiliation(s)
- Christoph Höner Zu Siederdissen
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany.
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Zhang L, Zhang FK. Recent advances in treatment of chronic hepatitis B with entecavir. Shijie Huaren Xiaohua Zazhi 2017; 25:7-16. [DOI: 10.11569/wcjd.v25.i1.7] [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] [Indexed: 02/06/2023] Open
Abstract
Entecavir (ETV) is a potent hepatitis B virus inhibitor with a high barrier to resistance, and it has been recommended as one of the first-line drugs for treating chronic hepatitis B (CHB) by guidelines from several international and national societies. This paper reviews the recent advances in the treatment of CHB with ETV, in terms of treatment adherence, efficacy in the treatment of various kinds of patients with CHB, management of patients with partial virological response, viral resistance or treatment failure to ETV, treatment cessation, sequential or combination therapy with ETV and pegylated interferon, as well as the surveillance of hepatocellular carcinoma.
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24
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Chong CH, Lim SG. When can we stop nucleoside analogues in patients with chronic hepatitis B? Liver Int 2017; 37 Suppl 1:52-58. [PMID: 28052620 DOI: 10.1111/liv.13314] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 11/10/2016] [Indexed: 12/12/2022]
Abstract
Treatment with nucleoside analogue (NAs) is now the most common treatment for chronic hepatitis B (CHB) and is recommended by all guidelines. Stopping NAs is a controversial issue in these patients, unless the clinical endpoints of HBeAg seroconversion or HBsAg seroclearance are achieved. While HBeAg seroconversion can occur in a significant number of patients, HBsAg seroclearance rates are low. HBsAg seroclearance is increasingly accepted as the ideal end of treatment, representing a functional cure. Treatment withdrawal leads to relapse in 50% of patients who achieve HBeAg seroconversion and complete at least 12 months of consolidation therapy. In HBeAg negative CHB, the Asian Pacific Association for the Study of the Liver (APASL) stopping rules show that although clinical relapse occurs in approximately 43% and virological relapse occurs in 70%, very few patients experience flare or decompensation. NAs treatment for >2 years was associated with a lower rate of relapse. Recently, stopping NA therapy was shown to be associated with HBsAg in 20%-39% of HBeAg negative patients and more frequently in those with low quantitative HBsAg (qHBsAg). However, the most optimal level is unclear. Quantitative HBsAg is becoming a useful tool to predict a sustained response or relapse before stopping therapy. In conclusion, stopping NA therapy is generally safe and can be an option in specific situations such as HBeAg seroconversion. However, it is associated with disease relapse. Thus, patient selection based on qHBsAg may help identify patients who are more likely to achieve HBsAg seroclearance or a sustained response.
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Affiliation(s)
- Chern Hao Chong
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | - Seng Gee Lim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore.,Faculty of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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