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Maung ST, Chaiteerakij R. Scoping Review on Strategies for Safe Nucleot(s)ide Analogue Discontinuation and Optimising Functional Cure in Chronic Hepatitis B. J Viral Hepat 2025; 32:e70040. [PMID: 40478218 DOI: 10.1111/jvh.70040] [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: 05/05/2025] [Revised: 05/05/2025] [Accepted: 05/22/2025] [Indexed: 06/11/2025]
Abstract
Chronic hepatitis B (CHB) remains a global health challenge, contributing to significant morbidity and mortality. While long-term nucleos(t)ide analogue (NA) therapy effectively suppresses viral replication, achieving a functional cure remains rare. Current treatment guidelines primarily recommend indefinite therapy. However, long-term NA use poses many challenges, prompting interest in finite therapy. Recent studies suggest that carefully selected patients may safely discontinue NAs, leading to a functional cure in some cases. This review evaluates the latest evidence on NA discontinuation, highlighting key factors influencing outcomes. This review synthesises established and emerging evidence on NA discontinuation in CHB. It explores early studies that identified quantitative HBsAg (qHBsAg) as a predictor of sustained response and HBsAg seroclearance, followed by systematic reviews and meta-analyses reinforcing finite therapy as a feasible approach. Advances in predictive modelling, incorporating biomarkers, have refined patient selection for safe NA withdrawal. Additionally, this review assesses the risks associated with NA discontinuation, highlighting the importance of identifying high-risk patients for hepatic decompensation. Ethnicity-specific qHBsAg cut-offs are also discussed, recognising variations in treatment response between Asian and Caucasian populations. Finite NA therapy is emerging as a viable approach for achieving functional cure. Future strategies should integrate liver fibrosis assessment to enhance patient selection before NA discontinuation. Optimising re-treatment approaches requires balancing timing, immune response, and qHBsAg kinetics to maximise HBsAg seroclearance. Clinical perspectives on NA discontinuation remain a key research priority, necessitating standardised guidelines and improved post-NA monitoring strategies to ensure safe and effective finite therapy in CHB management.
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Affiliation(s)
- Soe Thiha Maung
- Division of Graduate Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Ma Har Myaing Hospital, Yangon, Myanmar
| | - Roongruedee Chaiteerakij
- Integrated Innovation and Digital Technologies Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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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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Hsu WF, Chen CF, Lai HC, Su WP, Wang HW, Chen SH, Huang GT, Peng CY. Trajectories and Decline of Serum Hepatitis B Surface Antigen Predict Outcomes in Patients With Chronic Hepatitis B. Open Forum Infect Dis 2024; 11:ofae699. [PMID: 39679354 PMCID: PMC11639628 DOI: 10.1093/ofid/ofae699] [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: 10/10/2024] [Accepted: 11/25/2024] [Indexed: 12/17/2024] Open
Abstract
Background The kinetics of serum hepatitis B surface antigen (HBsAg) levels during long-term nucleos(t)ide analogue (NA) therapy remains unclear. We delineated the kinetics of HBsAg and analyzed its association with long-term treatment outcomes. Methods We enrolled 912 treatment-naïve patients with chronic hepatitis B (CHB) who had received NA therapy for >12 months and analyzed the kinetic patterns through group-based trajectory models (GBTMs). Results The median treatment duration for the entire cohort was 60.3 months. GBTMs revealed 4 patterns in patients achieving HBsAg loss (groups 1-4) in the study population and in patients achieving HBsAg <100 IU/mL among those with HBeAg-negative CHB with baseline HBsAg ≥100 IU/mL (groups A-D). Patients in groups 1 and A had the highest rates of HBsAg loss (22.2%, 6/27) and of achieving HBsAg <100 IU/mL (47.5%, 56/118), respectively. HBsAg <40 IU/mL and <400 IU/mL at 12 months of treatment predicted group 1 and group A membership among all patients and those with HBeAg-negative CHB, respectively. Multivariable Cox regression analysis identified HBsAg trajectory group (group 1 vs groups 3 and 4: hazard ratio [HR], 179.46; P < .001; group 2 vs groups 3 and 4: HR, 24.34; P < .001) and HBsAg decline (HR, 82.14; P < .001) as independent predictors of both HBsAg loss and achieving HBsAg <100 IU/mL. Conclusions Serum HBsAg trajectories and decline can predict HBsAg loss and the achievement of HBsAg <100 IU/mL in patients with CHB receiving long-term NA therapy.
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Affiliation(s)
- Wei-Fan Hsu
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Chuen-Fei Chen
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
| | - Hsueh-Chou Lai
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Wen-Pang Su
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Hung-Wei Wang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Sheng-Hung Chen
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Guan-Tarn Huang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
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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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Huang CW, Yang CT, Su PY, Chen YY, Huang SP, Yen HH. Long-Term Hepatitis B Surface Antigen Profile and Seroclearance Following Antiviral Treatment: A Single-Center, Real-World Cohort Study. Biomedicines 2023; 11:2966. [PMID: 38001966 PMCID: PMC10669103 DOI: 10.3390/biomedicines11112966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 10/04/2023] [Accepted: 11/01/2023] [Indexed: 11/26/2023] Open
Abstract
Hepatitis B surface antigen (HBsAg) seroclearance, an indicator of recovery from hepatitis B virus (HBV) infection, is uncommon in long-term nucleos(t)ide analog (NUC) therapy. We compared the incidence of HBsAg seroclearance in patients with and without NUC discontinuation to identify predictors of HBsAg seroclearance. This retrospective study enrolled adult patients with a chronic HBV infection followed for ≥12 months after NUC discontinuation (finite group) and those treated with NUCs for >3 years (non-finite group). Demographic, clinical, and laboratory data were analyzed. The study cohort included 978 patients, including 509 and 469 patients in the finite and non-finite groups, respectively. Cumulative HBsAg seroclearance incidence was significantly higher in the finite group than in the non-finite group (p = 0.006). The 5- and 10-year cumulative HBsAg seroclearance incidence were 6.6% and 18.9% in the finite group and 3% and 14.6% in the non-finite group, respectively. The likelihood of HBsAg seroclearance was higher in those with end of treatment (EOT) HBsAg levels of <100 IU/mL and in those without clinical relapse (CR). The cumulative 3-year CR incidence was 16.8%. The incidence of liver decompensation and hepatocellular carcinoma were 4.1 and 0.4 per 1000 person-years, respectively. The hepatocellular carcinoma incidence did not significantly differ between the finite and non-finite groups (p = 0.941). In conclusion, higher HBsAg seroclearance incidence in patients receiving finite therapy, and the increased likelihood of HBsAg seroclearance in those with EOT HBsAg levels of <100 IU/mL and in those without CR should be considered during decision-making of treatment options.
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Affiliation(s)
- Chih-Wen Huang
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan
| | - Chen-Ta Yang
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Pei-Yuan Su
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Yang-Yuan Chen
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Siou-Ping Huang
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan
| | - Hsu-Heng Yen
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
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Xie Y, Li M, Ou X, Zheng S, Gao Y, Xu X, Yang Y, Ma A, Li J, Nan Y, Zheng H, Liu J, Wei L, Feng B. Lower end of treatment HBsAg and HBcrAg were associated with HBsAg loss after nucleos(t)ide analog cessation. BMC Gastroenterol 2023; 23:224. [PMID: 37386460 PMCID: PMC10308768 DOI: 10.1186/s12876-023-02852-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 06/13/2023] [Indexed: 07/01/2023] Open
Abstract
BACKGROUND Since hepatitis B surface antigen (HBsAg) loss is rarely achieved with nucleos(t)ide analog (NA) treatment, most patients require life-long NA treatment. Previous studies have shown that some patients remain virologically responsive even after NA cessation. However, there is still controversy surrounding whether NA discontinuation increases the HBsAg loss rate. Therefore, this study aimed to assess the cumulative rate of HBsAg loss and identify the predictors of HBsAg loss after NA discontinuation. METHODS This multicenter prospective study included HBV e antigen (HBeAg)-positive patients without cirrhosis from 12 hospitals in China who met the inclusion criteria. The enrolled patients stopped NA and were followed up with clinical and laboratory assessments every 3 months for 24 months after NA cessation or until clinical relapse (CR) occurred. RESULTS Overall, 158 patients were classified into two groups. Group A included patients with HBsAg positivity at NA cessation (n = 139), and Group B included patients with HBsAg negativity at NA cessation (n = 19). In Group A, the 12-month and 24-month cumulative rates of HBsAg loss were4.3%and 9.4%, respectively. End of treatment (EOT) HBsAg (hazard ratio (HR) = 0.152, P < 0.001) and EOT hepatitis B core-related antigen (HBcrAg) (HR = 0.257, P = 0.001) were associated with HBsAg loss. The areas under the receiver operating characteristic curves for EOT HBsAg and HBcrAg levels were 0.952 (P < 0.001) and 0.765 (P < 0.001), respectively. Patients with EOT HBsAg ≤ 135 IU/mL (59.2% vs. 1.3%, P < 0.001) or HBcrAg ≤ 3.6 logU/mL (17% vs. 5.4%, P = 0.027) had a higher 24-month cumulative HBsAg loss rate. In Group B, none of the patients experienced virological relapse after NA cessation. Only 1 (5.3%) patient had HBsAg reversion. CONCLUSIONS EOT HBsAg ≤ 135 IU/mL or HBcrAg ≤ 3.6 logU/mL can be used to identify patients with a higher likelihood of HBsAg loss after NA cessation. Patients with HBsAg negativity after NA cessation have favorable clinical outcomes, and HBsAg loss was durable in most cases.
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Affiliation(s)
- Yandi Xie
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, 100044, China
| | - Minghui Li
- Department of Hepatology Division, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Sujun Zheng
- Complicated Liver Diseases and Artificial Liver Treatment and Training Center, Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment and Research, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Yinjie Gao
- Department of Infectious Diseases, The Fifth Medical Center, General Hospital of PLA, Beijing, 100039, China
| | - Xiaoyuan Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Ying Yang
- Department of Infectious Diseases, The Second Hospital of Xingtai, Xingtai, Hebei, 054001, China
| | - Anlin Ma
- Department of Infectious Disease, Friendship Hospital, Beijing, 100029, China
| | - Jia Li
- Department of Liver Disease, Tianjin Second People's Hospital, Tianjin, 300192, China
| | - Yuemin Nan
- Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, China
| | - Huanwei Zheng
- Department of Liver Disease, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei, 050021, China
| | - Juan Liu
- Research Center for Technologies in Nucleic Acid-Based Diagnostics, Changsha, Hunan, 410205, China
| | - Lai Wei
- Department of Hepatopancreatobiliary Disease, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China
| | - Bo Feng
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, 100044, China.
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Liang LY, Wong VWS, Wong GLH, Yip TCF. Moving toward hepatitis B virus functional cure - the impact of on-treatment kinetics of serum viral markers. Clin Mol Hepatol 2023; 29:113-117. [PMID: 36314042 PMCID: PMC9845680 DOI: 10.3350/cmh.2022.0333] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 10/26/2022] [Accepted: 10/26/2022] [Indexed: 02/02/2023] Open
Affiliation(s)
- Lilian Yan Liang
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Vincent Wai-Sun Wong
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Grace Lai-Hung Wong
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Terry Cheuk-Fung Yip
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
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Li M, Zhang L, Xie S, Sun F, Zeng Z, Deng W, Jiang T, Bi X, Lin Y, Yang L, Lu Y, Shen G, Liu R, Wu S, Chang M, Hu L, Dong J, Yi W, Xie Y. Dynamic Changes of Cytokine Profiles and Virological Markers Associated With HBsAg Loss During Peginterferon Alpha-2a Treatment in HBeAg-Positive Chronic Hepatitis B Patients. Front Immunol 2022; 13:892031. [PMID: 35603222 PMCID: PMC9114800 DOI: 10.3389/fimmu.2022.892031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
Objective To explore dynamic changes of cytokines and virological markers associated with hepatitis B surface antigen (HBsAg) loss during peginterferon alpha-2a (PEG-IFN α-2a) treatment in hepatitis B e antigen (HBeAg) positive chronic hepatitis B (CHB) patients. Methods It was a single-center prospective cohort study. HBeAg-positive CHB patients were prospectively and consecutively enrolled. Cytokines were detected at baseline, week 12 and 24 of PEG-IFN treatment. HBsAg disappearance rate was the primary evaluation index at 48 weeks of PEG-IFN treatment. Results Among 100 patients who completed the 48-week PEG-IFN α-2a treatment, 38 patients achieved serum HBeAg disappearance, 25 patients achieved HBeAg seroconversion, 9 patients achieved functional cure, 37 patients had HBsAg decline of ≥1 log IU/ml, and 8 patients produced hepatitis B surface antibody (HBsAb). Albumin (ALB), fms-like tyrosine kinase 3 ligand (FLT3-L) and interferon-alpha2 (IFN-α2) in the clinical cure group were significantly lower than those in the non-clinical-cure group at baseline. After 12 weeks of treatment, HBsAg in the clinical cure group was significantly lower than that in the non-clinical-cure group (median 1.14 vs. 3.45 log10IU/ml, Z=-4.355, P < 0.001). The decrease of HBsAg and hepatitis B virus desoxyribose nucleic acid (HBV DNA) in the clinical cure group was significantly higher than that in non-clinical-cure group (median: HBsAg 1.96 vs. 0.33 log10IU/ml, Z=-4.703, P< 0.001; HBV DNA 4.49 vs.3.13 log10IU/ml, Z=-3.053, P=0.002). The increase of IFN-α2 in the cure group was significantly higher than that in the non-clinical-cure group (497.89 vs. 344.74, Z=-2.126, P=0.034). After 24 weeks of treatment, HBsAg, HBeAg, Flt3-L, and IL-10 in the clinical cure group were significantly lower than those in the non-clinical-cure group (median: HBsAg 0.70 vs. 3.15 log10IU/ml, Z=-4.535, P< 0.001; HBeAg 1.48 vs. 13.72 S/CO, Z = 2.512, P = 0.012; Flt3-l 0.00 vs 2.24 pg/ml, Z = 3.137, P=0.002; IL-10 0.70 vs. 2.71 pg/ml, Z=-4.067, P < 0.001). HBsAg decreased significantly in the clinical cure group compared with non-clinical-cure group (median 3.27 vs. 0.45, Z=-4.463, P < 0.001). Conclusion Dynamic changes of cytokines and virology markers during early PEG IFN α-2a treatment were associated with HBsAg loss in HBeAg-positive CHB patients.
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Affiliation(s)
- Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Luxue Zhang
- Infectious Disease Department, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Si Xie
- Division of Hepatology, Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Fangfang Sun
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Zhan Zeng
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Wen Deng
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Tingting Jiang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyue Bi
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yanjie Lin
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Liu Yang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ge Shen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ruyu Liu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shuling Wu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Min Chang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Leiping Hu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Jianping Dong
- Department of Infectious Diseases, Haidian Hospital, Beijing Haidian Section of Peking University Third Hospital, Beijing, China
| | - Wei Yi
- Department of Gynecology and Obstetrics, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
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10
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Luo M, Zhou B, Hou J, Jiang D. Biomarkers for predicting nucleos(t)ide analogs discontinuation and hepatitis B virus recurrence after drug withdrawal in chronic hepatitis B patients. Hepatol Res 2022; 52:337-351. [PMID: 35089634 DOI: 10.1111/hepr.13749] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/22/2021] [Accepted: 01/20/2022] [Indexed: 12/11/2022]
Abstract
AIM To summarize HBV-related biomarkers predicting nucleos(t)ide analogs (NAs) discontinuation and hepatitis B virus (HBV) recurrence after drug withdrawal in chronic hepatitis B (CHB) patients, providing references for clinical medication, so as to manage CHB patients more scientifically. METHODS Related pieces of literature were retrieved in PubMed and the results were sorted out. We then analyzed and summarized these articles. RESULTS We found that HBV related biomarkers maybe could predict NAs withdrawal safely and the possibility of relapse after treatment cessation, including hepatitis B e antigen (HBeAg), hepatitis B surface antigen (HBsAg), HBV DNA, HBV RNA, pregenomic-RNA (pgRNA), hepatitis B core-related antigen (HBcrAg), hepatitis B core antibody (anti-HBc), and models containing several indicators for predicting the effectiveness of treatment. CONCLUSIONS HBV DNA, HBV RNA, pgRNA, HBcrAg, anti-HBc, as well as the prediction models formed by several biomarkers could predict the safe discontinuation of NAs before HBsAg loss and recurrence.
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Affiliation(s)
- Mengqi Luo
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bin Zhou
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Deke Jiang
- Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
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11
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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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12
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Current Trend in Antiviral Therapy for Chronic Hepatitis B. Viruses 2022; 14:v14020434. [PMID: 35216027 PMCID: PMC8877417 DOI: 10.3390/v14020434] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/13/2022] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
Since active hepatitis B virus (HBV) replication is the key driver of hepatic necroinflammation and disease progression, the treatment aim of chronic hepatitis B (CHB) is to suppress HBV replication permanently to prevent hepatic decompensation, liver cirrhosis and/or hepatocellular carcinoma and prolong survival. Currently, pegylated interferon (Peg-IFN), entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are the first-line drugs of choice. Peg-IFN therapy has been used rarely due to its subcutaneous injection and significant side effect profile. Once daily oral ETV, TDF and TAF can suppress HBV DNA profoundly but have no direct action on cccDNA of the HBV-infected hepatocytes, hence continuing long-term therapy is usually needed to maintain HBV suppression, but the ultimate goal of HBsAg loss was rarely achieved (10 year 2%). In addition, long-term NUC therapy comes with several concerns such as increasing cost, medication adherence and loss-to-follow-up. Studies, mainly from Taiwan, have shown that finite NUCs therapy of two to three years in HBeAg-negative patients is feasible, safe and has a great benefit of much increasing HBsAg loss rate up to 30%/5 year. These have led an emerging paradigm shift to finite NUC therapy in HBeAg-negative patients globally. However, off-NUC relapse with hepatitis B flares may occur and have a risk of decompensation or even life-threatening outcomes. Therefore, proper monitoring, assessment, and retreatment decisions are crucial to ensure safety. Ideally, retreatment should be not too late to ensure safety and also not too early to allow further immune response for further HBsAg decline toward HBsAg loss. Assessment using combined HBsAg/ALT kinetics during hepatitis flare is better than biochemical markers alone to make a right retreatment decision. The strategy of finite NUC therapy has set a benchmark of high HBsAg loss rate to be achieved by the new anti-HBV drugs which are under preclinical or early phase study.
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13
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van Bömmel F, Berg T. Risks and Benefits of Discontinuation of Nucleos(t)ide Analogue Treatment: A Treatment Concept for Patients With HBeAg-Negative Chronic Hepatitis B. Hepatol Commun 2021; 5:1632-1648. [PMID: 34558833 PMCID: PMC8485892 DOI: 10.1002/hep4.1708] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/29/2021] [Accepted: 02/15/2021] [Indexed: 12/11/2022] Open
Abstract
Systematic discontinuation of long-term treatment with nucleos(t)ide analogues (NAs) is one strategy to increase functional cure rates in patients with chronic hepatitis B e antigen (HBeAg)-negative hepatitis B. Currently, available study results are heterogeneous; however, long-term hepatitis B surface antigen (HBsAg) loss rates of up to 20% have been reported in prospective trials. This review proposes criteria that can be used when considering NA discontinuation in patients with chronic hepatitis B virus (HBV). Discontinuing NA treatment frequently results in a virologic and biochemical relapse that runs through different phases: the lag phase, reactivation phase, and consolidation phase. The HBV-DNA flares observed during the reactivation phase are often transient and most likely represent a trigger for inducing a long-term immune control by specific CD8+ T cells, and therefore do not need immediate interventions but close follow-up evaluation. Low HBsAg levels at the time of treatment cessation predict a positive long-term response to NA discontinuation associated with a higher likelihood of HBsAg clearance. Other host and viral biomarkers are currently under evaluation that may prove to be helpful to further characterize the population that may benefit most from the finite NA treatment concept. Potential harmful biochemical flares during the reactivation phase need to be identified early and can be effectively terminated by reintroducing NA treatment. Hepatic decompensation represents a risk to patients with cirrhosis undergoing NA discontinuation. Therefore, the finite NA approach should only be considered after excluding advanced fibrosis and cirrhosis and if a close follow-up of the patient and supervision by an experienced physician can be guaranteed. Conclusion: For selected patients, NA discontinuation has become a powerful tool to achieve control over HBeAg-negative HBV infections. Its significant effect represents a challenge to novel treatment approaches, but it may also serve as their enhancer.
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Affiliation(s)
- Florian van Bömmel
- Division of HepatologyDepartment of Medicine IILeipzig University Medical CenterLeipzigGermany
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14
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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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15
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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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16
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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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17
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Gao L, Hu Y, Shi X, Li X, Zhang D, Ren H. 48 weeks outcome after cessation of nucleos(t)ide analogue therapy in chronic hepatitis B patients. Ann Hepatol 2021; 19:329-334. [PMID: 31884016 DOI: 10.1016/j.aohep.2019.10.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 09/22/2019] [Accepted: 10/01/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVE The aim of the present study was to investigate the significance of serum HBsAg levels in treatment cessation of nucleoside analogues (NAs) in patients with chronic hepatitis B (CHB) infection. METHODS In 158 CHB patients with long-term NAs treatment, 74 patients were in HBeAg negative and had a HBsAg level <1500IU/mL, 36 of whom were informed and consented to cease NAs. HBsAg, HBV DNA and liver function were examined in the 1st, 3rd, 6th, 9th and 12th month after treatment cessation. RESULTS The sustained response rate was 88.89% (32/36) within one year after NAs cessation. Sub-group analysis was based on HBsAg levels of patients with NAs cessation, there was no relapse case in 11 patients whose HBsAg <50IU/mL, and the negative predictive value (NPV) was 100%. Seroconversion of HBsAg occurred in 3 patients. 2 patients from 21 cases whose HBsAg was between 50IU/mL and 1000IU/mL relapsed. 2 of 4 patients whose in HBsAg >1000IU/mL relapsed. HBsAg of patients with a sustained response decreased slowly. In contrast, HBsAg levels increased gradually in relapsed patients, and the increase of HBsAg was precedent to relapses of HBV DNA and ALT. Multivariate analysis suggested that only HBsAg level showed a close correlation with HBV DNA relapses. ROC curve analysis suggested that the increase of HBsAg level in the 3rd and 6th month after NAs cessation had a great predictive value for relapses. CONCLUSION Monitoring of base line HBsAg level can predict outcomes of NAs cessation in HBeAg-negative chronic hepatitis B. HBsAg <50IU/mL has higher predictive values of better sustained responses in HBeAg-negative CHB patients.
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Affiliation(s)
- Li Gao
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Virus Hepatitis and Department of Infectious Diseases, the Second Affiliated Hospital of Chongqing Medical University, PR China
| | - Yue Hu
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Virus Hepatitis and Department of Infectious Diseases, the Second Affiliated Hospital of Chongqing Medical University, PR China
| | - Xiaofeng Shi
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Virus Hepatitis and Department of Infectious Diseases, the Second Affiliated Hospital of Chongqing Medical University, PR China.
| | - Xin Li
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Virus Hepatitis and Department of Infectious Diseases, the Second Affiliated Hospital of Chongqing Medical University, PR China
| | - Dazhi Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Virus Hepatitis and Department of Infectious Diseases, the Second Affiliated Hospital of Chongqing Medical University, PR China
| | - Hong Ren
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Virus Hepatitis and Department of Infectious Diseases, the Second Affiliated Hospital of Chongqing Medical University, PR China
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18
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Li M, Zhang L, Lu Y, Chen Q, Lu H, Sun F, Zeng Z, Wan G, Zhao L, Xie Y. Early Serum HBsAg Kinetics as Predictor of HBsAg Loss in Patients with HBeAg-Negative Chronic Hepatitis B after Treatment with Pegylated Interferonα-2a. Virol Sin 2021; 36:311-320. [PMID: 32975731 PMCID: PMC8087759 DOI: 10.1007/s12250-020-00290-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 07/16/2020] [Indexed: 01/05/2023] Open
Abstract
Hepatitis B surface antigen (HBsAg) loss is an ideal treatment endpoint for patients with chronic hepatitis B (CHB). We investigated the predictive value of on-treatment HBsAg levels for HBsAg loss in hepatitis B e antigen (HBeAg)-negative CHB patients who received 120-week PEG-IFNα-2a treatment. Serum HBV DNA, HBsAg, and anti-HBs levels were assayed at baseline and every 3 months during the treatment. Of 81 patients, 12 achieved HBsAg loss, 20 achieved HBsAg < 100 IU/mL, and 49 maintained HBsAg ≥ 100 IU/mL. HBsAg loss rate was only 3.7% at 48 weeks, while it reached to 11.1% and 14.8% after treatment of 96 weeks and 120 weeks. The cutoff HBsAg levels at 12 weeks predicting HBsAg loss at 96 weeks and 120 weeks of treatment were 400 IU/mL and 750 IU/mL, with AUC 0.725 and 0.722, positive predictive value (PPV) 29.41% and 30.56%, and negative predictive value (NPV) 93.75% and 97.78%, respectively. The cutoff HBsAg levels at 24 weeks predicting HBsAg loss at 96 weeks and 120 weeks of treatment were 174 IU/mL and 236 IU/mL respectively, with AUC 0.925 and 0.922, PPV 40.0% and 46.15%, and both NPV 100%. The predictive ability of the cutoff HBsAg levels at 24 weeks was better than that at 12 weeks for HBsAg loss at either 96 or 120 weeks (χ2 = 3.880, P = 0.049 and χ2 = 4.412, P = 0.036). These results indicate that extended therapy is critical to HBsAg loss in HBeAg-negative CHB patients during PEG-IFN treatment, and the HBsAg level at 24 weeks can be used to predict HBsAg loss during tailoring PEG-IFN therapy.
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Affiliation(s)
- Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, 100015, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Qiqi Chen
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, 100015, China
| | - Huihui Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Fangfang Sun
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Zhan Zeng
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, 100015, China
| | - Gang Wan
- Department of Biostatistics, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Linqing Zhao
- Laboratory of Virology Capital Institute of Pediatrics, Beijing, 100020, China.
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, 100015, China.
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Manolakopoulos S, Kranidioti H, Kourikou A, Deutsch MM, Triantos C, Tsolias C, Manesis EK, Mathou N, Alexopoulou A, Hadziyannis E, Papatheodoridis G. Long-term clinical outcome of HBeAg-negative chronic hepatitis B patients who discontinued nucleos(t)ide analogues. Liver Int 2021; 41:48-57. [PMID: 33373114 DOI: 10.1111/liv.14654] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 08/11/2020] [Accepted: 08/24/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Discontinuation of nucleos(t)ide analogues (NA) remains a debatable issue in HBeAg-negative chronic hepatitis B (CHB). This study aimed to address the outcome of HBeAg-negative CHB patients who discontinued NA therapy. METHODS This prospective study included 57 non-cirrhotic HBeAg-negative Caucasian CHB patients who discontinued NA therapy after median virological remission of 6 years. All patients had regular blood tests. Virological relapse was defined as HBV DNA > 2000 IU/mL or >20 000 IU/mL and biochemical relapse as ALT > ULN (40 IU/mL) or >2xULN. All patients with retreatment predefined criteria restarted entecavir or tenofovir. RESULTS Of the 57 patients, 29 remained without retreatment after median follow-up of 65 months (range: 36-87) following treatment discontinuation. At 3, 6, 12, 24, 36 and 48 months, cumulative rates of retreatment were 16%, 20%, 32%, 35%, 46% and 50%, while the proportion of patients with HBV DNA < 2000 IU/mL and ALT < ULN were 73%, 60%, 52%, 52%, 47% and 37% respectively. All patients had virological and biochemical response after retreatment. No patient developed liver failure, hepatocellular carcinoma or death. Cumulative rates of HBsAg loss were 2%, 4%, 7%, 10% and 20% at 3, 6, 12, 24 and 36 months. HBsAg levels < 100 IU/mL at the end of NA treatment could predict HBsAg loss (P = .001). CONCLUSIONS Our study supports that NA therapy can be safely stopped in non-cirrhotic patients with HBeAg-negative CHB. Over a median follow-up of more than 5 years, half of the patients remained without retreatment with a substantial proportion of them achieving functional cure.
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Affiliation(s)
- Spilios Manolakopoulos
- Liver-GI Unit, 2nd Academic Department of Internal Medicine, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
- Academic Department of Gastroenterology, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Hariklia Kranidioti
- Liver-GI Unit, 2nd Academic Department of Internal Medicine, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Anastasia Kourikou
- Liver-GI Unit, 2nd Academic Department of Internal Medicine, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Melanie-Maria Deutsch
- Liver-GI Unit, 2nd Academic Department of Internal Medicine, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Athens, Greece
| | - Chrysostomos Tsolias
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Athens, Greece
| | | | - Nicoletta Mathou
- Department of Gastroenterology, "Konstantopoulio-Patission" General Hospital, Nea Ionia, Athens, Greece
| | - Alexandra Alexopoulou
- Liver-GI Unit, 2nd Academic Department of Internal Medicine, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Emilia Hadziyannis
- Liver-GI Unit, 2nd Academic Department of Internal Medicine, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - George Papatheodoridis
- Academic Department of Gastroenterology, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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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: 23] [Impact Index Per Article: 4.6] [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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Abstract
Currently, despite the use of a preventive vaccine for several decades as well as the use of effective and well-tolerated viral suppressive medications since 1998, approximately 250 million people remain infected with the virus that causes hepatitis B worldwide. Hepatitis C virus (HCV) and hepatitis B virus (HBV) are the leading causes of liver cancer and overall mortality globally, surpassing malaria and tuberculosis. Linkage to care is estimated to be very poor both in developing countries and in high-income countries, such as the United States, countries in Western Europe, and Japan. In the United States, by CDC estimates, only one-third of HBV-infected patients or less are aware of their infection. Some reasons for these low rates of surveillance, diagnosis, and treatment include the asymptomatic nature of chronic hepatitis B until the very late stages, a lack of curative therapy with a finite treatment duration, a complex natural history, and a lack of knowledge about the disease by both care providers and patients. In the last 5 years, more attention has been focused on the important topics of HBV screening, diagnosis of HBV infection, and appropriate linkage to care. There have also been rapid clinical developments toward a functional cure of HBV infection, with novel compounds currently being in various phases of progress. Despite this knowledge, many of the professional organizations provide guidelines focused only on specific questions related to the treatment of HBV infection. This focus leaves a gap for care providers on the other HBV-related issues, which include HBV's epidemiological profile, its natural history, how it interacts with other viral hepatitis diseases, treatments, and the areas that still need to be addressed in order to achieve HBV elimination by 2030. Thus, to fill these gaps and provide a more comprehensive and relevant document to regions worldwide, we have taken a global approach by using the findings of global experts on HBV as well as citing major guidelines and their various approaches to addressing HBV and its disease burden.
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Papatheodoridi M, Papatheodoridis G. Emerging Diagnostic Tools to Decide When to Discontinue Nucleos(t)ide Analogues in Chronic Hepatitis B. Cells 2020; 9:cells9020493. [PMID: 32093411 PMCID: PMC7072769 DOI: 10.3390/cells9020493] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 02/09/2020] [Accepted: 02/15/2020] [Indexed: 12/27/2022] Open
Abstract
The aim of this review is to outline emerging biomarkers that can serve as diagnostic tools to identify non-cirrhotic chronic hepatitis B (CHB) patients who could safely discontinue nucleos(t)ide analogues (NAs) before HBsAg loss. Regarding possible predictors of post-NAs outcomes, a number of studies have evaluated numerous factors, which can be categorised in markers of hepatitis B virus (HBV) activity, markers of host immune response and markers of other patient characteristics. In clinical practice, the most important question for patients who discontinue NAs is to differentiate those who will benefit by achieving HBsAg loss or at least by remaining in remission and those who will relapse requiring retreatment. Most of the discontinuation studies so far came from Asian and only few from European populations and examined the rates and predictors of post-NA virological and/or combined relapses or HBsAg loss. To date, there is still controversy about predictors of post-NA relapses, while only HBsAg serum levels at NA discontinuation seem to be the most robust predictive marker of the probability of subsequent off-treatment HBsAg seroclearance. Newer viral markers such as HBV RNA and hepatitis B core-related antigen seem promising, but further research is required.
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Affiliation(s)
- Margarita Papatheodoridi
- Institute of Liver and Digestive Health, Royal Free Hospital, University College of London, London NW3 2QG, UK;
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, 11527 Athens, Greece
| | - George Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, 11527 Athens, Greece
- Correspondence: ; Tel.: +30-2132061115
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Papatheodoridis GV, Rigopoulou EI, Papatheodoridi M, Zachou K, Xourafas V, Gatselis N, Hadziyannis E, Vlachogiannakos J, Manolakopoulos S, Dalekos GN. DARING-B: discontinuation of effective entecavir or tenofovir disoproxil fumarate long-term therapy before HBsAg loss in non-cirrhotic HBeAg-negative chronic hepatitis B. Antivir Ther 2019; 23:677-685. [PMID: 30044765 DOI: 10.3851/imp3256] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/17/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND The remission rates after stopping antivirals in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) vary among studies, while reliable predictors of relapse have not been identified. This prospective study assessed rates and predictors of relapse and retreatment in 57 non-cirrhotic hepatitis B surface antigen (HBsAg)-positive patients with HBeAg-negative CHB who discontinued effective ≥4-year entecavir or tenofovir disoproxil fumarate (TDF) therapy. METHODS A total of 57 patients discontinued therapy after median virological remission of 5.3 years and remained under close follow-up. They were retreated with entecavir/TDF if they fulfilled predetermined criteria. RESULTS During median follow-up of 18 months, no patient died, developed jaundice or liver decompensation. The cumulative relapse rates varied according to HBV DNA and alanine aminotransferase cutoffs; for HBV DNA >2,000 IU/ml, they were 56%, 70% and 72% at 3, 12 and 18 months after stopping entecavir/TDF. The cumulative probability of retreatment was 18% and 26% at 3 and 12 months being significantly affected only by pretreatment fibrosis severity (adjusted relative hazard: 3.43; P=0.015). Cumulative rates of HBsAg loss were 5%, 16% and 25% at 6, 12 and 18 months being higher in patients with lower HBsAg levels at treatment discontinuation. CONCLUSIONS Our prospective study shows that effective ≥4-year entecavir/TDF therapy can be safely discontinued in non-cirrhotic HBeAg-negative CHB patients. The probability of relapse decreased after month 6. Despite common virological relapses, most patients, particularly those with mild-moderate pretreatment fibrosis, remain without retreatment, at least in the first 18 months, as a substantial proportion of them clear HBsAg and the majority eventually enters into an inactive carrier state.
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Affiliation(s)
- George V Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Eirini I Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Margarita Papatheodoridi
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Vassilios Xourafas
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Nikolaos Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Emilia Hadziyannis
- 2nd Department of Internal Medicine, Medical School of National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - John Vlachogiannakos
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Spilios Manolakopoulos
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.,2nd Department of Internal Medicine, Medical School of National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
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Finite nucleos(t)ide analog therapy in HBeAg-negative chronic hepatitis B: an emerging paradigm shift. Hepatol Int 2019; 13:665-673. [PMID: 31559604 DOI: 10.1007/s12072-019-09989-6] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 09/03/2019] [Indexed: 12/14/2022]
Abstract
Potent nucleos(t)ide analogs (NUC), such as entecavir and tenofovir disoproxil fumarate, are able to suppress HBV DNA to undetectable level. These agents have no direct action on cccDNA, which is a very stable template for HBV production, hence long-term or even life-long NUC therapy is required in HBeAg-negative patients to maintain HBV suppression and to achieve the ultimate goal of HBsAg loss. However, there are concerns of indefinite or life-long NUC therapy, including drug resistance, 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. This Review integrated the cumulated evidence and assessed the strategy of finite NUC therapy in HBeAg-negative patients which was first tried in early 2000s. Earlier Asian findings that 2-year NUC therapy is feasible and safe have founded APASL stopping rule for patients on NUC therapy over 2-3 years since 2008. Subsequent studies have supported the strategy of finite NUC therapy, which has finally been accepted as an option by American and European liver associations since 2016. More recent studies have further shown greatly increased HBsAg loss rate (up to 5-year 39%) after stopping NUC therapy. The cumulated evidence has shown that the paradigm shift from indefinite long-term therapy to finite NUC therapy in HBeAg-negative patients is emerging. More studies are needed to fine-tuning the strategy including research for the optimal duration of consolidation therapy, timing to stop and to start re-treatment.
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25
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Papatheodoridi M, Papatheodoridis G. Can we stop nucleoside analogues before HBsAg loss? J Viral Hepat 2019; 26:936-941. [PMID: 30803099 DOI: 10.1111/jvh.13091] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 02/04/2019] [Indexed: 12/11/2022]
Abstract
Most of the current guidelines and the existing data suggest that long-term therapy with nucleos(t)ide analogue(s) [NA(s)] may be stopped in carefully selected chronic hepatitis B patients who remain HBsAg positive. In particular, NA(s) may be discontinued in such patients without pre-existing cirrhosis who achieved long-term on-therapy virological remission (>12 months of HBeAg seroconversion and HBV DNA undetectability for initially HBeAg-positive cases; ≥3 years of HBV DNA undetectability for HBeAg-negative cases) and are expected to remain under close follow-up after NA(s) discontinuation. The majority of patients will develop post-NA(s) virological relapses and a proportion of them will have biochemical relapses and occasionally flares, but prompt retreatment can reintroduce remission. No reliable predictor(s) of post-NA(s) relapses have been identified so far. HBsAg loss develops in a progressively increasing proportion of chronic hepatitis B patients who discontinue NA(s) with HBsAg loss rates being higher in Caucasian patients with HBeAg-negative chronic hepatitis B. Follow-up at least every 3 months for the first year seems to be appropriate for all chronic hepatitis B patients who discontinue NA(s), while HBeAg-negative patients need to be followed more closely (monthly) during the first 3 months. Predefined criteria for retreatment are quite important, and the best candidates for retreatment are probably the patients with persistent (≥3 months) liver disease activity and those with severe flares.
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Affiliation(s)
- Margarita Papatheodoridi
- Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - George Papatheodoridis
- Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
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26
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Kranidioti H, Manolakopoulos S, Kontos G, Breen MS, Kourikou A, Deutsch M, Quesada-Del-Bosque ME, Martinez-Nunez RT, Naiyer MM, Woelk CH, Sanchez-Elsner T, Hadziyannis E, Papatheodoridis G, Khakoo SI. Immunological biomarkers as indicators for outcome after discontinuation of nucleos(t)ide analogue therapy in patients with HBeAg-negative chronic hepatitis B. J Viral Hepat 2019; 26:697-709. [PMID: 30702196 DOI: 10.1111/jvh.13068] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 01/09/2019] [Indexed: 02/07/2023]
Abstract
The optimal duration of treatment with nucleos(t)ide analogues (NAs) for patients with HBeAg-negative chronic hepatitis B (CHB) is unknown. The aim of this study was to identify an immune signature associated with off-treatment remission to NA therapy. We performed microarray analysis of peripheral blood mononuclear cell (PBMCs) from six patients with chronic hepatitis B who stopped NA therapy (three with off-treatment remission, three with relapse) and five patients with chronic HBV infection (previously termed 'inactive carriers') served as controls. Results were validated using qRT-PCR on a second group of 21 individuals (17 patients who stopped treatment and four controls). PBMCs from 38 patients on long-term NA treatment were analysed for potential to stop treatment. Microarray analysis indicated that patients with off-treatment remission segregated as a distinct out-group. Twenty-one genes were selected for subsequent validation. Ten of these were expressed at significantly lower levels in the patients with off-treatment remission compared to the patients with relapse and predicted remission with AUC of 0.78-0.92. IFNγ, IL-8, FASLG and CCL4 were the most significant by logistic regression. Twelve (31.6%) of 38 patients on long-term NA therapy had expression levels of all these four genes below cut-off values and hence were candidates for stopping treatment. Our data suggest that patients with HBeAg-negative CHB who remain in off-treatment remission 3 years after NA cessation have a distinct immune signature and that PBMC RNA levels of IFNγ, IL-8, FASLG and CCL4 may serve as potential biomarkers for stopping NA therapy.
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Affiliation(s)
- Hariklia Kranidioti
- Department of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.,2nd Academic Department of Internal Medicine, Hippokration General Hospital of Athens, Athens, Greece
| | - Spilios Manolakopoulos
- 2nd Academic Department of Internal Medicine, Hippokration General Hospital of Athens, Athens, Greece.,Academic Department of Gastroenterology, Laiko General Hospital of Athens, Athens, Greece
| | - George Kontos
- 2nd Academic Department of Internal Medicine, Hippokration General Hospital of Athens, Athens, Greece
| | - Michael S Breen
- Department of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Anastasia Kourikou
- 2nd Academic Department of Internal Medicine, Hippokration General Hospital of Athens, Athens, Greece
| | - Melanie Deutsch
- 2nd Academic Department of Internal Medicine, Hippokration General Hospital of Athens, Athens, Greece
| | | | - Rocio T Martinez-Nunez
- Department of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Mohammed M Naiyer
- Department of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Christopher H Woelk
- Department of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Tilman Sanchez-Elsner
- Department of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Emilia Hadziyannis
- Academic Department of Gastroenterology, Laiko General Hospital of Athens, Athens, Greece
| | - George Papatheodoridis
- Academic Department of Gastroenterology, Laiko General Hospital of Athens, Athens, Greece
| | - Salim I Khakoo
- Department of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
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Chan HLY. Okuda lecture: Challenges of hepatitis B in the era of antiviral therapy. J Gastroenterol Hepatol 2019; 34:501-506. [PMID: 30402981 DOI: 10.1111/jgh.14534] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 10/25/2018] [Accepted: 10/30/2018] [Indexed: 12/13/2022]
Abstract
Nucleos(t)ide analogs (NAs) are effective, safe, and convenient antiviral therapy to suppress replication of hepatitis B virus, which can be translated into improved long-term outcome of chronic hepatitis B patients. The current recommended first-line NAs, namely, entecavir and tenofovir, are largely free from problems of drug resistance. Nonetheless, there are still a few challenges in the era of NA. First, the risk of hepatocellular carcinoma can only be reduced but not eliminated, particularly among cirrhotic patients. For cirrhotic patients who have persistent low-level viremia on NA, that is, partial responders, the risk of hepatocellular carcinoma is higher than those with complete viral suppression. The best strategy to manage partial responders to entecavir or tenofovir is uncertain. Second, immune-tolerant patients are very difficult to treat with NA. A significant proportion of immune-tolerant patients will have detectable viremia despite a few years of continuous NA treatment, and the rate of hepatitis B e-antigen seroconversion is very low. Third, most patients need long-term treatment as NA cannot eliminate covalently closed circular DNA in the hepatocytes. Some patients can consider stop NA according to treatment guidelines, but viral and clinical relapses often occur after treatment cessation. There is no concrete consensus on when one should stop NA in a hepatitis B e-antigen-negative patient among different treatment guidelines. New biomarkers such as hepatitis B surface antigen level can be used to select patients to stop NA, but the data are still preliminary.
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Affiliation(s)
- Henry Lik Yuen Chan
- Department of Medicine and Therapeutics, Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong
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28
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Wong GLH, Wong VWS, Chan HLY. Towards finite oral antiviral treatment for chronic hepatitis B. Lancet Gastroenterol Hepatol 2019; 4:260-262. [PMID: 30795959 DOI: 10.1016/s2468-1253(19)30045-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 01/25/2019] [Indexed: 12/26/2022]
Affiliation(s)
- Grace Lai-Hung Wong
- Institute of Digestive Disease, Department of Medicine and Therapeutics, and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Vincent Wai-Sun Wong
- Institute of Digestive Disease, Department of Medicine and Therapeutics, and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Henry Lik-Yuen Chan
- Institute of Digestive Disease, Department of Medicine and Therapeutics, and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
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29
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Lampertico P, Brunetto MR, Craxì A, Gaeta GB, Rizzetto M, Rozzi A, Colombo M. Add-on peginterferon alfa-2a to nucleos(t)ide analogue therapy for Caucasian patients with hepatitis B 'e' antigen-negative chronic hepatitis B genotype D. J Viral Hepat 2019; 26:118-125. [PMID: 30187599 DOI: 10.1111/jvh.12999] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 08/14/2018] [Indexed: 12/13/2022]
Abstract
Nucleos(t)ide analogues (NAs) and peginterferon have complementary effects in chronic hepatitis B, but it is unclear whether combination therapy improves responses in genotype D-infected patients. We conducted an open-label study of peginterferon alfa-2a 180 μg/wk added to ongoing NA therapy in hepatitis B e antigen (HBeAg)-negative, genotype D-infected patients with hepatitis B virus DNA <20 IU/mL. The primary endpoint was proportion of patients with ≥50% decline in serum HBsAg by the end of the 48-week add-on phase. Seventy patients received treatment, 11 were withdrawn at week 24 for no decrease in HBsAg, and 14 withdrew for other reasons. Response rate (per-protocol population) was 67.4% (29/43) at week 48 (95% confidence interval [CI]: 51, 81) and 50.9% (28/55) at week 96 (95% CI: 38, 66). Median serum HBsAg decreased throughout peginterferon alfa-2a treatment and was significantly lower than baseline at weeks 48, 72 and 96 (P < 0.001). Decreases in HBsAg of ≥0.5-log10 and ≥1-log10 were documented in 19 (44.2%) and 6 (14.0%) patients at week 48 and 6 (10.9%) and 17 (30.9%) patients at week 96. The proportion of patients with HBsAg <1000, <500, <100 and <10 IU/mL at ≥1 timepoint during treatment was 78.6% (n = 44), 57.1% (n = 32), 21.4% (n = 12) and 7.1% (n = 4). Interferon gamma-induced protein 10 increased from baseline up to week 48, with week 12 levels significantly associated with response at week 48. Addition of peginterferon alfa-2a to ongoing NA therapy significantly decreased HBsAg levels in HBeAg-negative patients with genotype D infection (ClinicalTrials.gov NCT01706575).
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Affiliation(s)
- Pietro Lampertico
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Maurizia R Brunetto
- Internal Medicine, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Antonio Craxì
- Gastroenterology and Hepatology, Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Giovanni B Gaeta
- Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Mario Rizzetto
- Department of Gastroenterology, University of Turin, Turin, Italy
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Xia M, Liao G, Chen H, Wu Y, Fan R, Zhang X, Peng J. Plasma CXCL13 is a predictive factor for HBsAg loss and clinical relapse after discontinuation of nucleos(t)ide analogue treatment. Clin Immunol 2018; 198:31-38. [PMID: 30503407 DOI: 10.1016/j.clim.2018.11.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 07/27/2018] [Accepted: 11/29/2018] [Indexed: 02/06/2023]
Abstract
In this study, we investigated whether plasma cytokine/chemokine levels could predict HBsAg loss or clinical relapse (CR) after stopping nucleos(t)ides analogue (NA) treatment. Theplasma cytokines/chemokines levels were measured at 0, 4, 8, 12, 24 and 48 weeks after NA discontinuation by using the enzyme-linked immunoassay (ELISA) kit. Cox regression analysis revealed that CXCL13 level at the end of treatment (EOT) was an independent predictor for CR (HR 0.26, p < 0.001) and HBsAg loss (HR 3.01, p = 0.008) after treatment cessation. Among the patients with EOT CXCL13 level < 80 pg/ml, the cumulative incidences of CR and HBsAg loss were 65% and 0% at 4 years, respectively. As for the patients with EOT CXCL13 level ≥ 1000 pg/ml, 47.5% cases had HBsAg loss. Our study showed that EOT CXCL13 level was associated with off-treatment response, which may be used to guide cessation of NA treatment in clinical practice.
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Affiliation(s)
- Muye Xia
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, 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 and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hongjie Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yin Wu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Rong Fan
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, 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 and Hepatology Unit, 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 and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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31
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Höner Zu Siederdissen C, Maasoumy B, Cornberg M. New viral biomarkers for Hepatitis B: Are we able to change practice? J Viral Hepat 2018; 25:1226-1235. [PMID: 30187603 DOI: 10.1111/jvh.12993] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 08/28/2018] [Indexed: 12/13/2022]
Abstract
The management of chronic hepatitis B virus (HBV) infection is challenged by its varying natural course and its stealthy nature. Not all HBV-infected patients will develop complications of infection; however, it is of utmost importance to identify patients who are at risk and require antiviral treatment and/or close surveillance. Hepatic inflammation and quantification of HBV DNA have guided treatment decisions in the last decade, and these guided interventions have been shown to reduce liver-related complications and death. Data on the quantification of additional HBV markers such as hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) and hepatitis B virus RNA (HBV RNA) have accumulated in recent years. Here, we review the current evidence of how to use these markers and discuss open issues that require additional research.
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Affiliation(s)
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
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32
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Liu YY, Liang XS. Progression and status of antiviral monitoring in patients with chronic hepatitis B: From HBsAg to HBV RNA. World J Hepatol 2018; 10:603-611. [PMID: 30310538 PMCID: PMC6177569 DOI: 10.4254/wjh.v10.i9.603] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 07/10/2018] [Accepted: 07/16/2018] [Indexed: 02/06/2023] Open
Abstract
As alternative indexes of hepatitis B virus (HBV), covalently closed circular DNA (cccDNA) transcriptional activity, hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg), and peripheral blood RNA known as pgRNA, have been advocated as novel serum markers for prediction of prognosis and treatment response in chronic hepatitis B (CHB). Since the availability of commercial quantitative assays of HBsAg in 2011, HBsAg has been widely used for predicting treatment response of patients with CHB. Patients who received interferon therapy have shown a sharper reduction of HBsAg level than those who received nucleoside drug (NAs) therapy. Upon peginterferon treatment, sustained responders have presented a larger reduction of HBsAg level than the non-responders. An absence of HBsAg decline, together with < 2log reduction in HBV DNA at week 12, can serve as a stopping rule in HBsAg-negative patients infected with genotype D HBV. A sharp reduction of HBsAg titer in the NAs therapy is a predictor of HBsAg clearance in long-term treatment. HBcrAg, which consists of three species of related proteins sharing an identical 149 amino acid sequence, including HbcAg, hepatitis B e antigen (HBeAg), and a truncated 22-kDa precore protein, is still detectable in situations where serum HBV DNA levels become undetectable or HBsAg loss is achieved. Therefore, HBcrAg remains a measurable serum marker to correlate with cccDNA in this situation. The decline in HBcrAg has been observed with NAs therapy and the pattern of decline might provide prognostic information on the risk of HBV post-treatment reactivation. Peripheral blood RNA, which is known as pgRNA, directly derives from cccDNA and reflects intrahepatic cccDNA level. Quantitative pgRNA has been suggested to be helpful in CHB management. However, commercial quantitative assays are lacking. Additionally, the use of simultaneous and continuous clearance of HBV RNA and HBV DNA in serum has been suggested to be a safe stopping rule of NAs therapy for patients with CHB. However, clinical studies of large sample sizes are needed to prove the feasibility and significance of using serum HBV RNA as the assessment standard of antiviral therapy in CHB and the safety of the stopping rule in clinics.
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Affiliation(s)
- Ya-Yun Liu
- Department of Infectious Diseases, Changhai Hospital of Second Military Medical University, Shanghai 200433, China
| | - Xue-Song Liang
- Department of Infectious Diseases, Changhai Hospital of Second Military Medical University, Shanghai 200433, China
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33
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Jeng WJ, Chen YC, Chien RN, Sheen IS, Liaw YF. Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B. Hepatology 2018; 68:425-434. [PMID: 29108132 DOI: 10.1002/hep.29640] [Citation(s) in RCA: 246] [Impact Index Per Article: 35.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 10/06/2017] [Accepted: 11/02/2017] [Indexed: 12/11/2022]
Abstract
UNLABELLED Hepatitis B surface antigen (HBsAg) loss is a rare event during nucleos(t)ide analogue (Nuc) therapy. Limited data suggest that stopping Nuc therapy may increase HBsAg loss rate in hepatitis B e antigen-negative patients. A large study was conducted to investigate this issue in more detail. Of the 1,075 hepatitis B e antigen-negative patients treated with Nuc for a median of 156 (61-430) weeks, 5 showed HBsAg seroclearance during treatment at an estimated annual incidence of 0.15%. Of the patients who remained HBsAg-seropositive, 691 (52.3 years old, 86% male, 44.6% cirrhosis) had stopped Nuc therapy by the Asian-Pacific Association for the Study of the Liver stopping rule and then were prospectively followed up. Baseline and on-treatment clinical and viral features, treatment duration, consolidation duration, time to undetectable hepatitis B virus DNA, time to normal alanine aminotransferase, end-of-treatment HBsAg, and HBsAg log reduction were compared between patients with and without HBsAg seroclearance after end of treatment. During a median off-therapy follow-up period of 155 (2-614) weeks, HBsAg seroclearance was confirmed in 42 patients. The 6-year cumulative incidence was 13% with an estimated annual incidence of 1.78%. Cox regression analysis showed that shorter time to undetectable hepatitis B virus DNA (<12 weeks), greater HBsAg reduction during therapy (>1 log10 ), lower end-of-treatment HBsAg level (<100 IU/mL), patients with sustained response, and relapsers not retreated were factors for off-therapy HBsAg seroclearance. CONCLUSION The incidence of HBsAg seroclearance after stopping Nuc was much higher than that during therapy and highest in patients without virologic and clinical relapse; patients with clinical relapse who remained untreated had a 7.34 times higher incidence of HBsAg clearance than those who received retreatment, suggesting that transient untreated clinical relapse may drive sufficient immune control to functional cure. (Hepatology 2017).
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Affiliation(s)
- Wen-Juei Jeng
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City, Taiwan
| | - Yi-Cheng Chen
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City, Taiwan
| | - Rong-Nan Chien
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City, Taiwan
| | - I-Shyan Sheen
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
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Moreno-Cubero E, Arco RTSD, Peña-Asensio J, Villalobos ESD, Míquel J, Larrubia JR. Is it possible to stop nucleos(t)ide analogue treatment in chronic hepatitis B patients? World J Gastroenterol 2018; 24:1825-1838. [PMID: 29740199 PMCID: PMC5937201 DOI: 10.3748/wjg.v24.i17.1825] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Revised: 04/21/2018] [Accepted: 04/23/2018] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB) remains a challenging global health problem, with nearly one million related deaths per year. Nucleos(t)ide analogue (NA) treatment suppresses viral replication but does not provide complete cure of the hepatitis B virus (HBV) infection. The accepted endpoint for therapy is the loss of hepatitis B surface antigen (HBsAg), but this is hardly ever achieved. Therefore, indefinite treatment is usually required. Many different studies have evaluated NA therapy discontinuation after several years of NA treatment and before HBsAg loss. The results have indicated that the majority of patients can remain off therapy, with some even reaching HBsAg seroconversion. Fortunately, this strategy has proved to be safe, but it is essential to consider the risk of liver damage and other comorbidities and to ensure a close follow-up of the candidates before considering this strategy. Unanswered questions remain, namely in which patients could this strategy be effective and what is the optimal time point at which to perform it. To solve this enigma, we should keep in mind that the outcome will ultimately depend on the equilibrium between HBV and the host’s immune system. Viral parameters that have been described as good predictors of response in HBeAg(+) cases, have proven useless in HBeAg(-) ones. Since antiviral immunity plays an essential role in the control of HBV infection, we sought to review and explain potential immunological biomarkers to predict safe NA discontinuation in both groups.
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Affiliation(s)
| | - Robert T Sánchez del Arco
- Internal Medicine Service, Guadalajara University Hospital, University of Alcalá, Guadalajara 19002, Spain
| | - Julia Peña-Asensio
- Department of Biology of Systems, University of Alcalá, Alcalá de Henares (Madrid) 28805, Spain
| | | | | | - Juan Ramón Larrubia
- Department of Medicine and Medical Specialties, University of Alcalá, Alcalá de Henares (Madrid) 28805, Spain
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35
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Chen CH, Hsu YC, Lu SN, Hung CH, Wang JH, Lee CM, Hu TH. The incidence and predictors of HBV relapse after cessation of tenofovir therapy in chronic hepatitis B patients. J Viral Hepat 2018; 25:590-597. [PMID: 29274189 DOI: 10.1111/jvh.12851] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 11/20/2017] [Indexed: 12/31/2022]
Abstract
This study investigates the incidences and predictors of hepatitis B virus (HBV) relapse after tenofovir disoproxil fumarate (TDF) therapy in hepatitis B e antigen (HBeAg)-positive and -negative patients. We retrospectively recruited 143 chronic hepatitis B (CHB) patients without cirrhosis (39 HBeAg-positive and 104 HBeAg-negative patients) who were previously treated with TDF and had post-treatment follow-up for at least 6 months (median: 55, IQR 36-85 weeks). All the patients fulfilled the stopping criteria of APASL 2012. The virological and clinical relapse rates at 104 weeks in HBeAg-positive patients were 66.6% and 59.1%, while they were 72.3% and 55.9%, respectively, in HBeAg-negative patients. Cox regression analysis revealed that the higher end-of-treatment HBsAg levels were an independent factor of virological relapse in HBeAg-positive and HBeAg-negative patients. The end-of-treatment HBsAg levels of 200 (area under the receiver operating characteristic (AUROC): 0.624) and 80 IU/mL (AUROC: 0.959) were the optimal values for predicting HBV relapse in HBeAg-positive and HBeAg-negative patients, respectively. The virological relapse rate at 78 weeks was 14.3% and 19.6% in HBeAg-positive and HBeAg-negative patients who achieved HBsAg ≤200 IU/mL and HBsAg ≤80 IU/mL, respectively. Two patients experienced hepatic decompensation upon hepatitis flares, and no patient died after timely retreatment. Seven patients experienced off-therapy HBsAg loss. The cumulative rates of HBsAg loss at 104 weeks were 45.5% and 59.3% in patients with end-of-treatment HBsAg ≤80 IU/mL and ≤50 IU/mL, respectively. In conclusions, the end-of-treatment HBsAg levels were a useful marker for predicting HBV relapse in HBeAg-positive and HBeAg-negative CHB patients.
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Affiliation(s)
- C-H Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Y-C Hsu
- Division of Gastroenterology, E-Da Hospital, Kaohsiung, Taiwan
| | - S-N Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - C-H Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - J-H Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - C-M Lee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - T-H Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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36
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Hsu WF, Chen CF, Lai HC, Su WP, Lin CH, Chuang PH, Chen SH, Chen CH, Wang HW, Huang GT, Peng CY. Trajectories of serum hepatitis B surface antigen kinetics in patients with chronic hepatitis B receiving long-term nucleos(t)ide analogue therapy. Liver Int 2018; 38:627-635. [PMID: 28857411 DOI: 10.1111/liv.13564] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 08/23/2017] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS The kinetics of serum hepatitis B surface antigen (HBsAg) levels during long-term nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB) patients remains unclear. We investigated the patterns of serum HBsAg kinetics and their association with therapeutic outcomes in genotype B- or C-infected CHB patients receiving long-term NA therapy. METHODS We enrolled 329 treatment-naive CHB patients receiving NA therapy for >5 years to analyse the kinetic patterns by using group-based trajectory models (GBTMs). RESULTS Most patients (82.4%) received entecavir therapy. The median treatment duration was 83.6 (68.5-89.7) months. The GBTMs revealed three groups for both the hepatitis B e antigen (HBeAg)-positive and -negative patients. The median annual decline in serum HBsAg levels during the first 5 years was significantly higher in Group 1 than in Groups 2 and 3 in HBeAg-positive (0.78 vs 0.10 vs 0.10 log10 IU/mL) and HBeAg-negative (0.71 vs 0.08 vs 0.09 log10 IU/mL) patients. HBsAg levels at the baseline and 12 months combined with an HBsAg decline from the baseline to 12 months of treatment predicted trajectory pattern 1 in HBeAg-positive (sensitivity, 77.8%; specificity, 99.1%; positive predictive value [PPV], 87.5%; and negative predictive value [NPV], 98.2%) and HBeAg-negative (sensitivity, 100%; specificity, 99.5%; PPV, 88.9%; and NPV, 100%) patients. The trajectory patterns were significantly associated with HBeAg loss in the HBeAg-positive patients and the achievement of HBsAg <100 IU/mL or HBsAg loss in HBeAg-positive and HBeAg-negative patients. CONCLUSIONS The trajectory of serum HBsAg levels predicts HBsAg loss in CHB patients receiving long-term NA therapy.
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Affiliation(s)
- Wei-Fan Hsu
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chuen-Fei Chen
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
| | - Hsueh-Chou Lai
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Wen-Pang Su
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chia-Hsin Lin
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Po-Heng Chuang
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Sheng-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Medicine, China Medical University, Taichung, Taiwan
| | - Ching-Hsiang Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Hung-Wei Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Guan-Tarn Huang
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Medicine, China Medical University, Taichung, Taiwan
| | - Cheng-Yuan Peng
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Medicine, China Medical University, Taichung, Taiwan
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37
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Marciano S, Gadano A. Why not to stop antiviral treatment in patients with chronic hepatitis B. Liver Int 2018; 38 Suppl 1:97-101. [PMID: 29427480 DOI: 10.1111/liv.13627] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 11/04/2017] [Indexed: 12/22/2022]
Abstract
Treatment of chronic hepatitis B with entecavir or tenofovir leads to viral suppression in almost all patients. However, prolonged or lifelong treatment is necessary. At present, there is no consensus among the three major guidelines for the treatment of chronic hepatitis B on whether or not to stop antiviral treatment. One of the main reasons for this controversy is that virological relapse has been well documented in patients with chronic hepatitis B who stop treatment. Relapse rate is particularly high in patients who are HBeAg-negative when treatment begins, with reported relapse rates of up to 70% 36 months after treatment discontinuation. Moreover, hepatic decompensation, jaundice and death have been described in patients with cirrhosis after treatment discontinuation. The main reason for stopping antiviral treatment is related to cost, however there is no robust evidence to support treatment discontinuation in most patients.
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Affiliation(s)
- Sebastián Marciano
- Liver Unit and Department of Research, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Adrián Gadano
- Liver Unit and Department of Research, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
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38
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van Bömmel F, Berg T. Stopping long-term treatment with nucleos(t)ide analogues is a favourable option for selected patients with HBeAg-negative chronic hepatitis B. Liver Int 2018; 38 Suppl 1:90-96. [PMID: 29427489 DOI: 10.1111/liv.13654] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 11/24/2017] [Indexed: 12/14/2022]
Abstract
The immune response against the infection is impaired in patients with chronic hepatitis B, and although HBV DNA can effectively be suppressed by nucleos(t)ide analogues (NA), durable immune control is only established in a minority of patients. This especially applies in HBeAg-negative patients who usually must receive lifelong NA treatment. Calculated withdrawal of NA leads to a relapse of HBV DNA in most patients. There is evidence that this sudden exposure of viral antigens can trigger immune control in some patients which may result in HBsAg loss or a form of immune control, then sustained low HBV DNA levels and normal alanine aminotransferase (ALT). In the first prospective randomized trial investigating tenofovir treatment cessation in HBeAg-negative patients, most patients did not need retreatment after NA cessation, although all patients showed a transient relapse in HBV DNA. HBsAg loss was identified in almost 20% nearly 3 years after stopping NA. Further confirmation of these findings is needed in larger randomized trials and patients who are most likely to benefit from finite therapy must be identified to individualize NA stopping strategies. However, these results suggest that in patients without risk factors such as cirrhosis or other severe conditions, NA treatment may be stopped, as long as adequate safety rules for retreatment are followed.
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Affiliation(s)
- Florian van Bömmel
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - Thomas Berg
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
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39
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Chen CH, Hung CH, Wang JH, Lu SN, Hu TH, Lee CM. Long-term incidence and predictors of hepatitis B surface antigen loss after discontinuing nucleoside analogues in noncirrhotic chronic hepatitis B patients. Clin Microbiol Infect 2017; 24:997-1003. [PMID: 29288020 DOI: 10.1016/j.cmi.2017.12.013] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 10/21/2017] [Accepted: 12/17/2017] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To investigate the long-term incidence and predictors for hepatitis B surface antigen (HBsAg) loss after nucleoside analogue therapy. METHODS The study included 411 noncirrhotic chronic hepatitis B patients (148 hepatitis B e antigen (HBeAg)-positive and 263 HBeAg-negative patients) who were treated with lamivudine (n = 110) or entecavir (n = 301) with posttreatment follow-up of at least 12 months. RESULTS In HBeAg-positive patients, the 8-year cumulative rates of virologic relapse, clinical relapse and HBsAg loss were 55.6%, 47.7% and 19.6%, respectively. In HBeAg-negative patients, the rates were 69.3%, 58.9% and 33.1%, respectively. Cox regression analysis showed that hepatitis B virus genotype C and lower end-of-treatment HBsAg levels were independent predictors of HBsAg loss in HBeAg-positive and -negative patients. The 5-year HBsAg loss rate was 47.3% in HBeAg-positive patients with end-of-treatment HBsAg levels <300 IU/mL, while the 8-year HBsAg loss rate was 69.3% in HBeAg-negative patients with end-of-treatment HBsAg levels <200 IU/mL. Five patients experienced hepatitis flares with decompensation after stopping nucleoside analogue therapy, and one died after retreatment. Of the 48 patients who developed off-therapy HBsAg loss, two developed hepatocellular carcinoma. CONCLUSIONS The rate of HBsAg loss was relatively high and the rate of hepatic events was low in noncirrhotic patients who discontinued nucleoside analogue therapy.
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Affiliation(s)
- C-H Chen
- Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan.
| | - C-H Hung
- Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan
| | - J-H Wang
- Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan
| | - S-N Lu
- Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan
| | - T-H Hu
- Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan
| | - C-M Lee
- Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan
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40
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Chien NH, Huang YT, Wu CY, Chang CY, Wu MS, Kao JH, Mo LR, Tai CM, Lin CW, Yang TH, Lin JT, Hsu YC. Time-varying serum gradient of hepatitis B surface antigen predicts risk of relapses after off-NA therapy. BMC Gastroenterol 2017; 17:154. [PMID: 29221441 PMCID: PMC5723064 DOI: 10.1186/s12876-017-0697-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 11/20/2017] [Indexed: 02/06/2023] Open
Abstract
Background The serum gradient of hepatitis B surface antigen (HBsAg) varies over time after cessation of nucleos(t)ide analog (NA) treatment in patients with chronic hepatitis B (CHB). The association between the time-varying HBsAg serum gradient and risk of relapse has not been elucidated. Methods This multicenter cohort study prospectively enrolled CHB patients who discontinued 3 year-NA treatment. Eligible patients were serologically negative for HBeAg and viral DNA at NA cessation. The participants (n = 140) were followed every 3 months through HBsAg quantification. Virological and clinical relapses were defined as viral DNA levels >2000 IU/mL and alanine aminotransferase (ALT) levels >80 U/mL, respectively. The association of time-varying HBsAg levels with relapses was assessed through a time-dependent Cox analysis. Results During a median follow-up of 19.9 (interquartile range [IQR], 10.6–25.3) months, virological and clinical relapses occurred in 94 and 49 patients, with a 2-year cumulative incidence of 79.2% (95% confidence interval [CI], 70.9%–86.4%) and 42.9% (95% CI, 34.1%–52.8%), respectively. The serum level of HBsAg was associated with virological (P < 0.001) and clinical (P = 0.01) relapses in a dose–response manner, with adjusted hazard ratios of 2.10 (95% CI, 1.45–3.04) and 2.32 (95% CI, 1.28–4.21). Among the patients (n = 19) whose HBsAg levels ever dropped below 10 IU/mL, only one and three patients subsequently developed clinical and virological relapses. Conclusion The serum gradient of HBsAg measured throughout the off-therapy observation is associated with the subsequent occurrence of virological and clinical relapses in CHB patients who discontinue NA treatment.
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Affiliation(s)
- Nai-Hsuan Chien
- Cathay General Hospital, Taipei, Taiwan.,School of Medicine, Fu Jen Catholic University, New Taipei, Taiwan.,Sijhih Cathay General Hospital, New Taipei, Taiwan
| | - Yen-Tsung Huang
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Chun-Ying Wu
- Division of Gastroenterology, Taichung Veterans General Hospital, Taichung, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chi-Yang Chang
- School of Medicine, Fu Jen Catholic University, New Taipei, Taiwan.,Division of Gastroenterology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan.,Division of Gastroenterology, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan
| | - Lein-Ray Mo
- Department of Internal Medicine, Tainan Municipal Hospital, Tainan, Taiwan
| | - Chi-Ming Tai
- Division of Gastroenterology, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Chih-Wen Lin
- Division of Gastroenterology, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Tzeng-Huey Yang
- Department of Internal Medicine, Lotung Poh-Ai Hospital, Yilan Country, Taiwan
| | - Jaw-Town Lin
- School of Medicine, Fu Jen Catholic University, New Taipei, Taiwan.,Division of Gastroenterology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan.,Division of Gastroenterology, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Yao-Chun Hsu
- School of Medicine, Fu Jen Catholic University, New Taipei, Taiwan. .,Division of Gastroenterology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan. .,Division of Gastroenterology, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan. .,, No.510, Zhongzheng Rd., Xinzhuang Dist, New Taipei City, 24205, Taiwan.
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Wong GLH, Wong VWS, Chan HLY. Virus and Host Testing to Manage Chronic Hepatitis B. Clin Infect Dis 2017; 62 Suppl 4:S298-305. [PMID: 27190319 DOI: 10.1093/cid/ciw024] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma worldwide. The past 50 years have seen rapid developments in HBV testing. Beginning from traditional serologic tests, the availability of sensitive HBV DNA assays allows a thorough understanding of the virology and natural history of chronic HBV infection. Quantification of hepatitis B surface antigen levels reflects the amount and transcriptional activities of covalently closed circular DNA in the liver and may be used to evaluate the stage of disease and guide antiviral therapy. The natural history of chronic HBV infection is also a manifestation of the interaction between the host and the virus, and recent genomic works have shed light on the host-virus relationship and may provide novel tests in the future. This review highlights recent advances in the application of HBV tests in the management of chronic hepatitis B.
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Affiliation(s)
- Grace Lai-Hung Wong
- Department of Medicine and Therapeutics Institute of Digestive Disease State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics Institute of Digestive Disease State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China
| | - Henry Lik-Yuen Chan
- Department of Medicine and Therapeutics Institute of Digestive Disease State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China
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Correlation of Quantitative Assay of HBsAg and Hepatitis B Virus DNA Levels Among Chronic HBV Patients Attending Pathologist Lancet Laboratory in Nairobi, Kenya. ARCHIVES OF CLINICAL INFECTIOUS DISEASES 2017. [DOI: 10.5812/archcid.13306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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43
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Stopping nucleos(t)ide analog treatment in chronic hepatitis B — Who and when? LIVER RESEARCH 2017. [DOI: 10.1016/j.livres.2017.06.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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44
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Hsu YC, Mo LR, Chang CY, Wu MS, Yang TH, Kao JH, Chen CC, Tseng CH, Tai CM, Lin CW, Wu CY, Lin JT. Serum viral load at the virological relapse predicts subsequent clinical flares in chronic hepatitis B patients off entecavir therapy. J Gastroenterol Hepatol 2017; 32:1512-1519. [PMID: 28122151 DOI: 10.1111/jgh.13728] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 12/18/2016] [Accepted: 01/10/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM Therapeutic duration of nucleos(t)ide analogues for chronic hepatitis B (CHB) is not indefinite in many parts of the world. Viral reactivation is common off therapy, but the risk of subsequent clinical outcome remains unclear and unpredictable. We aimed to quantify the incidence of and explore the predictors for clinical flare following virological relapse in CHB patients who discontinue entecavir therapy. METHODS This multicenter cohort study prospectively monitored 133 CHB patients who were HBeAg-negative and viral DNA-undetectable when discontinuing entecavir after at least 3 years on therapy. Following virological relapse (viral DNA >2,000 IU/mL) that occurred in 92 patients, the incidences of subsequent clinical flare and persistent (unremittent for 3 months) or severe hepatitis (with jaundice or coagulopathy) were determined, and risk factors were explored. Patients did not resume antiviral therapy until occurrence of persistent or severe hepatitis. RESULTS The cumulative incidence of clinical hepatitis 2 years after virological relapse was 61.0% (95% confidence interval [CI], 49.9-72.3%) and that of persistent or severe hepatitis was 53.0% (95% CI, 40.9-66.2%). Serum viral load at the virological relapse was associated with both clinical hepatitis (adjusted hazard ratio [HR], 1.31 per log IU/mL; 95% CI, 1.07-1.60) and persistent or severe hepatitis (adjusted HR, 1.63 per log IU/mL; 95% CI, 1.27-2.10), after adjustment for serum aminotransferase and alfa-fetoprotein levels in the multivariate analysis. Viral DNA >100 000 IU/mL predicted a nearly inevitable occurrence of clinical flare (P < 0.0001). CONCLUSIONS A high viral load at the virological relapse predicts subsequent clinical hepatitis in CHB patients who discontinue entecavir.
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Affiliation(s)
- Yao-Chun Hsu
- Center for Database Research, E-Da Hospital, Kaohsiung, Taiwan.,Department of Medicine, E-Da Hospital, Kaohsiung, Taiwan.,School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan.,Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.,School of Medicine, Fu Jen Catholic University, New Taipei, Taiwan
| | - Lein-Ray Mo
- Superintendent Office, Tainan Municipal Hospital, Tainan, Taiwan
| | - Chi-Yang Chang
- Department of Medicine, E-Da Hospital, Kaohsiung, Taiwan
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Tzeng-Huey Yang
- Division of Gastroenterology, Lotung Poh-Ai Hospital, Ilan, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chieh-Chang Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | | | - Chi-Ming Tai
- Department of Medicine, E-Da Hospital, Kaohsiung, Taiwan
| | - Chih-Wen Lin
- Department of Medicine, E-Da Hospital, Kaohsiung, Taiwan
| | - Chun-Ying Wu
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.,Division of Gastroenterology, Taichung Veterans General Hospital, Taichung, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
| | - Jaw-Town Lin
- Department of Medicine, E-Da Hospital, Kaohsiung, Taiwan.,Big Data Research Center, Fu Jen Catholic University, New Taipei, Taiwan
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45
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Hung CH, Wang JH, Lu SN, Hu TH, Lee CM, Chen CH. Hepatitis B surface antigen loss and clinical outcomes between HBeAg-negative cirrhosis patients who discontinued or continued nucleoside analogue therapy. J Viral Hepat 2017; 24:599-607. [PMID: 28130815 DOI: 10.1111/jvh.12683] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 01/07/2017] [Indexed: 12/21/2022]
Abstract
We investigated the incidence and predictors of post-treatment hepatitis B virus (HBV) relapse and hepatitis B surface antigen (HBsAg) loss. After cessation of nucleoside analogue (NA) treatment in hepatitis B e antigen (HBeAg)-negative patients with cirrhosis. The rates of HBsAg loss and hepatocellular carcinoma (HCC) development in HBeAg-negative patients with cirrhosis who continued NA treatment were compared with those who discontinued treatment. Patients with compensated cirrhosis who had discontinued NA treatment for at least 12 months (discontinuing group; n=73) and patients who continued entecavir treatment for at least 4 years (continuing group; n=158) were recruited. Serum HBsAg levels were analysed at the end of treatment (discontinuing group) or at 2.5-3 years of treatment (continuing group). In the discontinuing group, the 6-year cumulative incidence of post-treatment virological relapse and HBsAg loss were 56.3% and 46.7%, respectively. The end-of-treatment HBsAg level of 300 IU/mL was a cut-off value for subsequent post-treatment HBsAg loss and sustained response. In the continuing group, HBsAg loss occurred in five of 158 patients. Cox regression analysis showed that HBsAg levels in the discontinuing group were independent predictors for HBsAg loss in all patients and 104 propensity score (PS)-matched patients. There was no significant difference in HCC development between the groups in all patients and 104 PS-matched patients. Two patients experienced post-treatment alanine aminotransferase flare with hepatic decompensation, and neither of them died after retreatment. In conclusion, HBeAg-negative patients with cirrhosis who discontinued NA treatment might have a higher rate of HBsAg loss and their risk of developing HCC did not increase compared with those who continued entecavir treatment.
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Affiliation(s)
- C-H Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - J-H Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - S-N Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - T-H Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - C-M Lee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - C-H Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Höner Zu Siederdissen C, Maasoumy B, Cornberg M. What is new on HBsAg and other diagnostic markers in HBV infection? Best Pract Res Clin Gastroenterol 2017; 31:281-289. [PMID: 28774410 DOI: 10.1016/j.bpg.2017.04.009] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 04/28/2017] [Indexed: 01/31/2023]
Abstract
Challenges in the management of chronic hepatitis B virus (HBV) infection involve the prediction of the natural course to identify patients who require antiviral therapy and the prediction of functional cure as ultimate goal of antiviral therapy. HBV DNA as marker for viral replication is important but not sufficient for an adequate management of patients with chronic HBV infection. Data on the quantification of additional HBV marker such as hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) and hepatitis B virus RNA (HBV RNA) have accumulated in recent years. Here we review the current evidence how to use these markers and discuss open issues that require additional research.
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Affiliation(s)
- Christoph Höner Zu Siederdissen
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany.
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Incidence and predictors of HBV relapse after cessation of nucleoside analogues in HBeAg-negative patients with HBsAg ≤ 200 IU/mL. Sci Rep 2017; 7:1839. [PMID: 28500322 PMCID: PMC5431802 DOI: 10.1038/s41598-017-02010-w] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 04/05/2017] [Indexed: 12/26/2022] Open
Abstract
The predictors of hepatitis B virus (HBV) relapse and HBsAg loss after cessation of nucleos(t)ide analogues (NA) in HBeAg-negative patients with end-of-treatment HBsAg ≤ 200 IU/mL remains unclear. The study recruited 119 chronic hepatitis B (CHB) patients who achieved end-of-treatment HBsAg ≤ 200 IU/mL, were treated with lamivudine (n = 34) and entecavir (n = 85). The 5-year rates of post-treatment virological relapse, clinical relapse, and HBsAg loss at 60 months were 39.4%, 27.6%, and 45.9%, respectively. Cox regression analysis revealed that HBV DNA at entry and end-of-treatment HBsAg levels were independent predictors of virolgical and clinical relapse. HBV genotype C and end-of-treatment HBsAg were independent factors of HBsAg loss. Patients with a combination of end-of-treatment HBsAg < 50 IU/mL and HBV DNA < 2 × 105 IU/mL at entry experienced the lowest virological and clinical relapse rates (5% and 0% at 60 months, respectively). In contract, patients with a combination of end-of-treatment HBsAg ≥ 50 IU/mL and HBV DNA ≥ 2 × 105 IU/mL at entry experienced high virological and clinical relapse (80.7% and 71.5% at 60 months, respectively). No patients experienced hepatic decompensation when clinical relapse occurred after timely retreatment. A combination of HBV DNA levels at entry and end-of-treatment HBsAg levels was useful for predicting the post-treatment HBV relapse in HBeAg-negative patients with HBsAg ≤ 200 IU/mL.
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Cao J, Chi H, Yu T, Li Z, Hansen BE, Zhang X, Zhong C, Sun J, Hou J, Janssen HLA, Peng J. Off-Treatment Hepatitis B Virus (HBV) DNA Levels and the Prediction of Relapse After Discontinuation of Nucleos(t)ide Analogue Therapy in Patients With Chronic Hepatitis B: A Prospective Stop Study. J Infect Dis 2017; 215:581-589. [PMID: 28329347 DOI: 10.1093/infdis/jix025] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2016] [Accepted: 01/10/2017] [Indexed: 12/26/2022] Open
Abstract
Background The optimal management remains unknown after nucleos(t)ide analogue (NA) discontinuation in patients with chronic hepatitis B (CHB). This prospective study investigated the role of off-treatment viral kinetics in predicting relapse after discontinuation of NA therapy. Methods A total of 82 noncirrhotic Asian patients with CHB who discontinued NA therapy according to international guidelines were prospectively followed. Patients with a hepatitis B virus (HBV) DNA level of >2000 IU/mL and an alanine aminotransferase (ALT) level of >2 times the upper limit of normal (clinical relapse) were retreated. Results Sixty patients were HBV envelope antigen (HBeAg) positive at the start of treatment, and 22 were HBeAg negative. Clinical relapse developed in 28 patients (2-year rates, 31% among HBeAg-positive patients and 53% among HBeAg-negative patients). Age of ≤35 years (hazard ratio [HR], 0.37; P = .026) and end-of-treatment HBsAg level of ≤200 IU/mL (HR, 0.39; P = .078) were independently associated with lower relapse rates. A high risk of biochemical relapse (defined as an ALT level of >2 times the upper limit of normal) was observed if the HBV DNA level was >200000 IU/mL when the level was initially elevated, compared with HBV DNA levels of >2000 to ≤200000 IU/mL (HR, 8.42; P < .001). The risk of biochemical relapse was also high in patients with persistent elevation in the HBV DNA level (confirmed to be >2000 IU/mL within 3 months), compared with the group with transient elevation (HR, 6.87; P < .001). Conclusions After NA discontinuation, a lower relapse rate was observed in younger patients and in those with low end-of-treatment HBsAg levels. The level and persistence of off-treatment elevated HBV DNA levels were useful in the prediction of a subsequent biochemical relapse and may thus be used to guide off-treatment management.
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Affiliation(s)
- Jiawei Cao
- Department of Infectious Diseases, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Heng Chi
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, The Netherlands
| | - Tao Yu
- Department of Infectious Diseases, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhandong Li
- Department of Infectious Diseases, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bettina E Hansen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, The Netherlands
| | - Xiaoyong Zhang
- Department of Infectious Diseases, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chunxiu Zhong
- Department of Infectious Diseases, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Sun
- Department of Infectious Diseases, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- Department of Infectious Diseases, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Harry L A Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, The Netherlands.,Toronto Centre of Liver Disease, University Health Network, Toronto General Hospital, University of Toronto, Canada
| | - Jie Peng
- Department of Infectious Diseases, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Karakaya F, Özer S, Kalkan Ç, Tüzün EA, Çalışkan A, Keskin O, Kabaçam G, Karatayli S, Karatayli E, Bozdayi AM, Idilman R, Yurdaydin C. Discontinuation of lamivudine treatment in HBeAg-negative chronic hepatitis B: a pilot study with long-term follow-up. Antivir Ther 2017; 22:559-570. [PMID: 28240596 DOI: 10.3851/imp3144] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/30/2017] [Indexed: 10/20/2022]
Abstract
BACKGROUND Finite treatment of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) with nucleoside/nucleotide analogues (NAs) is important in resource-limited countries. Outcome of treatment discontinuation in patients on long-term lamivudine (LVD) was assessed in a single centre observational pilot study in the current study. METHODS Non-cirrhotic patients on LVD for at least 5 years with undetectable HBV DNA on at least two consecutive assessments were offered to stop treatment. Biochemical, serological and virological measures were determined at 3-6 month intervals after treatment discontinuation. Serum quantitative hepatitis B surface antigen (HBsAg) was determined at treatment discontinuation and 5-6 years thereafter. NA treatment was re-instituted in patients with confirmed viral rebound defined as HBV DNA >20,000 IU/ml. Relapser patients were no longer followed but were re-assessed 6 years after treatment cessation. RESULTS LVD was discontinued in 23 patients. 8 patients relapsed within 1 year and NA treatment was restarted; 15 patients (65%) were non-relapsers. Thirteen of them were followed for at least 5 years. Two patients had undetectable HBV DNA throughout the follow-up period. In the rest, HBV DNA fluctuated at low levels. Two patients cleared HBsAg 24 and 36 months after stopping treatment. Quantitative HBsAg levels 5-7 years after treatment discontinuation were lower in non-relapser compared to relapser patients (1.21 IU/ml ±0.98 versus 2.71 ±0.76; P=0.002). Of 8 relapser patients 1 patient had HBsAg levels less than 100 IU/ml compared to 11 out of 13 non-relapser patients (P=0.0022). CONCLUSIONS These data suggest that cessation of NA treatment is a viable option after a reasonable treatment duration in patients with HBeAg-negative CHB and that HBsAg clearance may become an achievable target in these patients.
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Affiliation(s)
- Fatih Karakaya
- Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey
| | - Sevil Özer
- Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey
| | - Çağdaş Kalkan
- Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey
| | - E Ali Tüzün
- Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey
| | - Aysun Çalışkan
- Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey
| | - Onur Keskin
- Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey
| | - Gökhan Kabaçam
- Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey
| | | | | | | | - Ramazan Idilman
- Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey
- Hepatology Institute, University of Ankara, Ankara, Turkey
| | - Cihan Yurdaydin
- Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey
- Hepatology Institute, University of Ankara, Ankara, Turkey
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Early hepatitis B surface antigen decline predicts treatment response to entecavir in patients with chronic hepatitis B. Sci Rep 2017; 7:42879. [PMID: 28220833 PMCID: PMC5318891 DOI: 10.1038/srep42879] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 01/16/2017] [Indexed: 02/06/2023] Open
Abstract
Early declines in serum hepatitis B surface (HBsAg) levels, their optimal cutoffs, and association with therapeutic endpoints in chronic hepatitis B (CHB) patients receiving entecavir treatment remain unclear. We prospectively enrolled 529 patients (195 hepatitis B e antigen [HBeAg]-positive and 334 HBeAg-negative) with a median treatment duration of 49.2 months. Median HBsAg levels declined significantly in both groups at Month 3, but only at Months 6–12 in the HBeAg-negative group. Both groups exhibited a significant HBsAg decline with each successive year of treatment. An HBsAg decline of ≥75% from baseline, assessed at Months 3 and 12 of treatment in the HBeAg-positive and -negative patients, respectively, independently predicted a virological response and HBeAg seroconversion in the HBeAg-positive patients, an HBsAg level of <100 IU/mL in the HBeAg-negative patients, and HBsAg loss in all the patients during treatment. HBsAg levels of <3,000 IU/mL at baseline combined with an HBsAg decline of ≥75% from baseline provided a predictive algorithm for HBsAg loss (positive and negative predictive values: 70% and 100%, respectively) during 5 years of treatment. The proposed cutoffs for defining an HBsAg decline may assist clinicians in early assessments of treatment responses in genotype B-infected or C-infected CHB patients receiving entecavir therapy.
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