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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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Liaw YF, Jeng WJ. Prediction of HBsAg loss after cessation of entecavir therapy. J Hepatol 2025; 82:e128-e129. [PMID: 39299458 DOI: 10.1016/j.jhep.2024.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 09/04/2024] [Accepted: 09/10/2024] [Indexed: 09/22/2024]
Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Taiwan; College of Medicine, Chang Gung University, Taiwan.
| | - Wen-Juei Jeng
- Liver Research Unit, Chang Gung Memorial Hospital, Taiwan; Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taiwan; College of Medicine, Chang Gung University, Taiwan
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Fang HW, Jeng WJ, Hu TH, Wang JH, Hung CH, Lu SN, Chen CH. Higher Relapse Rate in HBeAg-Negative Patients After Cessation of Tenofovir Alafenamide Compared With Entecavir or Tenofovir Disoproxil Fumarate. Am J Gastroenterol 2025:00000434-990000000-01557. [PMID: 39820130 DOI: 10.14309/ajg.0000000000003324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 11/20/2024] [Indexed: 01/19/2025]
Abstract
INTRODUCTION There is limited information comparing the off-therapy relapse rates of patients discontinued tenofovir alafenamide (TAF) to those stopping entecavir or tenofovir disoproxil fumarate (TDF). METHODS A total of 805 hepatitis B e antigen-negative patients without cirrhosis receiving entecavir (n = 406), TDF (n = 260), or TAF (n = 139) were enrolled. Propensity score matching method was applied to eliminate the significant differences in clinical characteristics. RESULTS The cumulative incidences of virological relapse, clinical relapse, and retreatment at 96 weeks were higher in the off-TAF group (89.6%, 70.3%, and 59.2%, respectively) than that in the off-entecavir group (65.9%, 42.8%, and 28.8%, respectively) or the off-TDF group (73.7%, 49.8%, and 35.7%, respectively). The median time to clinical relapse was much earlier for off-TAF patients than for off-entecavir or off-TDF (median 14, 57, and 26 weeks, respectively), and these findings persisted even after propensity score matching. Multivariate analysis indicated that TAF therapy was an independent risk factor of virological relapse, clinical relapse, and retreatment when compared with entecavir or TDF. Hepatitis B surface antigen levels at end of treatment were predictive of virological, but not clinical, relapse in the off-TAF group, although this group had a lower rate of severe hepatitis on clinical relapse than the off-TDF group. Finally, there was no significant difference in the hepatic decompensation rate among the entecavir, TDF, and TAF groups. DISCUSSION There is an earlier and higher hepatitis B virus relapse rate in patients who discontinue TAF therapy than in comparable patients discontinuing entecavir or TDF therapy. Close monitoring is necessary after TAF withdrawal, particularly in the first 3 months.
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Affiliation(s)
- Hsin-Wei Fang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Chang Gung University College of Medicine, Taoyuan City, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Lim SG, Teo AED, Chan ESY, Phyo WW, Chen DHY, Hargreaves CA. Stopping Nucleos(t)ide Analogues in Chronic Hepatitis B Using HBsAg Thresholds: A Meta-Analysis and Meta-Regression. Clin Gastroenterol Hepatol 2024; 22:2403-2412. [PMID: 38871150 DOI: 10.1016/j.cgh.2024.05.040] [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: 11/16/2023] [Revised: 04/30/2024] [Accepted: 05/28/2024] [Indexed: 06/15/2024]
Abstract
BACKGROUND AND AIMS Recommendations for stopping nucleoside analogue (NA) therapy in hepatitis B e antigen-negative chronic hepatitis B (CHB) are unclear. End-of-treatment quantitative hepatitis B serum antigen (EOTqHBsAg) thresholds <100 IU/mL or <1000 IU/mL have been proposed as stopping criteria, which we assessed by meta-analysis and meta-regression. METHODS We searched PubMed, EMBASE, and conference abstracts for studies of hepatitis B e antigen-negative CHB NA discontinuation. Extracted studies were analyzed for risk of bias, pooled risk of hepatitis B serum antigen (HBsAg) loss, virological relapse (VR), and biochemical relapse (BR). Significant heterogeneity (I2) was addressed by subgroup analysis and random-effects meta-regression with known important covariates, including EOTqHBsAg thresholds, ethnicity, duration of therapy, and follow-up. RESULTS We found 24 articles (3732 subjects); 16 had low and 8 had moderate risk of bias. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <100 IU/mL were 41.8%, 33.4%, and 17.3%, respectively, vs 4.6%, 72.1%, and 34.6%, respectively, for EOTqHBsAg ≥100 IU/mL. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <1000 IU/mL were 22.0%, 52.7%, and 15.9%, respectively, vs 3.4%, 63.8%, and 26.4%, respectively, for EOTqHBsAg ≥1000 IU/mL. Multivariable analysis for HBsAg loss showed that ethnicity, follow-up duration, and EOTqHBsAg <100 IU/mL and ≥100 IU/mL explained 85% of the variance in heterogeneity; Asians with EOTqHBsAg <100 IU/mL had 28.2%, while non-Asians with EOTqHBsAg <1000 IU/mL had 38.4% HBsAg loss. Multivariable analysis showed EOTqHBsAg <100 IU/mL and ≥100 IU/mL and other covariates only explained 43% and 63% of the variance in heterogeneity for VR and BR, respectively, suggesting that other factors are also important for relapse. CONCLUSIONS While EOTqHBsAg thresholds, ethnicity, and follow-up duration strongly predict HBsAg loss, this is not true for VR and BR, hence stopping NA therapy should be considered cautiously.
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Affiliation(s)
- Seng Gee Lim
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, National University Health System, Singapore.
| | - Ada Ee Der Teo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Edwin Shih-Yen Chan
- Singapore Clinical Research Institute, Consortium for Clinical Research and Innovation Singapore, Singapore; Cochrane Singapore, Singapore; Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore
| | - Wah Wah Phyo
- Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - David Hsing Yu Chen
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Carol Anne Hargreaves
- Data Analytics Consulting Centre, Faculty of Science, National University of Singapore, Singapore
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Hirode G, Hansen BE, Chen CH, Su TH, Wong GLH, Seto WK, d'Almeida AF, Papatheodoridi M, Brakenhoff SM, Lens S, Choi HSJ, Chien RN, Feld JJ, Forns X, Sonneveld MJ, Papatheodoridis GV, Vanwolleghem T, Yuen MF, Chan HLY, Kao JH, Hsu YC, Cornberg M, Jeng WJ, Janssen HLA. Limited Sustained Remission After Nucleos(t)ide Analog Withdrawal: Results From a Large, Global, Multiethnic Cohort of Patients With Chronic Hepatitis B (RETRACT-B Study). Am J Gastroenterol 2024; 119:1849-1856. [PMID: 38483300 DOI: 10.14309/ajg.0000000000002759] [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: 10/24/2023] [Accepted: 02/14/2024] [Indexed: 04/20/2024]
Abstract
INTRODUCTION Complete viral suppression with nucleos(t)ide analogs (NAs) has led to a profound reduction in hepatocellular carcinoma and mortality among patients with chronic hepatitis B. Finite therapy yields higher rates of functional cure; however, initial hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) elevations are almost certain after treatment interruption. We aimed to analyze off-treatment outcomes beyond 12 months after NA cessation. METHODS Patients with well-suppressed chronic hepatitis B who were hepatitis B e antigen-negative at NA cessation and remained off treatment without hepatitis B surface antigen (HBsAg) loss at 12 months were included (n = 945). HBV DNA and ALT fluctuations were allowed within the first 12 months. We used Kaplan-Meier methods to analyze outcomes beyond 12 months. Sustained remission was defined as HBV DNA <2,000 IU/mL and ALT <2× upper limit of normal (ULN) and an ALT flare as ALT ≥5× ULN. RESULTS Cumulative probability of sustained remission was 29.7%, virological relapse was 65.2% with a mean peak HBV DNA of 5.0 ± 1.5 log 10 IU/mL, an ALT flare was 15.6% with a median peak ALT × ULN of 8.3 (5.7-11.3), HBsAg loss was 9.9% and retreatment was 34.9% at 48 months after NA cessation. A single occurrence of virological relapse or an ALT flare within the first 12 months off-treatment were associated with significantly lower rates of sustained remission beyond 12 months. DISCUSSION Despite allowing for HBV DNA and ALT fluctuations within the first 12 months off-treatment, most patients without HBsAg loss did not maintain a sustained response thereafter. The best candidates for NA withdrawal are patients with low HBsAg levels at NA cessation, and those without profound or recurrent virological and biochemical relapses in the first off-treatment year.
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Affiliation(s)
- Grishma Hirode
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
- The Toronto Viral Hepatitis Care Network (VIRCAN), Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
- Department of Epidemiology, Biostatistics, Erasmus Medical Center, Rotterdam, Netherlands
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | | | - Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Grace L H Wong
- Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong, China
| | - Wai-Kay Seto
- Department of Medicine and State Key Laboratory of Liver Research, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Arno Furquim d'Almeida
- Viral Hepatitis Research Group, Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium
| | | | - Sylvia M Brakenhoff
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Sabela Lens
- Hospital Clinic Barcelona, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Hannah S J Choi
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Linkou, Taiwan
| | - Jordan J Feld
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
- The Toronto Viral Hepatitis Care Network (VIRCAN), Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Xavier Forns
- Hospital Clinic Barcelona, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Milan J Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, the Netherlands
| | | | - Thomas Vanwolleghem
- Viral Hepatitis Research Group, Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Man-Fung Yuen
- Department of Medicine and State Key Laboratory of Liver Research, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Henry L Y Chan
- Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong, China
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yao-Chun Hsu
- Center for Liver Diseases, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- Centre for Individualized Infection Medicine (CiiM), Hannover, Germany
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Linkou, Taiwan
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, the Netherlands
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Jeng WJ, Chien RN, Liaw YF. Reply: Halting antiviral therapy in patients with cirrhosis and chronic hepatitis B: A dangerous game? Hepatology 2024; 79:E134-E135. [PMID: 38150032 DOI: 10.1097/hep.0000000000000737] [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: 11/29/2023] [Accepted: 11/29/2023] [Indexed: 12/28/2023]
Affiliation(s)
- Wen-Juei Jeng
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Rong-Nan Chien
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Taiwan
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Liaw YF. When to Stop Antiviral Therapy in HBeAg-Negative Patients with Chronic Hepatitis B? CURRENT HEPATOLOGY REPORTS 2024; 23:221-226. [DOI: 10.1007/s11901-024-00663-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/16/2024] [Indexed: 01/03/2025]
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Lin CL, Kao JH. Precision Management of Patients with HBV Infection. CURRENT HEPATOLOGY REPORTS 2024; 23:22-31. [DOI: 10.1007/s11901-024-00632-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/02/2024] [Indexed: 01/03/2025]
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Lim SG, Tan YC. Additional Measures After Stopping Nucleoside Analogues in HbeAg-Negative Chronic Hepatitis B: Better But Not Enough. Gastroenterology 2024; 166:23-24. [PMID: 37832923 DOI: 10.1053/j.gastro.2023.10.005] [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: 10/06/2023] [Revised: 10/10/2023] [Accepted: 10/10/2023] [Indexed: 10/15/2023]
Affiliation(s)
- Seng Gee Lim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System; Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
| | - Yong Chuan Tan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
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Schlaak JF. Current Therapy of Chronic Viral Hepatitis B, C and D. J Pers Med 2023; 13:964. [PMID: 37373953 DOI: 10.3390/jpm13060964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
The majority of chronic viral hepatitis cases are induced via infection with the hepatitis B virus (HBV), hepatitis C virus (HCV), or hepatitis D virus (HDV). These patients are at increased risk for progressive liver disease leading to cirrhosis as well as hepatocellular carcinoma (HCC). HBV infection is well controlled by the currently available nucleosides as well as nucleotides, and the development of cirrhosis can be prevented. Additionally, it has been shown that HBV-induced liver fibrosis can regress during successful antiviral treatment; however, a "functional cure", i.e., loss of HBsAg, is a rare event when these drugs are used. Therefore, novel therapeutic strategies are aiming at the selective suppression of HBsAg levels in combination with immunostimulation. The development of directly acting antivirals (DAAs) has revolutionized HCV therapy, as almost all patients can be cured via this treatment. Additionally, DAA therapy has few, if any, side effects, and is generally well tolerated by patients. HDV remains the most challenging type of chronic viral hepatitis. Although novel therapeutic options have recently been approved, response rates are still less favorable compared to HBV and HCV. This review discusses current and future options for the treatment of chronic HBV, HCV, and HDV infection.
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Affiliation(s)
- Jörg F Schlaak
- Department of Internal Medicine, Ameos Hospital Oberhausen, Wilhelmstr. 34, 46145 Oberhausen, Germany
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Hui RWH, Mak LY, Seto WK, Yuen MF, Fung J. Chronic hepatitis B: a scoping review on the guidelines for stopping nucleos(t)ide analogue therapy. Expert Rev Gastroenterol Hepatol 2023; 17:443-450. [PMID: 36972516 DOI: 10.1080/17474124.2023.2196405] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 03/24/2023] [Indexed: 03/29/2023]
Abstract
INTRODUCTION Nucleos(t)ide analogues (NAs) are effective in suppressing the replication of the hepatitis B virus. However, NAs cannot effectively induce hepatitis B surface antigen (HBsAg) seroclearance, which represents the optimal treatment endpoint in chronic hepatitis B (CHB). Hence, most CHB patients are advised for indefinite NA therapy, but recent data has supported the concept of finite NA therapy before HBsAg seroclearance. AREAS COVERED This article covered the latest evidence on stopping NAs in CHB, with a focused analysis on international guidelines. Articles were retrieved by a literature search on PubMed with the keywords 'chronic hepatitis B,' 'antiviral therapy,' 'nucleos(t)ide analogue,' 'cessation,' 'stopping', and 'finite.' Studies up till 1 December 2022 were included. EXPERT OPINION Finite NA therapy in CHB has the potential in enhancing HBsAg seroclearance, however it also carries rare but potentially severe risks. NA cessation before HBsAg seroclearance is only suitable for a highly selected group of patients, whereas the majority of CHB patients should be treated indefinitely or until HBsAg seroclearance. Current guidelines have provided recommendations on stopping NAs, but further research is required to optimize the monitoring and retreatment protocol after stopping NAs.
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Affiliation(s)
- Rex Wan-Hin Hui
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - James Fung
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
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Emerging Therapies for Chronic Hepatitis B and the Potential for a Functional Cure. Drugs 2023; 83:367-388. [PMID: 36906663 DOI: 10.1007/s40265-023-01843-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/01/2023] [Indexed: 03/13/2023]
Abstract
Worldwide, an estimated 296 million people are living with chronic hepatitis B virus (HBV) infection, with a significant risk of morbidity and mortality. Current therapy with pegylated interferon (Peg-IFN) and indefinite or finite therapy with nucleoside/nucleotide analogues (Nucs) are effective in HBV suppression, hepatitis resolution, and prevention of disease progression. However, few achieve hepatitis B surface antigen (HBsAg) loss (functional cure), and relapse often occurs after the end of therapy (EOT) because these agents have no direct effect on durable template: covalently closed circular DNA (cccDNA) and integrated HBV DNA. Hepatitis B surface antigen loss rate increases slightly by adding or switching to Peg-IFN in Nuc-treated patients and this loss rate greatly increases up to 39% in 5 years with finite Nuc therapy with currently available Nuc(s). For this, great effort has been made to develop novel direct-acting antivirals (DAAs) and immunomodulators. Among the DAAs, entry inhibitors and capsid assembly modulators have little effect on reducing HBsAg levels; small interfering RNA, antisense oligonucleotides, and nucleic acid polymers in combination with Peg-IFN and Nuc may reduce HBsAg levels significantly, even a rate of HBsAg loss sustained for > 24 weeks after EOT up to 40%. Novel immunomodulators, including T-cell receptor agonists, check-point inhibitors, therapeutic vaccines, and monoclonal antibodies may restore HBV-specific T-cell response but not sustained HBsAg loss. The safety issues and the durability of HBsAg loss warrant further investigation. Combining agents of different classes has the potential to enhance HBsAg loss. Compounds directly targeting cccDNA would be more effective but are still in the early stage of development. More effort is required to achieve this goal.
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Yao Y, Zhang J, Li X, Zao X, Cao X, Chen G, Ye Y. Systematic review: Clinical outcomes of discontinuation of oral antivirals in hepatitis B-related liver cirrhosis. Front Public Health 2022; 10:1037527. [PMID: 36407996 PMCID: PMC9670108 DOI: 10.3389/fpubh.2022.1037527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022] Open
Abstract
Background Discontinuation of Nucleos(t)ide analogs (NAs) remains one of the most controversial topics in the management of hepatitis B-related liver cirrhosis. However, clinical outcomes after NAs discontinuation have not been studied. Aim The aim of this systematic review is to evaluate existing data on clinical outcomes of NAs withdrawal in chronic hepatitis B (CHB) patients with cirrhosis. Methods A literature search (until May 2022) was performed in order to identify all published studies including hepatitis B-related cirrhotic patients who discontinued NAs in virological remission with off-therapy follow-up >12 months. Results Nineteen studies with 1,287 hepatitis B-related cirrhotic patients were included. Most cirrhotic patients were compensated and achieved complete virological suppression when they stopped the antiviral therapy. The pooled proportions of virological relapse and clinical relapse after NAs discontinuation in cirrhotic patients were 55.23 (95% CI: 40.33-69.67) and 43.56% (95% CI: 26.13-61.85), respectively. HBsAg loss was observed in 56 of 500 (pooled proportion = 13.68%, 95% CI: 5.82-24.18) cirrhotic patients. And the pooled proportions of HCC development, hepatic decompensation and overall mortality were 8.76 (95% CI: 2.25-18.95), 3.63 (95% CI: 1.31-7.03), and 0.85% (95% CI: 0.35-1.57), respectively, after NAs discontinuation in cirrhotic patients. Conclusion In hepatitis B-related compensated cirrhosis, who have achieved complete virological suppression, discontinuation of oral antivirals still carries a high relapse rate, but the incidence of adverse events is generally low and controlled during follow-up of at least 12 months. Of attention is that discontinuation of NAs can achieve a high rate of HBsAg seroclearance. This study may be helpful in the management of NAs in cirrhotic patients. Systematic review registration http://www.crd.york.ac.uk/PROSPERO, identifier: CRD42020170103.
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Affiliation(s)
- Yuhao Yao
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- First School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Jiaxin Zhang
- 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
| | - 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
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xu Cao
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Guang Chen
- 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
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
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15
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Liem KS, Chi H, Fung S, Wong DK, Yim C, Noureldin S, Chen J, de Man RA, Sarowar A, Feld JJ, Hansen BE, Hou J, Peng J, Janssen HLA. Early virologic relapse predicts alanine aminotransferase flares after nucleos(t)ide analogue withdrawal in patients with chronic hepatitis B. J Viral Hepat 2022; 29:986-993. [PMID: 36048970 DOI: 10.1111/jvh.13742] [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: 04/14/2022] [Revised: 06/28/2022] [Accepted: 07/06/2022] [Indexed: 12/09/2022]
Abstract
When patients with chronic hepatitis B (CHB) stop nucleos(t)ide analogue (NA) therapy before achieving HBsAg loss, flares often ensue which are challenging to predict early. We determined the incidence, severity, outcome and predictors of flares after NA withdrawal. Forty-five patients enrolled in an RCT were included; 107 patients from an external, prospective cohort were used for validation. Retreatment criteria were pre-defined. Pre- and post-treatment predictors of alanine aminotransferase (ALT) flare (>5× ULN) were evaluated by Cox proportional-hazards regression. Seventy-two weeks after NA withdrawal, 23/45 (51%) patients had developed >5× ULN and 14 (31%) >20× ULN. Median time to develop ALT >5× ULN was 12 weeks after NA withdrawal. Independent predictors of ALT >5× ULN were male sex (HR [95% CI] 3.2 [1.2-8.9]; p = 0.03) and serum HBV DNA (1.2 [1.0-1.8]; p = 0.03) at Week 6 off-therapy. Specifically, week 6 HBV DNA >10,000 IU/ml predicted ALT >5× ULN (3.4 [1.4-8.4]; p = 0.01), which was externally validated. In conclusion, this study on post-treatment flares revealed a high cumulative incidence in CHB. Week 6 HBV DNA >10,000 IU/ml independently predicted flares. The proposed threshold enables prediction of imminent flares in patients who may benefit from closer monitoring and earlier retreatment.
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Affiliation(s)
- Kin Seng Liem
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada.,Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Heng Chi
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Scott Fung
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
| | - David K Wong
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
| | - Colina Yim
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
| | - Seham Noureldin
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
| | - Jiayun Chen
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
| | - Robert A de Man
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Arif Sarowar
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
| | - Jordan J Feld
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada.,McLaughlin-Rotman Centre for Global Health, Toronto, Ontario, Canada
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada.,Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.,Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Jinlin Hou
- Department of Infectious Diseases, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jie Peng
- Department of Infectious Diseases, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada.,Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
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16
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Liaw YF. Perspectives on current controversial issues in the management of chronic HBV infection. J Gastroenterol 2022; 57:828-837. [PMID: 36053366 DOI: 10.1007/s00535-022-01918-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 08/18/2022] [Indexed: 02/04/2023]
Abstract
Clinical and basic research in the past decades has achieved consensus in the understanding of chronic hepatitis B virus (HBV) infection and the management of chronic hepatitis B and HBV-cirrhosis. However, debatable challenges to the existing consensus in the concept and/or definitions have emerged. These include (1). alanine aminotransferase upper limit of normal: traditional laboratory-defined vs fixed; (2). nomenclature for phases of chronic HBV infection: classical vs EASL proposal; (3). indication of antiviral therapy: to treat patients vs to treat HBV; (4). finite vs indefinite long-term antiviral therapy: A. finite therapy in HBV-cirrhosis; B. retreatment decision: biochemical markers vs HBsAg/ALT kinetics. The pros and cons of these controversial issues were reviewed, assessed, and discussed in depth based on relevant lines of scientific evidence, intended to clarify or solve these controversial issues.
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Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 199, Tung Hwa North Road, Taipei, 105, Taiwan.
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17
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Chang ML, Chien RN, Liaw YF. Evidence-Based Management of Oral Nucleos(t)ide Analogue Withdrawal in Virally Suppressed Patients with Chronic HBV Infection. CURRENT HEPATOLOGY REPORTS 2022; 21:52-58. [DOI: 10.1007/s11901-022-00587-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/11/2022] [Indexed: 01/02/2025]
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18
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Finite versus Indefinite Nucleos(t)ide Analogue Therapy of Patients with Chronic Hepatitis B Exhibiting Negative HBsAg Levels after Treatment. BIOMED RESEARCH INTERNATIONAL 2022; 2022:6069781. [PMID: 35872855 PMCID: PMC9307367 DOI: 10.1155/2022/6069781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 12/14/2021] [Accepted: 12/17/2021] [Indexed: 11/17/2022]
Abstract
Aim To determine whether a decrease in HBsAg to <0.05 IU/mL could be a criterion for cessation of finite nucleos(t)ide analogue (NUC) therapy in patients with chronic hepatitis B (CHB). Methods This was a retrospective analysis of 6715 patients with CHB between January 1998 and May 2016. Patients were followed up every 12–24 weeks. Among 104 patients achieving HBsAg levels < 0.05 IU/mL, 71 were eligible for inclusion in the analysis: 31 received finite NUC therapy, and 40 received indefinite NUC therapy. In the finite therapy group, 9 patients received no NUC consolidation therapy, 6 received short-term (<1 year) consolidation, and 16 received long-term (>1 year) consolidation. The outcome measures were alanine aminotransferase (ALT), total bilirubin, albumin, hepatitis B virus DNA, and HBsAg levels. Results Baseline parameters and characteristics at the time when HBsAg levels had fallen to <0.05 IU/mL were similar between the finite and indefinite therapy groups. No patients experienced viral breakthrough/relapse during a median follow-up of 120 weeks. There were little or no differences in long-term outcomes between the finite and indefinite therapy groups and between the short-term and long-term consolidation groups. Conclusions Discontinuation of NUCs may be acceptable in patients whose HBsAg levels fall to <0.05 IU/mL. Consolidation therapy lasting <1 year appears adequate to prevent poor long-term prognosis.
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19
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Comparison of the Effect of Entecavir and Tenofovir on Serum HBsAg Levels in Chronic HBe-Negative Hepatitis B Patients. HEPATITIS MONTHLY 2022. [DOI: 10.5812/hepatmon-118965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Background: The quantification of hepatitis B surface antigen (qHBsAg) was proposed as a helpful tool to monitor treatment efficacy with nucleos(t)ide analogs (NA) in HB e antigen-negative chronic HB. Objectives: The present study aimed to assess the effect of entecavir (ETV) and tenofovir dipivoxil (TDF) on qHBsAg kinetics and estimate the time necessary to achieve HBsAg clearance with each of these drugs. Methods: The study was conducted on 93 patients, 54 and 39 of whom were treated with ETV and TDF for a median time of 42 months, respectively. The qHBsAg was measured in 6-month intervals with the Elecsys HBsAg II Quantitative assay. The estimated time to undetectable HBsAg was calculated using the best-fitted curve analysis. Results: There was a significant decrease in qHBsAg titers in 79 (84.9%) patients with no difference between ETV and TDF groups (P = 0.754). The median quantitative HBsAg drop was 2003 IU/mL (interquartile range: 638.1 - 5010). The HBsAg levels decreased by 40.3 ± 25.9% on average. The expected time required for HBsAg clearance was comparable in both groups, equaling 104 and 114 months for TDF and ETV, respectively. Conclusions: The HBsAg clearance can be achieved in a substantial proportion of patients after additional 5 years of treatment with NA. The potency of TDF and ETV in qHBsAg reduction is similar.
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20
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Sonneveld MJ, Chiu SM, Park JY, Brakenhoff SM, Kaewdech A, Seto WK, Tanaka Y, Carey I, Papatheodoridi M, van Bömmel F, Berg T, Zoulim F, Ahn SH, Dalekos GN, Erler NS, Höner Zu Siederdissen C, Wedemeyer H, Cornberg M, Yuen MF, Agarwal K, Boonstra A, Buti M, Piratvisuth T, Papatheodoridis G, Chen CH, Maasoumy B. Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels. J Hepatol 2022; 76:1042-1050. [PMID: 35092743 DOI: 10.1016/j.jhep.2022.01.007] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/14/2021] [Accepted: 01/04/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Nucleo(s)tide analogue (NUC) withdrawal may result in HBsAg clearance in a subset of patients. However, predictors of HBsAg loss after NUC withdrawal remain ill-defined. METHODS We studied predictors of HBsAg loss in a global cohort of HBeAg-negative patients with undetectable HBV DNA who discontinued long-term NUC therapy. Patients requiring retreatment after treatment cessation were considered non-responders. RESULTS We enrolled 1,216 patients (991 with genotype data); 98 (8.1%) achieved HBsAg loss. The probability of HBsAg loss was higher in non-Asian patients (adjusted hazard ratio [aHR] 8.26, p <0.001), and in patients with lower HBsAg (aHR 0.243, p <0.001) and HBV core-related antigen (HBcrAg) (aHR 0.718, p = 0.001) levels. Combining HBsAg (<10, 10-100 or >100 IU/ml) and HBcrAg (<2log vs. ≥2 log) levels improved prediction of HBsAg loss, with extremely low rates observed in patients with HBsAg >100 IU/ml with detectable HBcrAg. HBsAg loss rates also varied with HBV genotype; the highest rates were observed for genotypes A and D, and none of the patients with HBV genotype E experienced HBsAg loss (p <0.001 for the overall comparison across genotypes; p <0.001 for genotypes A/D vs. genotypes B/C). HBV genotype C was independently associated with a higher probability of HBsAg loss when compared to genotype B among Asian patients (aHR 2.494; 95% CI 1.490-4.174, p = 0.001). CONCLUSIONS The probability of HBsAg loss after NUC cessation varies according to patient ethnicity, HBV genotype and end-of-treatment viral antigen levels. Patients with low HBsAg (<100 IU/ml) and/or undetectable HBcrAg levels, particularly if non-Asian or infected with HBV genotype C, appear to be the best candidates for treatment withdrawal. LAY SUMMARY A subset of patients may achieve clearance of hepatitis B surface antigen (HBsAg) - so-called functional cure - after withdrawal of nucleo(s)tide analogue therapy. In this multicentre study of 1,216 patients who discontinued antiviral therapy, we identified non-Asian ethnicity, HBV genotype C, and low hepatitis B surface antigen and hepatitis B core-related antigen levels as factors associated with an increased chance of HBsAg loss.
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Affiliation(s)
- Milan J Sonneveld
- Departments of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
| | - Shao-Ming Chiu
- Department of Internal Medicine, Koahsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Jun Yong Park
- Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Sylvia M Brakenhoff
- Departments of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Apichat Kaewdech
- Faculty of Medicine, Prince of Songkla University, Hatyai, Thailand
| | - Wai-Kay Seto
- Department of Medicine, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
| | - Yasuhito Tanaka
- Department of Gastroenterology & Hepatology, Kumamoto University, Kumamoto, Japan
| | - Ivana Carey
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Margarita Papatheodoridi
- Department of Gastroenterology, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Greece
| | - Florian van Bömmel
- Division of Hepatology, Clinic for Oncology, Gastroenterology, Hepatology, Infectious Diseases and Pneumology, University Clinic Leipzig, Germany
| | - Thomas Berg
- Division of Hepatology, Clinic for Oncology, Gastroenterology, Hepatology, Infectious Diseases and Pneumology, University Clinic Leipzig, Germany
| | | | - Sang Hoon Ahn
- Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - George N Dalekos
- Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Nicole S Erler
- Department of Biostatistics, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | | | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Man-Fung Yuen
- Department of Medicine, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
| | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Andre Boonstra
- Departments of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Maria Buti
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Ciberehd del Intituto Carlos III de Barcelona, Spain
| | | | - George Papatheodoridis
- Department of Gastroenterology, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Greece
| | - Chien-Hung Chen
- Department of Internal Medicine, Koahsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Benjamin Maasoumy
- Department of Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany
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21
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2022; 28:276-331. [PMID: 35430783 PMCID: PMC9013624 DOI: 10.3350/cmh.2022.0084] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 01/10/2023] Open
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22
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Sonneveld MJ, Park JY, Kaewdech A, Seto WK, Tanaka Y, Carey I, Papatheodoridi M, van Bömmel F, Berg T, Zoulim F, Ahn SH, Dalekos GN, Erler NS, Höner Zu Siederdissen C, Wedemeyer H, Cornberg M, Yuen MF, Agarwal K, Boonstra A, Buti M, Piratvisuth T, Papatheodoridis G, Maasoumy B. Prediction of Sustained Response After Nucleo(s)tide Analogue Cessation Using HBsAg and HBcrAg Levels: A Multicenter Study (CREATE). Clin Gastroenterol Hepatol 2022; 20:e784-e793. [PMID: 33309804 DOI: 10.1016/j.cgh.2020.12.005] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 11/25/2020] [Accepted: 12/06/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Predictors of successful nucleo(s)tide analogue (NA) therapy withdrawal remain elusive. We studied the relationship between end-of-treatment levels of hepatitis B core-related antigen (HBcrAg) and hepatitis B surface antigen (HBsAg) and outcome after therapy cessation. METHODS Patients who discontinued NA therapy in centers in Asia and Europe were enrolled. HBcrAg and HBsAg were measured at treatment cessation, and associations with off-treatment outcomes were explored. The SCALE-B (Surface antigen, Core-related antigen, Age, ALT, and tenofovir for HBV) score was calculated as previously reported. End points included sustained virologic response (VR; hepatitis B virus DNA level <2000 IU/mL), HBsAg loss, and alanine aminotransferase (ALT) flares (>3× upper limit of normal). Re-treated patients were considered nonresponders. RESULTS We analyzed 572 patients, 457 (80%) were Asian and 95 (17%) were hepatitis B e antigen positive at the start of NA therapy. The median treatment duration was 295 weeks. VR was observed in 267 (47%), HBsAg loss was observed in 24 (4.2%), and ALT flare was observed in 92 (16%). VR (67% vs 42%) and HBsAg loss (15% vs 1.5%) was observed more frequently in non-Asian patients when compared to Asian patients (P < .001). Lower HBcrAg levels were associated with higher rates of VR (odds ratio [OR], 0.701; P < .001) and HBsAg loss (OR, 0.476; P < .001), and lower rates of ALT flares (OR, 1.288; P = .005). Similar results were observed with HBsAg (VR: OR, 0.812; P = .011; HBsAg loss: OR, 0.380; P < .001; and ALT flare: OR, 1.833; P < .001). Lower SCALE-B scores were associated with higher rates of VR, HBsAg loss, and lower rates of ALT flares in both Asian and non-Asian patients (P < .001). CONCLUSIONS In this multicenter study, off-treatment outcomes after NA cessation varied with ethnicity. Lower levels of HBcrAg and HBsAg were associated with favorable outcomes. A risk score comprising both factors can be used for risk stratification.
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Affiliation(s)
- Milan J Sonneveld
- Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands.
| | - Jun Yong Park
- Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Apichat Kaewdech
- Faculty of Medicine, Prince of Songkla University, Hatyai, Thailand
| | - Wai-Kay Seto
- Department of Medicine, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan
| | - Ivana Carey
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Margarita Papatheodoridi
- Department of Gastroenterology, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Athens, Greece
| | - Florian van Bömmel
- Division of Hepatology, Clinic for Oncology, Gastroenterology, Hepatology, Infectious Diseases and Pneumology, University Clinic Leipzig, Leipzig, Germany
| | - Thomas Berg
- Division of Hepatology, Clinic for Oncology, Gastroenterology, Hepatology, Infectious Diseases and Pneumology, University Clinic Leipzig, Leipzig, Germany
| | | | - Sang Hoon Ahn
- Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - George N Dalekos
- Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Nicole S Erler
- Department of Biostatistics, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | | | - Heiner Wedemeyer
- Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany
| | - Man-Fung Yuen
- Department of Medicine, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
| | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands
| | - Maria Buti
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Ciberehd del Intituto Carlos III de Barcelona, Barcelona, Spain
| | | | - George Papatheodoridis
- Department of Gastroenterology, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Athens, Greece
| | - Benjamin Maasoumy
- Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany
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23
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Liaw YF, Chien RN. Finite nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B: From an "option" to an "active recommendation". Kaohsiung J Med Sci 2022; 38:295-301. [PMID: 35262284 DOI: 10.1002/kjm2.12518] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 01/27/2022] [Indexed: 12/12/2022] Open
Abstract
Nucleos(t)ide analogue (Nuc) including entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide may suppress hepatitis B virus (HBV) DNA profoundly but have no direct action on covalently closed circular DNA, which is a very stable template for HBV production. Therefore, decades of long-term Nuc therapy are required to maintain HBV suppression and to achieve hepatitis B surface antigen (HBsAg) loss in hepatitis B e antigen (HBeAg)-negative patients. However, there are concerns including financial burden, adherence, and willingness for indefinite long-term Nuc therapy. Patients lost to follow-up and hence not monitored may risk severe relapse that may deteriorate to hepatic decompensation or even hepatic failure. Cessation of Nuc therapy in HBeAg-negative patients was initially considered in early 2000s. Earlier findings in Asian patients that finite Nuc therapy over 2-3 years is feasible and safe have founded Asian-Pacific Association for the Study of Liver stopping rule since 2008. Subsequent studies have confirmed the feasibility and safety of the strategy of finite Nuc therapy, which has finally been accepted as "an option" by American and European liver associations since 2016. More recent large studies since 2018 have further confirmed the pivotal finding of greatly increased HBsAg loss rate (~5-year 39%) after stopping Nuc therapy. With the high HBsAg loss rate as the main justification, the paradigm shift from indefinite long-term therapy to finite Nuc therapy in HBeAg-negative patients has been changing from an "option" to an "active recommendation" aiming to achieve HBsAg loss. More studies are needed to fine-tuning the strategy, including research for the optimal duration of consolidation therapy, timing to stop, and to start retreatment.
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Affiliation(s)
- Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Rong-Nan Chien
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
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24
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Liu YC, Jeng WJ, Peng CW, Chien RN, Liaw YF. Off-tenofovir hepatitis flares in HBeAg-negative patients occur earlier, more frequent and severe than those off-entecavir therapies. Liver Int 2022; 42:551-560. [PMID: 34936719 DOI: 10.1111/liv.15140] [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: 05/20/2021] [Revised: 11/23/2021] [Accepted: 12/19/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Clinical relapse occurs much earlier and more frequently in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients after stopping tenofovir (TDF) therapy than those off-entecavir (ETV). Clinical relapse may subside or progress to hepatitis flare which poses a safety concern. This study compared the incidence, timing and severity of hepatitis flares after stopping TDF and ETV. METHODS HBeAg-negative CHB patients who had stopped ETV or TDF were included in the study. Off-therapy hepatitis flare patterns were compared between off-ETV and off-TDF patients before and after propensity score matching (PSM). RESULTS The off-therapy hepatitis flares occurred more frequently (2-year: 58% vs 38%, P < .001) and much earlier (12 vs. 38 weeks, P < .001) in TDF group, with higher alanine aminotransferase (ALT) levels (after PSM: 536 vs. 419 U/L, P = .020) and two times rate of hepatic decompensation (4.0% vs. 2.1%, P = .322). The cirrhotic status [aHR: 20.531 (2.645-159.365), P = .004] and off-TDF [aHR: 5.530 (1.728-17.694), P = .004] were two independent predictors for hepatic decompensation. CONCLUSIONS Hepatitis flare occurred more frequently, earlier, and more severe in off-TDF than off-ETV patients. More stringent off-therapy monitoring within 6 months off-TDF is mandatory whereas more attention is needed after 6 months off-ETV.
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Affiliation(s)
- Yen-Chun Liu
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wen-Juei Jeng
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chien-Wei Peng
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Rong-Nan Chien
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan
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25
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Hirode G, Choi HSJ, Chen CH, Su TH, Seto WK, Van Hees S, Papatheodoridi M, Lens S, Wong G, Brakenhoff SM, Chien RN, Feld J, Sonneveld MJ, Chan HLY, Forns X, Papatheodoridis GV, Vanwolleghem T, Yuen MF, Hsu YC, Kao JH, Cornberg M, Hansen BE, Jeng WJ, Janssen HLA. Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study). Gastroenterology 2022; 162:757-771.e4. [PMID: 34762906 DOI: 10.1053/j.gastro.2021.11.002] [Citation(s) in RCA: 120] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 10/28/2021] [Accepted: 11/01/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Functional cure, defined based on hepatitis B surface antigen (HBsAg) loss, is rare during nucleos(t)ide analogue (NA) therapy and guidelines on finite NA therapy have not been well established. We aim to analyze off-therapy outcomes after NA cessation in a large, international, multicenter, multiethnic cohort of patients with chronic hepatitis B (CHB). METHODS This cohort study included patients with virally suppressed CHB who were hepatitis B e antigen (HBeAg)-negative and stopped NA therapy. Primary outcome was HBsAg loss after NA cessation, and secondary outcomes included virologic, biochemical, and clinical relapse, alanine aminotransferase flare, retreatment, and liver-related events after NA cessation. RESULTS Among 1552 patients with CHB, cumulative probability of HBsAg loss was 3.2% at 12 months and 13.0% at 48 months of follow-up. HBsAg loss was higher among Whites (vs Asians: subdistribution hazard ratio, 6.8; 95% confidence interval, 2.7-16.8; P < .001) and among patients with HBsAg levels <100 IU/mL at end of therapy (vs ≥100 IU/mL: subdistribution hazard ratio, 22.5; 95% confidence interval, 13.1-38.7; P < .001). At 48 months of follow-up, Whites with HBsAg levels <1000 IU/mL and Asians with HBsAg levels <100 IU/mL at end of therapy had a high predicted probability of HBsAg loss (>30%). Incidence rate of hepatic decompensation and hepatocellular carcinoma was 0.48 per 1000 person-years and 0.29 per 1000 person-years, respectively. Death occurred in 7/19 decompensated patients and 2/14 patients with hepatocellular carcinoma. CONCLUSIONS The best candidates for NA withdrawal are virally suppressed, HBeAg- negative, noncirrhotic patients with CHB with low HBsAg levels, particularly Whites with <1000 IU/mL and Asians with <100 IU/mL. However, strict surveillance is recommended to prevent deterioration.
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Affiliation(s)
- Grishma Hirode
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; The Toronto Viral Hepatitis Care Network, Toronto, Canada
| | - Hannah S J Choi
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada
| | | | - Tung-Hung Su
- National Taiwan University Hospital, Taipei, Taiwan
| | - Wai-Kay Seto
- Department of Medicine and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Special administrative regions of China
| | - Stijn Van Hees
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | | | - Sabela Lens
- Hospital Clinic Barcelona, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Grace Wong
- The Chinese University of Hong Kong, Hong Kong, Special administrative regions of China
| | - Sylvia M Brakenhoff
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Linkou, Taiwan
| | - Jordan Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; The Toronto Viral Hepatitis Care Network, Toronto, Canada
| | - Milan J Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Henry L Y Chan
- The Chinese University of Hong Kong, Hong Kong, Special administrative regions of China
| | - Xavier Forns
- Hospital Clinic Barcelona, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | | | - Thomas Vanwolleghem
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Man-Fung Yuen
- Department of Medicine and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Special administrative regions of China
| | - Yao-Chun Hsu
- E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | | | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany Centre for Individualized Infection Medicine, Hannover, Germany
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; The Toronto Viral Hepatitis Care Network, Toronto, Canada
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Linkou, Taiwan
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; The Toronto Viral Hepatitis Care Network, Toronto, Canada.
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26
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Chang ML, Liaw YF. Hepatitis B Flare in Hepatitis B e Antigen-Negative Patients: A Complicated Cascade of Innate and Adaptive Immune Responses. Int J Mol Sci 2022; 23:ijms23031552. [PMID: 35163476 PMCID: PMC8836007 DOI: 10.3390/ijms23031552] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 01/19/2022] [Accepted: 01/26/2022] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a dynamic process involving interactions among HBV, hepatocytes, and the host immune system. The natural course of chronic hepatitis B (CHB) is divided into four chronological phases, including the hepatitis B e antigen (HBeAg)-positive and HBeAg-negative phases. During HBV flare, alanine aminotransferase (ALT) levels abruptly rise to >5× the upper limit of normal; this is thought to occur due to the immune response against an upsurge in serum HBV DNA and antigen levels. Hepatitis flares may occur spontaneously, during or after antiviral therapy, or upon immunosuppression or chemotherapy in both HBeAg-positive and HBeAg-negative patients. The clinical spectrum of HBV flares varies from asymptomatic to hepatic decompensation or failure. HBeAg seroconversion with ≥ 1 year of consolidation therapy is accepted as an endpoint of oral antiviral therapy in HBeAg-positive patients, but recommendations for treating HBeAg-negative patients differ. Thus, the management of HBeAg-negative patients has attracted increasing interest. In the current review, we summarize various types of HBV flares and the associated complex cascade of innate and adaptive immune responses, with a focus on HBeAg-negative CHB patients. Hopefully, this review will provide insight into immunopathogenesis to improve the management of HBV flares in HBeAg-negative CHB patients.
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Affiliation(s)
- Ming-Ling Chang
- College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan;
- Division of Hepatology, Department of Hepatogastroenterology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan
- Correspondence: ; Tel.: +886-3-3281200 (ext. 8107); Fax: +886-3-3272236
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan;
- Division of Hepatology, Department of Hepatogastroenterology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan
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27
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Controversies in Treating Chronic Hepatitis B virus: The Role of Hepatitis B Virus DNA and Surface Antigen Titer. Clin Liver Dis 2021; 25:763-784. [PMID: 34593152 DOI: 10.1016/j.cld.2021.06.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Controversial areas in chronic hepatitis B (CHB) are those where there is uncertainty, or differences of opinion in management, or where evidence may be insufficient. Areas of controversy include whether patients with high viral load but normal liver function tests should be treated to prevent hepatocellular carcinoma (HCC) or liver disease progression to cirrhosis. Another area is whether quantitative hepatitis B surface antigen (qHBsAg) can be used to better characterize phases of CHB and prognosticate. Finally, the utility of qHBsAg in the management of patients on antiviral therapy such as interferon and nucleoside analogues could improve management practices.
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28
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Gara N, Tana MM, Kattapuram M, Auh S, Sullivan L, Fryzek N, Walter M, Umarova R, Zhao X, Cloherty G, Doo E, Heller T, Liang TJ, Ghany MG. Prospective Study of Withdrawal of Antiviral Therapy in Patients with Chronic Hepatitis B after Prolonged Virological Response. Hepatol Commun 2021; 5:1888-1900. [PMID: 34558806 PMCID: PMC8557321 DOI: 10.1002/hep4.1761] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 04/17/2021] [Accepted: 04/25/2021] [Indexed: 01/05/2023] Open
Abstract
Nucleoside analogue (NA) therapy for chronic hepatitis B (CHB) is associated with improved clinical outcomes, but usually requires long-term use. Whether treatment can be safely withdrawn and the factors associated with post-withdrawal outcome are not well defined. To assess long-term outcomes after stopping antiviral therapy, patients with hepatitis B e antigen (HBeAg)-negative CHB who had received antiviral therapy for 4 or more years with hepatitis B virus (HBV) DNA (≤100 IU/mL) were prospectively withdrawn from antiviral therapy and monitored monthly for the initial 6 months and every 3 months thereafter. Those with clinical relapse were retreated according to severity of relapse. Fifteen patients were withdrawn from lamivudine (4), adefovir (5), or a combination of the two (6) after a mean treatment duration of 8.4 years. The mean age was 45 years, 13 were male, and 8 were initially HBeAg-positive before treatment. After a mean follow-up of 6.6 years, outcomes differed by pretreatment HBeAg status. All patients who were HBeAg+ before treatment experienced virological relapse (8 of 8); 6 of 8 experienced clinical relapse; 4 of 8 had ALT flares; 5 of 8 required re-initiation of treatment, one of whom cleared hepatitis B surface antigen (HBsAg); and 3 of 8 remained off treatment, one of whom cleared HBsAg. In contrast, 4 of 7 patients who were HBeAg-negative before treatment experienced virological relapse, 3 of 7 experienced clinical relapse, and 1 of 7 had an alanine aminotransferase (ALT) flare. None restarted treatment, and 4 of 7 cleared HBsAg. Low pre-withdrawal HBsAg level was predictive of HBsAg loss. Conclusion: NA therapy can be safely withdrawn with long-term remission and high rates of HBsAg loss in most HBeAg-negative patients without cirrhosis. Patients who were initially HBeAg+ should not be withdrawn from treatment, because clinical relapse was frequent and often severe.
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Affiliation(s)
- Naveen Gara
- Gastroenterology & Liver InstituteEscondidoCAUSA
| | - Michele M Tana
- University of California San Francisco School of MedicineSan FranciscoCAUSA
| | - Meera Kattapuram
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - Sungyoung Auh
- Clinical CoreNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - Lauren Sullivan
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - Nancy Fryzek
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - Mary Walter
- Clinical CoreNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - Regina Umarova
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - Xiongce Zhao
- Office of the DirectorNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | | | - Edward Doo
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - Theo Heller
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - T Jake Liang
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
| | - Marc G Ghany
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMDUSA
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29
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Lai CY, Yang SS, Lee SW, Tsai HJ, Lee TY. Cessation of Nucleos(t)ide Analogue Therapy in Non-Cirrhotic Hepatitis B Patients with Prior Severe Acute Exacerbation. J Clin Med 2021; 10:4883. [PMID: 34768403 PMCID: PMC8584579 DOI: 10.3390/jcm10214883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/20/2021] [Accepted: 10/20/2021] [Indexed: 11/16/2022] Open
Abstract
UNLABELLED Chronic hepatitis B (CHB) with severe acute exacerbation (SAE) is an urgent problem requiring nucleos(t)ide analogue (NA) therapy. We aim to evaluate the clinical relapse (CR) risk after discontinuing NA in patients with prior SAE. METHODS In this retrospective cohort study, CHB patients who discontinued NA therapy were screened between October, 2003 and January, 2019. A total of 78 non-cirrhotic patients who had received NA therapy for CHB with SAE, i.e., bilirubin ≥ 2 mg/dL and/or prothrombin time prolongation ≥3 s, (SAE group) were matched 1:2 with 156 controls without SAE (non-SAE group) by means of propensity scores (age, gender, NA categories, NA therapy duration, and HBeAg status). RESULTS The 5-year cumulative incidences of severe CR, i.e., ALT > 10X ULN, (42.78%, 95% CI: 27.84-57.73% vs. 25.42%, 95% CI: 16.26-34.58%; p = 0.045) and SAE recurrence (25.91%, 95% CI: 10.91-40.91% vs. 1.04%, 95% CI: 0-3.07%; p < 0.001) were significantly higher in the SAE group. Prior SAE history (HR 1.79, 95% CI: 1.04-3.06) was an independent factor for severe CR. The 5-year cumulative incidence of HBsAg seroclearance was significantly higher in the SAE group than that in the non-SAE group (16.82%, 95% CI: 2.34-31.30% vs. 6.02%, 95% CI: 0-13.23%; p = 0.049). CONCLUSIONS Even though it creates a greater chance of HBsAg seroclearance, NA therapy cessation may result in a high risk of severe CR in non-cirrhotic CHB patients with prior SAE.
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Affiliation(s)
- Chia-Yeh Lai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-Y.L.); (S.-S.Y.); (S.-W.L.); (H.-J.T.)
| | - Sheng-Shun Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-Y.L.); (S.-S.Y.); (S.-W.L.); (H.-J.T.)
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
- Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 40227, Taiwan
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan
| | - Shou-Wu Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-Y.L.); (S.-S.Y.); (S.-W.L.); (H.-J.T.)
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Hsin-Ju Tsai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-Y.L.); (S.-S.Y.); (S.-W.L.); (H.-J.T.)
| | - Teng-Yu Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-Y.L.); (S.-S.Y.); (S.-W.L.); (H.-J.T.)
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
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30
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Wehmeyer MH, Schulze Zur Wiesch J. Editorial: only steps away from prime time? Hepatitis B virus RNA as routine marker to guide HBV treatment decisions. Aliment Pharmacol Ther 2021; 54:970-971. [PMID: 34506655 DOI: 10.1111/apt.16560] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
- Malte H Wehmeyer
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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31
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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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32
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Liao G, Ding X, Xia M, Wu Y, Chen H, Fan R, Zhang X, Cai S, Peng J. Hepatitis B Core-Related Antigen is a Biomarker for off-Treatment Relapse After Long-Term Nucleos(t)ide Analog Therapy in Patients with Chronic Hepatitis B. Int J Gen Med 2021; 14:4967-4976. [PMID: 34483685 PMCID: PMC8409517 DOI: 10.2147/ijgm.s321253] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 07/16/2021] [Indexed: 12/30/2022] Open
Abstract
Objective It remains unknown how to stratify the risk of clinical relapse of chronic hepatitis B (CHB) patients after stopping nucleos(t)ide analogs (NAs) antiviral therapy. Methods The current post hoc analysis included 122 non-cirrhotic patients with chronic hepatitis B virus infection who were positive for hepatitis B envelope antigen (HBeAg) and discontinued long-term NA therapy after achieving HBeAg seroconversion for a median of 2.5 years. Post hoc analysis of end-of-treatment (EOT) hepatitis B core-related antigen (HBcrAg) levels was performed using a chemiluminescent enzyme immunoassay. Results A total of 78/122 (63.9%) patients experienced sustained response after NAs cessation, and 44/122 (36.1%) patients experienced clinical relapse. In multivariate analysis, EOT HBcrAg (hazard ratio [HR] = 2.105 95% CI: 1.440–3.077, p < 0.001), hepatitis B surface antigen (HBsAg) ≥100 IU/mL (HR = 4.406, 95% CI 1.567–12.389, p = 0.005) and age (HR = 1.051, 95% CI: 1.010–1.093, p = 0.049) were independently associated with clinical relapse. A cut-off value of 4.0 log10 U/mL of HBcrAg was defined by maximized Youden’s index. An EOT HBcrAg level of ≥4.0 log10 U/mL was associated with higher risks of clinical relapse (65.8% vs 23.2%, p<0.001) and HBeAg reversion (27.5% vs 1.6%, p < 0.001). In majority of patients (n = 91) who had a high EOT HBsAg level (≥100 IU/mL), serum HBcrAg level could further discriminate patients at low risk of clinical relapse. Patients with an HBcrAg level ≥4.0 log10 U/mL had significantly higher cumulative incidence rates of clinical relapse (78.1% vs 29.4%, p < 0.001) and HBeAg reversion (29.4% vs 0%, p < 0.001). Conclusion Serum EOT HBcrAg level can be a predictor of off-treatment relapse in patients with CHB. An HBcrAg level of 4.0 log10 U/mL may identify patients at high risk of clinical relapse after treatment cessation.
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Affiliation(s)
- Guichan Liao
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.,State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangzhou, People's Republic of China
| | - Xia Ding
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.,State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangzhou, People's Republic of China
| | - Muye Xia
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.,State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangzhou, People's Republic of China
| | - Yin Wu
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.,State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangzhou, People's Republic of China.,Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Hongjie Chen
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.,State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangzhou, People's Republic of China
| | - Rong Fan
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.,State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangzhou, People's Republic of China
| | - Xiaoyong Zhang
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.,State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangzhou, People's Republic of China
| | - Shaohang Cai
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.,State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangzhou, People's Republic of China
| | - Jie Peng
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.,State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangzhou, People's Republic of China
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33
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Medas R, Liberal R, Macedo G. Discontinuation of antiviral therapy in chronic hepatitis B patients. World J Clin Cases 2021; 9:6979-6986. [PMID: 34540953 PMCID: PMC8409197 DOI: 10.12998/wjcc.v9.i24.6979] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/29/2021] [Accepted: 07/02/2021] [Indexed: 02/06/2023] Open
Abstract
Nucleos(t)ide analogs (NUC) are the first-line therapy for patients with chronic hepatitis B (CHB) recommended by most current guidelines. NUC therapy decreases progression of liver disease, reduces the risk of liver-related complications, and improves the quality of life of patients with CHB. Although indefinite or long-term NUC therapy is usually recommended, this strategy raises several concerns, such as side-effects, adherence, costs, and patient willingness to stop therapy. Recent data showed the feasibility, efficacy, and safety of stopping antiviral therapy in carefully selected CHB patients, leading to its incorporation in international guidelines. Patients who discontinue NUC have a higher likelihood of hepatitis B surface antigen (HBsAg) loss compared to patients who continue on therapy. Recommendations pertaining endpoints allowing safety discontinuation of NUC therapy differ among international guidelines. For hepatitis B e antigen (HBeAg)-positive patients, durable HBeAg seroconversion is considered an acceptable treatment endpoint. For HBeAg-negative patients, some guidelines propose undetectability hepatitis B virus DNA for at least 2 or 3 years, while others consider HBsAg loss as the only acceptable endpoint. CHB patients who stop therapy should remain under strict clinical and laboratorial follow-up protocols to detect and manage relapses in a timely manner. No reliable predictor of relapse has been consistently identified to date, although quantitative HBsAg has been increasingly studied as a reliable biomarker to predict safe NUC discontinuation.
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Affiliation(s)
- Renato Medas
- Department of Gastroenterology and Hepatology, Centro Hospitalar Universitário de São João, Porto 4200-319, Portugal
| | - Rodrigo Liberal
- Department of Gastroenterology and Hepatology, Centro Hospitalar Universitário de São João, Porto 4200-319, Portugal
| | - Guilherme Macedo
- Department of Gastroenterology and Hepatology, Centro Hospitalar Universitário de São João, Porto 4200-319, Portugal
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Song DS, Jang JW, Yoo SH, Kwon JH, Nam SW, Bae SH, Choi JY, Yoon SK. Improving the Prediction of Relapse After Nucleos(t)ide Analogue Discontinuation in Patients With Chronic Hepatitis B. Clin Infect Dis 2021; 73:e892-e903. [PMID: 33417679 DOI: 10.1093/cid/ciab007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Current guidelines recommend rules for stopping nucleos(t)ide analogues (NAs) in patients with chronic hepatitis B (CHB), but off-therapy relapse is still high. This study aimed to identify predictors of off-therapy relapse and improve existing stopping rules. METHODS This retrospective study included 488 patients with CHB (262 hepatitis B e antigen [HBeAg]-positive and 226 HBeAg-negative) who discontinued NAs. Posttreatment relapse was investigated. RESULTS During the median follow-up period of 73.3 months, the cumulative 5-year and 10-year virologic relapse (VR) rates were 73.5% and 76.1%, respectively. In HBeAg-positive patients, end-of-therapy hepatitis B surface antigen (HBsAg) levels (hazard ratio [HR], 1.93 [95% confidence interval {CI}, 1.42-2.61]) and consolidation duration ≥2 years (HR, 0.31 [95% CI: .17-.58]) were independent predictors of VR. Consolidation ≥2 years and low HBsAg levels (≤560 IU/mL) significantly lowered VR rates. In HBeAg-negative patients, only the HBsAg level (HR, 1.61 [95% CI: 1.24-2.11]) was independently predictive of VR. Cirrhosis was significantly associated with higher VR rates in HBeAg-negative patients with low HBsAg levels (≤800 IU/mL). Combining end-of-therapy HBsAg levels with current stopping rules or consolidation duration further reduced off-therapy relapse, with 2-year VR rates of approximately 15%-25% in HBeAg-positive patients and 35% in HBeAg-negative patients. CONCLUSIONS End-of-therapy HBsAg levels, consolidation duration, and cirrhosis are key determinants of off-therapy relapse. Together with low HBsAg levels, extended consolidation therapy for ≥2 years should be ensured, and cirrhotic patients should continue NAs even if low HBsAg levels are achieved. A combination of these parameters will help identify individuals at low risk of relapse and significantly improve the predictive ability of the existing stopping rules.
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Affiliation(s)
- Do Seon Song
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jeong Won Jang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sun Hong Yoo
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jung Hyun Kwon
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Soon Woo Nam
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Si Hyun Bae
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jong Young Choi
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung Kew Yoon
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Berg T, Lampertico P. The times they are a-changing - A refined proposal for finite HBV nucleos(t)ide analogue therapy. J Hepatol 2021; 75:474-480. [PMID: 33957187 DOI: 10.1016/j.jhep.2021.04.040] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/09/2021] [Accepted: 04/26/2021] [Indexed: 12/11/2022]
Abstract
Although discontinuation of nucleos(t)ide analogue (NA) treatment before HBsAg loss is part of all current HBV treatment guidelines for HBeAg-positive patients who achieve HBeAg seroconversion, a treatment endpoint known to be associated with silencing of HBV transcriptional activity and restoration of HBV-specific immune control, whether it is even appropriate to consider NA discontinuation before HBsAg loss in the HBeAg-negative phase remains highly controversial. Despite the growing evidence that a relevant, albeit small, proportion of patients with HBeAg-negative disease can be cured by stopping NA treatment, the fear of discontinuation-associated relapse and the uncertainty of how to predict off-therapy response and monitor patients after discontinuation have generated scepticism and subsequently led to low implementation of this concept in the clinic. In this article, we propose a concept in which NA discontinuation-associated relapse is an integral part of the stop-to-cure approach and ultimately the trigger for achieving HBsAg loss. However, the relapse in this sense becomes functionally effective only if HBV-specific immune reinvigoration and silencing of HBV transcriptional activity have been achieved during the NA treatment period. The probability of functional cure and the severity of post-discontinuation flares depend on the underlying baseline transcriptional activity of HBV when NA therapy was started, as well as the duration of NA treatment, both factors that should be considered as we move towards individualised approaches to HBV cure.
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Affiliation(s)
- Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany.
| | - Pietro Lampertico
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy; CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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Abstract
Antiviral therapy has greatly improved the survival and reduced the incidence of adverse liver events such as hepatic decompensation and hepatocellular carcinoma in chronic hepatitis B patients with cirrhosis (hepatitis B virus [HBV]-cirrhosis). However, hepatitis B surface antigen loss, regarded as the ultimate goal of therapy or functional cure, was rarely achieved during long-term indefinite nucleos(t)ide analogues (Nuc) treatment. Emerging issues such as medication adherence and loss-to-follow-up may lead to increased risk of hepatic decompensation, even catastrophic life-threatening events. Studies have shown that finite therapy is feasible and reasonably safe, even in patients with HBV-cirrhosis. This review critically assesses the scientific evidence of the pros and cons for finite Nuc therapy in HBV-cirrhosis and proposes how to stop Nuc therapy and monitor the off-therapy patients. It also proposes the perspective and unsolved issues to be investigated in the future.
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Affiliation(s)
- Wen-Juei Jeng
- Liver Research Unit, Linkou Medical Center, Chang Gung University, Chang Gung Memorial Hospital, College of Medicine, Taoyuan, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Linkou Medical Center, Chang Gung University, Chang Gung Memorial Hospital, College of Medicine, Taoyuan, Taiwan
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37
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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: 34] [Impact Index Per Article: 8.5] [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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Transaminase Elevations during Treatment of Chronic Hepatitis B Infection: Safety Considerations and Role in Achieving Functional Cure. Viruses 2021; 13:v13050745. [PMID: 33922828 PMCID: PMC8146791 DOI: 10.3390/v13050745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/20/2021] [Accepted: 04/22/2021] [Indexed: 11/17/2022] Open
Abstract
While current therapies for chronic HBV infection work well to control viremia and stop the progression of liver disease, the preferred outcome of therapy is the restoration of immune control of HBV infection, allowing therapy to be removed while maintaining effective suppression of infection and reversal of liver damage. This “functional cure” of chronic HBV infection is characterized by the absence of detectable viremia (HBV DNA) and antigenemia (HBsAg) and normal liver function and is the goal of new therapies in development. Functional cure requires removal of the ability of infected cells in the liver to produce the hepatitis B surface antigen. The increased observation of transaminase elevations with new therapies makes understanding the safety and therapeutic impact of these flares an increasingly important issue. This review examines the factors driving the appearance of transaminase elevations during therapy of chronic HBV infection and the interplay of these factors in assessing the safety and beneficial nature of these flares.
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40
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Sonneveld MJ, van Meer S. Management of Patients With Chronic Hepatitis B (Hepadnaviridae) and Chronic Hepatitis D Infection (Deltavirus). ENCYCLOPEDIA OF VIROLOGY 2021:217-226. [DOI: 10.1016/b978-0-12-814515-9.00104-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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41
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Perspectives on stopping nucleos(t)ide analogues therapy in patients with chronic hepatitis B. Antiviral Res 2020; 185:104992. [PMID: 33279523 DOI: 10.1016/j.antiviral.2020.104992] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 11/30/2020] [Accepted: 12/01/2020] [Indexed: 02/07/2023]
Abstract
Long-term treatment with nucleos(t)ide analogs (NAs) is the current first line therapy for patients with chronic hepatitis B (CHB), recommended by most of the current guidelines. NAs prevent disease progression, liver failure, decrease the risk of hepatocellular carcinoma (HCC), and have favorable safety profiles. However, low rates of on-therapy functional cure (hepatitis B surface antigen [HBsAg] loss), which is regarded as the optimal end point, prevent many patients from stopping NA therapy with the need for a lifelong treatment. The higher likelihood of HBsAg loss associated with stopping as compared to continuing NAs has got a lot of attention recently. Recommendations regarding endpoints allowing for safely stopping NA therapy differ between international guidelines. Whereas in HBeAg-positive patients, HBeAg seroconversion with at least one year of consolidation therapy is an acceptable endpoint of treatment, the recommendations for HBeAg-negative ones differ. Some guidelines propose ≥3 years of HBV DNA undetectability to stop NA while others regard HBsAg loss as the only acceptable endpoint. Stopping NA can lead to substantial rates of virologic relapses and consequent ALT flares in some cases. Moreover, no reliable predictor(s) of post-NA relapses have been identified so far. Quantitative HBsAg is becoming an increasingly promising marker to predict safe NA cessation. On the other hand, investigating the role of the immune system in mediating sustained virologic responses after NA withdrawal is needed to suggest immunological biomarkers to safely stop NA. In this article, we will review relevant literature regarding NA stopping strategy and discuss promising viral and immunological biomarkers to predict antiviral responses and thus to help identify patients who are more likely to achieve HBsAg seroclearance.
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42
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Abreu RM, Bassit LC, Tao S, Jiang Y, Ferreira AS, Hori PC, Ganova-Raeva LM, Khudyakov Y, Schinazi RF, Carrilho FJ, Ono SK. Long-term virological and adherence outcomes to antiviral treatment in a 4-year cohort chronic HBV study. Antivir Ther 2020; 24:567-579. [PMID: 31799942 DOI: 10.3851/imp3338] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/01/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Chronic hepatitis B (CHB) treatment adherence has been poorly studied worldwide. We evaluated long-term virological and adherence outcomes to antiviral treatment in CHB patients. METHODS A prospective 183 Brazilian CHB patient cohort treated with monotherapy or combination adefovir dipivoxil, entecavir, lamivudine and/or tenofovir disoproxil fumarate was studied in a reference tertiary centre. Treatment adherence was evaluated by a validated questionnaire named 'Assessment of Adherence to Antiviral Therapy Questionnaire' (CEAT-HBV) within three yearly periods (2010/2011, 2013/2014 and 2014/2015). RESULTS CEAT-HBV identified 43% (79/183) patients with non-adherence to antiviral treatment and among them, 67% (53/79) were viral load positive. The main causes associated with non-response to antiviral treatment were drug resistance variants followed by non-adherence, insufficient treatment duration and other causes. Single-dose pharmacokinetics demonstrated 35% (23/65) antiviral non-adherence. 2 years after the first assessment, the CEAT-HBV indicated that 71% (101/143) of subjects adhered to treatment (per-protocol population). However, 21% (40/183) of the patients could not be evaluated and were excluded. The main reasons for exclusion were death (20/183), 11 out 20 deaths due to hepatocellular carcinoma. HBV booklet was used for medical education. The third CEAT-HBV assessment (2014/2015) showed that 83% (112/135) patients were compliant with treatment adherence (per-protocol population). Long-term evaluation showed that adherence rate based on CEAT-HBV continue to increase after 4-years (P<0.001). CONCLUSIONS The results highlight the importance of CHB therapy adherence assessment monitoring. Long-term adherence outcomes were dynamic and it is possible to increase the migration rate to adherence/HBV-DNA-negative group.
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Affiliation(s)
- Rodrigo M Abreu
- Divisão de Gastroenterologia e Hepatologia Clínica do Hospital das Clínicas HCFMUSP, Departamento de Gastroenterologia da Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil.,Divisão de Farmácia do Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, São Paulo, Brazil
| | - Leda C Bassit
- Laboratory of Biochemical Pharmacology, Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Sijia Tao
- Laboratory of Biochemical Pharmacology, Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Yong Jiang
- Laboratory of Biochemical Pharmacology, Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Aline S Ferreira
- Divisão de Gastroenterologia e Hepatologia Clínica do Hospital das Clínicas HCFMUSP, Departamento de Gastroenterologia da Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Patrícia Ca Hori
- Divisão de Farmácia do Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, São Paulo, Brazil
| | - Lilia M Ganova-Raeva
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Yury Khudyakov
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Raymond F Schinazi
- Laboratory of Biochemical Pharmacology, Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Flair J Carrilho
- Divisão de Gastroenterologia e Hepatologia Clínica do Hospital das Clínicas HCFMUSP, Departamento de Gastroenterologia da Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Suzane K Ono
- Divisão de Gastroenterologia e Hepatologia Clínica do Hospital das Clínicas HCFMUSP, Departamento de Gastroenterologia da Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
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Hadziyannis E, Hadziyannis S. Current practice and contrasting views on discontinuation of nucleos(t)ide analog therapy in chronic hepatitis B. Expert Rev Gastroenterol Hepatol 2020; 14:243-251. [PMID: 32162562 DOI: 10.1080/17474124.2020.1738219] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Long-term, even indefinite treatment with nucleos(t)ide analogs (NAs) is the current first-line therapy for patients with chronic hepatitis B (CHB), regardless of its histological stage. Guidelines and recommendations on duration and endpoints of NA therapy in CHB are not identical and change over time.Areas covered: The authors review NA discontinuation approaches and views with an emphasis on HBeAg-negative patients based on published studies relevant to the topic, stressing on whether or not the optimal endpoint of HBsAg loss is practically achievable.Expert opinion: Discontinuation of NA therapy in HBeAg-negative noncirrhotic patients has to be considered after long-term effective treatment with controlled liver disease activity, undetectable viremia, and significant decline in serum HBsAg titers. Close post-treatment monitoring is required for early intervention in cases of severe clinical relapse. Immediate retreatment hampers the favorable outcome of HBsAg clearance (functional cure) and should be avoided in transient ALT flares. Predictors of such relapses are still under investigation and include viral and patient factors. For HBeAg-positive noncirrhotic patients, there is wide acceptance of the endpoint of HBeAg seroconversion, after a long consolidation period.
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Affiliation(s)
- Emilia Hadziyannis
- Second Academic Department of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Stephanos Hadziyannis
- Second Academic Department of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
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Sbarigia U, Kariburyo F, Sah J, Colasurdo J, Xie L, Katz EG, Sylvester S. Evaluating the Effect of Standard of Care Treatment on Burden of Chronic Hepatitis B: A Retrospective Analysis of the United States Veterans Population. Adv Ther 2020; 37:1156-1172. [PMID: 32009232 PMCID: PMC7089729 DOI: 10.1007/s12325-020-01240-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Indexed: 12/13/2022]
Abstract
Introduction This study aimed to characterize chronic hepatitis B (CHB)-infected patients and estimate the association between nucleos(t)ide analogue (NA) persistence and economic outcomes using data from the Veterans Health Administration (VHA) database. Methods Patients (at least 18 years of age) with two or more claims for CHB and at least one pharmacy claim for NA were identified using VHA data from 1 April 2013 to 31 March 2018. The index date was the first NA prescription fill date during 1 October 2014 to 31 March 2017. Persistence and non-persistence to NA treatment were assessed during the first 2 years post index date. Non-persistence was defined as at least one failure to refill medication within 30 days from the run-out date. Generalized linear models were used to compare health care utilization and costs between persistent and non-persistent patients. Results Among patients treated with NAs (N = 2368), 1428 (60%) were CHB mono-infected and 748 (32%) were HIV co-infected. Total costs per patient per year (PPPY) were $39,240, $29,957, and $55,220 PPPY for NA-treated, mono-infected, and HIV co-infected patients, respectively. An inception cohort of 564 patients (24%), without a NA prescription in the 6 months pre-index period and at least 2 years of follow-up, was created. Persistence among the inception cohort was 29% for first year and 14% for first 2 years. After adjustment for baseline differences, persistent patients had lower cumulative overall health care costs compared to non-persistent patients, with a net cost saving of $851 (p > 0.05) in the first 2 years. Conclusion CHB is associated with considerable economic burden. We observed suboptimal persistence to NAs which decreased over time. Short-term savings could be generated for CHB-infected patients when they remain persistent to NAs. Electronic supplementary material The online version of this article (10.1007/s12325-020-01240-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Urbano Sbarigia
- Janssen Scientific Affairs, Pharmaceutica NV, Global Health Economics and Market Access, Beerse, Belgium
| | - Furaha Kariburyo
- STATinMED Research, Health Economics and Outcomes Research, Ann Arbor, MI, USA.
| | - Janvi Sah
- STATinMED Research, Health Economics and Outcomes Research, Ann Arbor, MI, USA
| | - Jamie Colasurdo
- Janssen Research and Development, Epidemiology, Raritan, NJ, USA
| | - Lin Xie
- STATinMED Research, Health Economics and Outcomes Research, Ann Arbor, MI, USA
| | - Eva G Katz
- Janssen Research and Development, Epidemiology, Raritan, NJ, USA
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Wu Y, Fan J, Liao G, Xia M, Jiang D, Peng J, Zhang X, Liu H. Genetic variations in the CXCR5 gene decrease the risk of clinical relapse after discontinuation of nucleos(t)ide analogue therapy in patients with chronic hepatitis B. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2020; 78:104124. [PMID: 31765828 DOI: 10.1016/j.meegid.2019.104124] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 11/06/2019] [Accepted: 11/21/2019] [Indexed: 12/30/2022]
Abstract
Discontinuation of nucleos(t)ide analogue (NA) therapy in patients with chronic hepatitis B (CHB) remains a global but controversial problem. Clinical outcomes of NA cessation depend on the interplay between viral factors and host immunity. Recent studies have shown that genetic polymorphisms might influence the immune response in chronic HBV infection. A total of 33 single-nucleotide polymorphisms (SNPs) from 16 genes (BCL6, CD40, CD40L, CTLA-4, CXCL13, CXCR5, ICOS, IL-21, HLA-C, NTCP, UBE2L3, STAT4, IFN-λ3, CYP27B1, INST10, and IPS1) were selected and analyzed in 106 CHB patients enrolled in an off-treatment cohort. Significantly unbalanced distributions between patients who experienced clinical relapse and those who did not were found regarding two SNPs, rs676925 in CXCR5 and rs733618 in CTLA-4. Furthermore, the genotype 'GC' of rs676925 were associated with decreased risk of clinical relapse, implicating that rs676925 may serve as a protective factor for HBV control and facilitate a virus-specific immune response. We also compared the expression of CXCR5 in lymphocytes and its ligand CXCL13 in plasma between different genotypes of rs676925. However, no significant differences were observed. In conclusion, this study suggested that the rs676925 'GC' genotype of the CXCR5 gene were associated with decreased risk of clinical relapse after discontinuation of long-term NA therapy in CHB patients.
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Affiliation(s)
- Yin Wu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiaojiao Fan
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Guichan Liao
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Muye Xia
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Deke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jie Peng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Xiaoyong Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Hongyan Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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Cornberg M, Lok ASF, Terrault NA, Zoulim F. Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference ‡. J Hepatol 2020; 72:539-557. [PMID: 31730789 DOI: 10.1016/j.jhep.2019.11.003] [Citation(s) in RCA: 224] [Impact Index Per Article: 44.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 10/07/2019] [Accepted: 11/03/2019] [Indexed: 12/11/2022]
Abstract
Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic HBV treatment endpoints to guide clinical trials aiming to 'cure' HBV. Agreement among the conference participants was reached on some key points. 'Functional' but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post-treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg-positive or negative chronic hepatitis, who are treatment-naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV 'functional cure', the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.
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Affiliation(s)
- Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany; Centre for Individualised Infection Medicine (CiiM), Hannover, Germany.
| | - Anna Suk-Fong Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Norah A Terrault
- Division of Gastrointestinal and Liver Diseases, Keck Medicine at University of Southern California, Los Angeles, CA, USA
| | - Fabien Zoulim
- Hepatology Department, Hospices Civils de Lyon, INSERM U1052, University of Lyon, France
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Chen CH, Hung CH, Wang JH, Lu SN, Lai HC, Hu TH, Lin CH, Peng CY. The Incidence of Hepatitis B Surface Antigen Loss Between Hepatitis B E Antigen-Negative Noncirrhotic Patients Who Discontinued or Continued Entecavir Therapy. J Infect Dis 2020; 219:1624-1633. [PMID: 30689910 DOI: 10.1093/infdis/jiy697] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Accepted: 12/20/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND We compared rates of hepatitis B surface antigen (HBsAg) loss and hepatocellular carcinoma (HCC) development in hepatitis B e antigen (HBeAg)-negative patients without cirrhosis who continued or discontinued entecavir. METHODS Patients who discontinued entecavir treatment for at least 12 months (discontinued group; n = 234) and patients who continued entecavir treatment for at least 4 years (continued group; n = 226) were recruited. RESULTS In the discontinued group, the 5-year cumulative incidences of virological relapse (VR), clinical relapse (CR), and HBsAg loss were 71.9%, 58.9%, and 13%, respectively. Patients with sustained response, VR but no CR, and CR without retreatment were 49-, 13-, and 18-fold more likely to develop HBsAg loss than those with retreatment. Patients who discontinued entecavir therapy had a higher rate of HBsAg loss than those who continued entecavir therapy, in all and 360 propensity score (PS)-matched patients. Cox regression analysis revealed that the discontinued group was an independent predictor for HBsAg loss. There was no significant difference in HCC development between the 2 groups in all and PS-matched patients. CONCLUSIONS HBeAg-negative patients without cirrhosis who discontinued entecavir treatment exhibited a higher HBsAg loss rate without an increased risk of HCC compared to those who continued entecavir treatment.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine
| | - Hsueh-Chou Lai
- Division of Hepatogastroenterology, Department of Internal Medicine
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine
| | - Chia-Hsin Lin
- Division of Hepatogastroenterology, Department of Internal Medicine
| | - Cheng-Yuan Peng
- Division of Hepatogastroenterology, Department of Internal Medicine.,School of Medicine, China Medical University, Taichung, Taiwan
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Gao X, Duan X, Cai H, Hu Y, Liu M, Kang K, Zhou M, Fu D, Yi W. Pregnancy Outcome of Women with Chronic Hepatitis B who Discontinued Antiviral Treatment before or in the Early Pregnancy. Int J Med Sci 2020; 17:170-175. [PMID: 32038100 PMCID: PMC6990883 DOI: 10.7150/ijms.38410] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Accepted: 12/12/2019] [Indexed: 01/15/2023] Open
Abstract
Background: The aim of this study was to describe biochemical, virological features and Mother-to child-transmission (MTCT) rate in chronic hepatitis B (CHB) women who stopped antiviral therapy before or in the early pregnancy. Methods: This was a single-center, retrospective study. Forty-three CHB women who stopped treatment before or in the early pregnancy and 103 CHB women with tenofovir disoproxil fumarate (TDF) treatment throughout pregnancy were enrolled. The virological and biochemical flares during pregnancy and postpartum period were studied. MTCT rates were also compared. Results: During pregnancy, ALT flares (43.9% vs 1.0%) and viral rebound (31.7% vs 0) were more common in women who stopped treatment (P<0.001). Postpartum ALT flares were less frequent in women with treatment than those stopped treatment (0 vs 6/35, P = 0.001). The birth defect rate in the mothers who stopped treatment did not statistically differ from that of mothers treated throughout pregnancy (4.9 % vs 3.9 %, P = 1.000). There were no significant differences of gestational complications between the two groups, except intrahepatic cholestasis of pregnancy (12.2% vs 0, P = 0.002). The rate of MTCT in mothers who discontinued treatment was higher (2.4% vs 0, P = 0.285), although there was no statistically significant. Conclusion: ALT flares were common in mothers who discontinued antiviral therapy. Thus, these pregnant women should be monitored closely. Cessation of treatment was not recommended although no hepatic failure was observed. Larger studies are needed to evaluate the safety of discontinuation before pregnancy.
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Affiliation(s)
- Xuesong Gao
- Department of General Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xuefei Duan
- Department of General Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Haodong Cai
- Hepatology clinic, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuhong Hu
- Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Min Liu
- Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Kai Kang
- Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Mingfang Zhou
- Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Dong Fu
- Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wei Yi
- Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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Kao JH, Berg T. Nucleos(t)ide analogues in patients with chronic hepatitis B: to stop or not to stop? Gut 2019; 68:2105-2106. [PMID: 31527067 DOI: 10.1136/gutjnl-2019-319648] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 08/21/2019] [Accepted: 08/22/2019] [Indexed: 01/06/2023]
Affiliation(s)
- Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Thomas Berg
- Clinic and Polyclinic of Gastroenterology, Hepatology, Infectiology and Pneumology, University Hospital Leipzig, Leipzig, Germany
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Cornberg M, Lok ASF, Terrault NA, Zoulim F. Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference. Hepatology 2019; 71:1070-1092. [PMID: 31713892 DOI: 10.1002/hep.31030] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic hepatitis B virus (HBV) treatment endpoints to guide clinical trials aiming to 'cure' HBV. Agreement among the conference participants was reached on some key points. 'Functional' but not sterilizing cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post-treatment. The primary endpoint of phase 3 trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss, 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity in predicting sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg-positive and HBeAg-negative chronic hepatitis, treatment-naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with increase in bilirubin or INR should prompt temporary or permanent cessation of investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase 3 trials for hepatitis D virus (HDV) co-infection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalization of ALT is considered an intermediate goal. CONCLUSION: For HBV 'functional cure', sustained HBsAg loss with undetectable HBV DNA after completion of treatment is the primary goal and sustained undetectable HBV DNA without HBsAg loss after stopping treatment an intermediate goal.
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Affiliation(s)
- Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany
- Centre for Individualised Infection Medicine (CiiM), Hannover, Germany
| | - Anna Suk-Fong Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Norah A Terrault
- Division of Gastrointestinal and Liver Diseases, Keck Medicine at University of Southern California, Los Angeles, CA, USA
| | - Fabien Zoulim
- Hepatology Department, Hospices Civils de Lyon, INSERM U1052, University of Lyon, France
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