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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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Tseng CH, Lee TY, Chen CY, Huang CF, Chen PY, Jang TY, Yang TH, Wu CC, Hsu YC. Incidences of Virological and Clinical Relapses After Cessation of Tenofovir Alafenamide, Tenofovir Disoproxil Fumarate, or Entecavir in Patients With HBeAg-Negative Chronic Hepatitis B. J Gastroenterol Hepatol 2025; 40:1245-1254. [PMID: 40032276 DOI: 10.1111/jgh.16923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/30/2025] [Accepted: 02/14/2025] [Indexed: 03/05/2025]
Abstract
BACKGROUND AND AIM The relapse pattern following the discontinuation of tenofovir alafenamide (TAF) in patients with chronic hepatitis B (CHB) remains unclear. This study aimed to compare the 2-year incidences of virological and clinical relapses among patients who discontinued TAF versus those who discontinued tenofovir disoproxil fumarate (TDF) or entecavir (ETV). METHODS This multicenter retrospective study enrolled noncirrhotic hepatitis B e antigen (HBeAg)-negative CHB patients who discontinued TAF, TDF, or ETV with undetectable HBV DNA at treatment cessation. For patients who switched from ETV or TDF to TAF, a minimum TAF exposure duration of 12 months was required for inclusion in the off-TAF group. Inverse probability of treatment weighting was employed to adjust for baseline differences. RESULTS A total of 162 patients (off-TAF: 37, off-TDF: 87, off-ETV: 38) were included in the primary analysis. The 2-year cumulative incidence of virological relapse was significantly higher in the off-TAF group (85.0%) compared to the off-TDF group (69.5%, p = 0.024) and the off-ETV group (51.5%, p = 0.010). Similarly, the 2-year cumulative incidence of clinical relapse was significantly higher in the off-TAF group (62.4%) compared to the off-TDF group (39.0%, p = 0.026) and the off-ETV group (22.5%, p = 0.024). Consistent results were observed in patients meeting the 2012 APASL stopping criteria. CONCLUSIONS HBeAg-negative patients who discontinue TAF face a higher risk of both virological and clinical relapses compared to those discontinuing TDF or ETV. These findings underscore the need for more intense monitoring in CHB patients after TAF cessation.
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Affiliation(s)
- Cheng-Hao Tseng
- Division of Gastroenterology and Hepatology, E-DA Cancer Hospital, Kaohsiung, Taiwan
- Division of Gastroenterology and Hepatology, E-DA Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Teng-Yu Lee
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Chi-Yi Chen
- Division of Gastroenterology and Hepatology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Po-Yueh Chen
- Division of Gastroenterology and Hepatology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan
| | - Tyng-Yuan Jang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tzeng-Huey Yang
- Department of Internal Medicine, Lotung Poh-Ai Hospital, Yilan, Taiwan
| | - Chia-Ching Wu
- Graduate Institute of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, E-DA Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, I-Shou University, Kaohsiung, Taiwan
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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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Fang HW, Jeng WJ, Hu TH, Wang JH, Hung CH, Lu SN, Chen CH. Higher Relapse Rate in HBeAg-Negative Patients After Cessation of Tenofovir Alafenamide Compared With Entecavir or Tenofovir Disoproxil Fumarate. Am J Gastroenterol 2025:00000434-990000000-01557. [PMID: 39820130 DOI: 10.14309/ajg.0000000000003324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 11/20/2024] [Indexed: 01/19/2025]
Abstract
INTRODUCTION There is limited information comparing the off-therapy relapse rates of patients discontinued tenofovir alafenamide (TAF) to those stopping entecavir or tenofovir disoproxil fumarate (TDF). METHODS A total of 805 hepatitis B e antigen-negative patients without cirrhosis receiving entecavir (n = 406), TDF (n = 260), or TAF (n = 139) were enrolled. Propensity score matching method was applied to eliminate the significant differences in clinical characteristics. RESULTS The cumulative incidences of virological relapse, clinical relapse, and retreatment at 96 weeks were higher in the off-TAF group (89.6%, 70.3%, and 59.2%, respectively) than that in the off-entecavir group (65.9%, 42.8%, and 28.8%, respectively) or the off-TDF group (73.7%, 49.8%, and 35.7%, respectively). The median time to clinical relapse was much earlier for off-TAF patients than for off-entecavir or off-TDF (median 14, 57, and 26 weeks, respectively), and these findings persisted even after propensity score matching. Multivariate analysis indicated that TAF therapy was an independent risk factor of virological relapse, clinical relapse, and retreatment when compared with entecavir or TDF. Hepatitis B surface antigen levels at end of treatment were predictive of virological, but not clinical, relapse in the off-TAF group, although this group had a lower rate of severe hepatitis on clinical relapse than the off-TDF group. Finally, there was no significant difference in the hepatic decompensation rate among the entecavir, TDF, and TAF groups. DISCUSSION There is an earlier and higher hepatitis B virus relapse rate in patients who discontinue TAF therapy than in comparable patients discontinuing entecavir or TDF therapy. Close monitoring is necessary after TAF withdrawal, particularly in the first 3 months.
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Affiliation(s)
- Hsin-Wei Fang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Chang Gung University College of Medicine, Taoyuan City, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Chu YD, Hsu CW, Ho PH, Chiou CY, Lin CL, Liang KH, Lai MW, Yeh CT. Evolution of hepatitis B virus polymerase and surface genes in patients receiving finite antiviral therapy. J Gastroenterol Hepatol 2025; 40:265-273. [PMID: 39500510 DOI: 10.1111/jgh.16791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 10/15/2024] [Accepted: 10/20/2024] [Indexed: 01/02/2025]
Abstract
BACKGROUND AND AIM Hepatitis B virus (HBV) reactivation could develop after withdrawal following a finite course of nucleoside analog (NA) therapy, leading to virological and clinical relapses. The genetic heterogeneity in the HBV surface and polymerase genes during finite NA therapy has not been carefully studied. METHODS Seven chronic HBV-infected patients experiencing relapses following entecavir (ETV; n = 5; Patients 1 to 5) or tenofovir disoproxil fumarate (TDF; n = 2; Patients 6 and 7) withdrawal were included. Sera obtained before treatment and at relapses were retrieved and submitted for DNA extraction and amplicon-specific deep sequencing. RESULTS ETV-treated patients had a longer time-to-relapse than that of TDF-treated patients (P = 0.0357). No drug-resistance related polymerase mutation was detected during relapses, except for a low percentage (1.4%) of rtM204I mutation in Patient 1. Two surface truncation mutations (sW216*; 40.9% and sW182*; 4.7%) detected before treatment in two TDF-treated patients (Patients 6 and 7, respectively) were overtaken by the wild types during subsequent drug-withdrawal-related relapses. The simultaneous presence of sG44E (T-cell epitope) and sE164G (B-cell epitope) mutations was associated with failure of HBV e antigen (HBeAg) seroclearance in ETV-treated patients. CONCLUSIONS In conclusion, HBV genome continues to evolve during the courses of finite antiviral therapies. Pre-existing surface truncation mutations can be overtaken by the wild types after relapses. The sG44E/sE164G mutations are associated with failure of HBeAg seroclearance.
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Affiliation(s)
- Yu-De Chu
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
| | - Chao-Wei Hsu
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Department of Hepatology and Gastroenterology, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
| | - Pei-Huan Ho
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Department of Hepatology and Gastroenterology, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
| | - Chih-Yung Chiou
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
| | - Chih-Lang Lin
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Liver Research Unit and Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Kung-Hao Liang
- Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Wei Lai
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Department of Pediatrics, Division of Pediatric Gastroenterology, Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Department of Hepatology and Gastroenterology, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Institute of Stem Cell and Translational Cancer Research, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
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Wang CW, Huang CF, Yeh ML, Liang PC, Jang TY, Wei YJ, Hsu PY, Hsieh MY, Lin YH, Huang JF, Dai CY, Chuang WL, Yu ML. Assessment of hepatitis B virus relapse in cancer patients receiving chemotherapy with prophylactic nucleos(t)ide analogues: Implications for overall mortality. Liver Int 2024; 44:2592-2604. [PMID: 38984849 DOI: 10.1111/liv.16030] [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: 02/16/2024] [Revised: 05/24/2024] [Accepted: 06/26/2024] [Indexed: 07/11/2024]
Abstract
BACKGROUND AND AIMS We aimed to explore the risk factors associated with virological and clinical relapse, as well as their impact on overall mortality, in hepatitis B virus (HBV)-infected patients receiving nucleos(t)ide analogues (NUCs) therapy prior to chemotherapy initiation. METHODS From 2010 to 2020, we conducted a prospective cohort study involving patients with HBV infection undergoing cytotoxic chemotherapy. We utilized the Kaplan-Meier method and Cox proportional hazard regression models to assess risk factors. RESULTS We observed that TDF or TAF (HR: 2.16, 95% CI 1.06-4.41; p = .034), anthracycline (HR: 1.73, 95% CI 1.10-2.73; p = .018), baseline HBV DNA (HR: 1.55, 95% CI 1.33-1.81; p < .001) and end-of-treatment HBsAg titre >100 IU/mL (HR: 7.81, 95% CI 1.94-31.51; p = .004) were associated with increased risk of virological relapse. Additionally, TDF or TAF (HR: 4.91, 95% CI 1.45-16.64; p = .011), baseline HBV DNA (HR: 1.48, 95% CI 1.10-1.99; p = .009) and end-of-treatment HBsAg titre >100 IU/mL (HR: 6.09, 95% CI .95-38.87; p = .056) were associated with increased risk of clinical relapse. Furthermore, we found that virological relapse (HR: 3.32, 95% CI 1.33-8.32; p = .010) and clinical relapse (HR: 3.59, 95% CI 1.47-8.80; p = .005) significantly correlated with all-cause mortality in HBV patients receiving cytotoxic chemotherapy with prophylactic NUCs therapy. CONCLUSIONS The risk of virological and clinical relapse was linked to baseline HBV DNA, end-of-treatment HBsAg levels and TDF or TAF for prophylaxis; additionally, experiencing relapse heightens the risk of all-cause mortality. Further research is warranted to explore potential strategies for preventing virological and clinical relapse in high-risk patients.
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Affiliation(s)
- Chih-Wen Wang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Po-Cheng Liang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tyng-Yuan Jang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yu-Ju Wei
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Po-Yao Hsu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Yen Hsieh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Hung Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan
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Tseng TC, Cheng HR, Su TH, Lin PH, Wang CC, Yang HC, Tsai CS, Liu CJ, Chen PJ, Kao JH. Higher hepatitis B core-specific T cell response is associated with a lower risk of clinical relapse after discontinuation of oral antiviral treatment. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2024; 57:700-708. [PMID: 39153879 DOI: 10.1016/j.jmii.2024.07.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 07/21/2024] [Accepted: 07/25/2024] [Indexed: 08/19/2024]
Abstract
BACKGROUND Hepatitis B virus (HBV)-specific T cell response is a major host immune response to control the virus. However, it is still unclear how it affects long-term outcomes of chronic hepatitis B patients, especially those who stop nucleos(t)ide analogue (NA) therapy. We aimed to explore whether the HBV-specific T cell response at the end of treatment (EOT) was associated with clinical outcomes. METHODS In a prospective cohort study, 51 HBeAg-negative patients who discontinued NA therapy were enrolled. RESULTS In a mean follow-up of 25.3 months, 25 patients developed clinical relapse. We found that a stronger hepatitis B core (HBc)-specific T cell response at EOT was associated with a lower risk of clinical relapse. Compared to the low-response group, the high-response group had a lower risk of clinical relapse with hazard ratio of 0.21 (95% CI: 0.05-0.88). The high HBc-specific T cell response was associated with reduced surge of HBV DNA and HBcrAg during the first year of follow-up. The T cell response at EOT was comparable between different NA treatments. Notably, the overall HBV-specific T cell response could be partially restored along with clinical relapse; however, such reinvigorated T cell response was not associated with HBsAg seroclearance. CONCLUSIONS A higher HBc-specific T cell response at EOT was associated with lower risk of clinical relapse and reduced surge of HBV DNA and HBcrAg levels off NA therapy.
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Affiliation(s)
- Tai-Chung Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Huei-Ru Cheng
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Ping-Hung Lin
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chih-Chiang Wang
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-Chih Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Cheng-Shiue Tsai
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
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Korkmaz P, Demirtürk N. Discontinuation of Nucleos(t)ide Analogues in HBeAg Negative Chronic Hepatitis B Patients: Risks and Benefits. INFECTIOUS DISEASES & CLINICAL MICROBIOLOGY 2024; 6:70-77. [PMID: 39005698 PMCID: PMC11243777 DOI: 10.36519/idcm.2024.339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 06/11/2024] [Indexed: 07/16/2024]
Abstract
Chronic hepatitis B (CHB) remains a major threat to global public health, affecting 296 million people worldwide. Although there is no curative treatment for CHB today, the virus can be effectively controlled with current antiviral treatment strategies. Since HBsAg loss can rarely (1%) be achieved with current nucleos(t)ide analogues (NA) options, lifelong treatment is usually required in HBeAg-negative patients. In recent years, guidelines have stated that long-term NA treatments can be discontinued for HBeAg-negative patients without achieving HBsAg loss. There is no general consensus on how discontinuation of NA can be included in the treatment approach. This review aimed to evaluate the current literature regarding the discontinuation of NA treatment in HBeAg-negative patients. Patients with HBeAg-negative CHB who have a higher chance of response after discontinuation of NA therapy can be defined as non-cirrhotic patients who have low HBsAg, HBcrAg, and HBV RNA levels at the discontinuation of treatment and accept close follow-up. The management of relapses that develop after NA discontinuation in patients is also unclear. The agent used in NA treatment itself may also affect the pattern of relapse development. Relapse after NA treatment occurs significantly slower and less frequently with entecavir compared to other regimens, including tenofovir dipivoxil. Prospective studies are needed in order to maintain the chance of HBsAg clearance in case of exacerbation and to treat acute exacerbations that can be fatal in a timely manner. Algorithms to be developed for use after discontinuation of NA treatment will help the clinician manage the patient safely.
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Affiliation(s)
- Pınar Korkmaz
- Department of Infectious Diseases and Clinical Microbiology, Kütahya Health Sciences University School of Medicine, Kütahya, Türkiye
| | - Neşe Demirtürk
- Department of Infectious Diseases and Clinical Microbiology, Afyonkarahisar Health Sciences University School of Medicine, Afyonkarahisar, Türkiye
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Fang HW, Tseng PL, Hu TH, Wang JH, Hung CH, Lu SN, Chen CH. Hepatitis B relapse after entecavir or tenofovir alafenamide cessation under anti-viral prophylaxis for cancer chemotherapy. Virol J 2024; 21:79. [PMID: 38570803 PMCID: PMC10993446 DOI: 10.1186/s12985-024-02338-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 03/08/2024] [Indexed: 04/05/2024] Open
Abstract
BACKGROUND No study has comparing hepatitis B virus (HBV) relapse rates among patients with both cancer and hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) who completed anti-viral prophylaxis for chemotherapy and then stopped taking entecavir or tenofovir alafenamide (TAF). METHODS A total of 227 HBeAg-negative cancer patients without cirrhosis who previously took entecavir (n = 144) or TAF (n = 83) for antiviral prophylaxis were enrolled. RESULTS The cumulative incidence of virological and clinical relapse at 2 years was 37% and 10.4%, respectively, in the entecavir group, and 46.7% and 19.5%, respectively, in the TAF group. The multivariate analysis revealed that the use of hematologic malignancy, TAF use, and high-viremia group at baseline were independent risk factors for virological relapse, and use of rituximab, TAF use, higher FIB-4 index and high-viremia group at baseline were independent risk factors for clinical relapse. After propensity score-matching, the patients who discontinued TAF therapy still exhibited higher virological (P = 0.031) and clinical relapse rates (P = 0.012) than did those who discontinued entecavir therapy. The patients were allocated to high- (> 2000 IU/mL), moderate- (between 20 and 2000 IU/mL) and low- (< 20 IU/mL) viremia groups. In the high-viremia group, those who had taken TAF for antiviral prophylaxis had higher rates of virological and clinical relapse than did those who had taken entecavir; in the moderate- and low-viremia groups, no significant difference in virological and clinical relapse rates was detected between the entecavir and TAF groups. Three patients experienced hepatic decompensation upon clinical relapse. All three patients were lymphoma and underwent rituximab therapy. One patient developed acute on chronic liver failure and died even though timely retreatment. CONCLUSIONS In patients with both cancer and CHB who underwent antiviral prophylaxis, TAF use was associated with a higher chance of HBV relapse than entecavir use after nucleos(t)ide analogue cessation, particularly in the high-viremia group. Patients who are hematologic malignancy and undergo a rituximab-containing cytotoxic therapy should be monitored closely after withdrawal from prophylactic NA treatment.
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Affiliation(s)
- Hsin-Wei Fang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Po-Lin Tseng
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan.
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Arslan E, Yildiz Y, Karaşahin Ö, Demir Y, Tümbül Mermutluoğlu Ç, Ünlü G, Kuşçu F, Kaya Ş, Akgül F, Damar Çakirca T, Yilmaz Karadağ F, Altunişik Toplu S, Nazik S, Akdemir İ, Özer Balin Ş, Kandemir FÖ, İnan D, Bayindir Y, Taşova Y, Çelen MK. Evaluation of chronic hepatitis B patients who voluntarily discontinued oral antiviral therapy: is there an answer to the controversial topic? Eur J Gastroenterol Hepatol 2024; 36:438-444. [PMID: 38407855 DOI: 10.1097/meg.0000000000002722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/27/2024]
Abstract
OBJECTIVE The uncertain treatment duration for nucleos(t)ide analogues (NA) used in the treatment of chronic hepatitis B (CHB) is an important problem for both patients and physicians. The aim of this study was to evaluate the determinants of virologic relapse (VR) and the optimum time of treatment discontinuation in the follow-up of CHB patients who voluntarily discontinued treatment after virological suppression was achieved under NA use. METHODS Data from 138 patients from 11 centers were included in this registry-based study. Factors associated with VR were investigated using multivariate Cox regression analysis. RESULTS Ninety-nine (71.7%) of the patients were HBeAg (Hepatitis B e antigen) negative. During the 24-month follow-up period after treatment discontinuation, VR occurred in 58.7% (n = 81) of all patients and 57.6% (n = 57) of HBeAg-negative patients. The duration of NA treatment was significantly shorter (cutoff 60 months) in HBeAg-negative patients who later developed VR. In addition, the duration of virologic remission achieved under NA treatment was significantly shorter (cutoff 52 months) in those who later developed VR. In the Cox multivariate regression model of HBeAg-negative patients, having less than 60 months of NA treatment (HR = 2.568; CI:1.280-5.148; P = 0.008) and the levels of alanine aminotransferase being equal to or higher than twice the upper level of normal at the beginning of treatment (HR = 3.753; CI:1.551-9.081; P = 0.003) were found to be statistically significant and independently associated with VR. CONCLUSION The findings of this study may provide clinical guidance in terms of determining the most appropriate discontinuation time for NA.
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Affiliation(s)
- Eyüp Arslan
- Department of Infectious Diseases and Clinical Microbiology, Sancaktepe Şehit Prof. Dr. İlhan Varank Training and Research Hospital, İstanbul
| | - Yeşim Yildiz
- Department of Infectious Diseases and Clinical Microbiology, Gazi University Faculty of Medicine, Ankara
| | - Ömer Karaşahin
- Department of Infectious Diseases and Clinical Microbiology, Erzurum Regional Training and Research Hospital, Erzurum
| | - Yakup Demir
- Department of Infectious Diseases and Clinical Microbiology, Dicle University Faculty of Medicine, Diyarbakir
| | - Çiğdem Tümbül Mermutluoğlu
- Department of Infectious Diseases and Clinical Microbiology, Dicle University Faculty of Medicine, Diyarbakir
| | - Gülten Ünlü
- Department of Infectious Diseases and Clinical Microbiology, Derince Training and Research Hospital, Kocaeli
| | - Ferit Kuşçu
- Department of Infectious Diseases and Clinical Microbiology, Çukurova University Faculty of Medicine, Adana
| | - Şafak Kaya
- Department of Infectious Diseases and Clinical Microbiology, Gazi Yasargil Training and Research Hospital, Diyarbakir
| | - Fethiye Akgül
- Department of Infectious Diseases and Clinical Microbiology, Batman Regional State Hospital, Batman, Turkey
| | - Tuba Damar Çakirca
- Department of Infectious Diseases and Clinical Microbiology, Şanliurfa Training and Research Hospital, Şanliurfa
| | - Fatma Yilmaz Karadağ
- Department of Infectious Diseases and Clinical Microbiology, Sancaktepe Şehit Prof. Dr. İlhan Varank Training and Research Hospital, İstanbul
| | - Sibel Altunişik Toplu
- Department of Infectious Diseases and Clinical Microbiology, Inonu University Faculty of Medicine, Malatya
| | - Selçuk Nazik
- Department of Infectious Diseases and Clinical Microbiology, Sütçü İmam University Faculty of Medicine, Kahramanmaraş
| | - İrem Akdemir
- Department of Infectious Diseases and Clinical Microbiology, Ankara University Faculty of Medicine, Ankara
| | - Şafak Özer Balin
- Department of Infectious Diseases and Clinical Microbiology, Fırat University Faculty of Medicine, Elazığ
| | - Fatma Özlem Kandemir
- Department of Infectious Diseases and Clinical Microbiology, Mersin University Faculty of Medicine, Mersin
| | - Dilara İnan
- Department of Infectious Diseases and Clinical Microbiology, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Yaşar Bayindir
- Department of Infectious Diseases and Clinical Microbiology, Inonu University Faculty of Medicine, Malatya
| | - Yeşim Taşova
- Department of Infectious Diseases and Clinical Microbiology, Çukurova University Faculty of Medicine, Adana
| | - Mustafa Kemal Çelen
- Department of Infectious Diseases and Clinical Microbiology, Dicle University Faculty of Medicine, Diyarbakir
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Wang YH, Tang H, Chen EQ. Quantitative Measurement of Serum HBcrAg Can Be Used to Assess the Feasibility of Safe Discontinuation of Antiviral Therapy for Chronic Hepatitis B. Viruses 2024; 16:529. [PMID: 38675872 PMCID: PMC11055047 DOI: 10.3390/v16040529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/19/2024] [Accepted: 03/22/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatitis B virus (HBV) infection is a serious global health problem, and chronic HBV infection significantly increases the risk of liver fibrosis, cirrhosis, and even hepatocellular carcinoma in patients. Current first-line therapeutics such as nucleos(t)ide analogues and interferons are unable to completely clear cccDNA, so the vast majority of patients need to take long-term or even lifelong medication. However, long-term virological and biochemical responses can be achieved in some patients after drug withdrawal. Successfully screening these patients with drug withdrawal advantages is difficult. Hepatitis-B-core-related antigen (HBcrAg) is a new HBV serological marker that which can reflect the level and transcription activity of cccDNA in hepatocytes. Therefore, HBcrAg has potential value in guiding patients in drug withdrawal. This review summarizes previous reports on HBcrAg and evaluates the application value of HBcrAg in safe drug discontinuation.
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Affiliation(s)
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China;
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China;
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12
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Tsai YN, Wu JL, Hsu YC. Letter: Estimating the incidence of HBsAg seroclearance after cessation of tenofovir and entecavir - potential influence of censored observation. Aliment Pharmacol Ther 2024; 59:136-137. [PMID: 38085940 DOI: 10.1111/apt.17767] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
LINKED CONTENTThis article is linked to Chen et al papers. To view these articles, visit https://doi.org/10.1111/apt.17602 and https://doi.org/10.1111/apt.17788
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Affiliation(s)
- Ying-Nan Tsai
- Division of Gastroenterology and Hepatology, E-Da Cancer Hospital, I-Shou University, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Jia-Ling Wu
- Department of Public Health, National Cheng Kung University, College of Medicine, Tainan, Taiwan
| | - Yao-Chun Hsu
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Division of Gastroenterology and Hepatology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
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Kumar K, Jindal A, Gupta E, Trehanpati N, Shasthry SM, Maiwall R, Arora V, Bhardwaj A, Kumar G, Kumar M, Sarin SK. Long Term HBsAg Responses to Peg-Interferon Alpha-2b in HBeAg Negative Chronic Hepatitis B Patients Developing Clinical Relapse after Stopping Long-Term Nucleos(t)ide Analogue Therapy. J Clin Exp Hepatol 2024; 14:101272. [PMID: 38076362 PMCID: PMC10709173 DOI: 10.1016/j.jceh.2023.08.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 08/17/2023] [Indexed: 09/23/2024] Open
Abstract
Background and aims A high proportion of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients develop clinical relapse after stopping long-term nucleotide analogues (NAs). The aim of this study was to assess the efficacy of pegylated interferon (PEG-IFN) alpha 2b in inducing hepatitis B surface antigen (HBsAg) loss in such patients. Methods NAs were stopped in 118 HBeAg-negative CHB patients fulfilling the Asian Pacific Association for the Study of Liver (APASL) 2015 criteria for stopping NAs; they had received NAs for a median interquartile range (IQR) of 60 (48-84) months. Results Overall, 82 of 118 (69.5%) patients developed clinical relapse after stopping NAs; 44 within 12 months (and treated with PEG-IFN alpha 2b 1.5 mcg/kg weekly subcutaneous injections for 48 weeks); and 38 after 12 months [and treated with tenofovir alafenamide fumarate (TAF) 25 mg daily] of follow-up. The decision to treat with either PEG-IFN or TAF was not a time-bound decision but was due to logistical problems.During the median IQR follow-up of 48 (43.5-52.5) months after the start of PEG-IFN, 14 of 44 (31.8%) patients developed clinical relapse after stopping PEG-IFN and were started on TAF. At the last follow-up visit, HBsAg was found to be negative in 7/44 (15.9%) of patients receiving PEG-IFN.Among 38 patients treated with TAF for clinical relapse, during the median IQR follow-up of 18 (12-30) months after start of TAF, no patient became HBsAg negative.36 patients did not develop clinical relapse during the follow-up, and after a median IQR follow-up of 60 (60-60) months after stopping NAs, HBsAg negative was found in 1/36 (2.8%) of patient at the last follow-up. Conclusions Among patients with HBeAg-negative chronic hepatitis B who developed clinical relapse after stopping long-term NAs therapy and were subsequently treated with PEG-IFN alpha 2b, 15.9% achieved HBsAg loss on long-term follow-up.
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Affiliation(s)
- Karan Kumar
- Department of Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ankur Jindal
- Department of Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ekta Gupta
- Department of Virology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Nirupma Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Saggere M. Shasthry
- Department of Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rakhi Maiwall
- Department of Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vinod Arora
- Department of Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ankit Bhardwaj
- Department of Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Guresh Kumar
- Department of Biostatistics, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Manoj Kumar
- Department of Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv K. Sarin
- Department of Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
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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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Chen YC, Hsu CW, Chien RN. Higher HBeAg-reversion virological relapse and lower sustained remission after treatment cessation in tenofovir-treated HBeAg-positive patients. J Med Virol 2023; 95:e29213. [PMID: 37933418 DOI: 10.1002/jmv.29213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 10/15/2023] [Accepted: 10/21/2023] [Indexed: 11/08/2023]
Abstract
A complete investigation of the clinical outcomes after treatment cessation in HBeAg-positive patients with HBeAg loss is limited. We retrospectively recruited 242 HBeAg-positive patients with HBeAg loss after a median duration of 37.2 months with tenofovir (TDF, n = 77) or entecavir (ETV, n = 165) treatment. There were 77 (31.8%) patients with sustained virological remission (SVR), 85 (35.1%) with HBeAg-reversion virological relapse, 80 (33.1%) with HBeAg-negative virological relapse after treatment cessation, and 23 (9.5%) with HBsAg loss. Clinical data at baseline, on-treatment and during off-treatment follow-up were analyzed. The 3-year cumulative incidences of overall, HBeAg-reversion and HBeAg-negative virological relapse were 70.2%, 54%, and 53.5%, respectively. The common factors associated with HBeAg-reversion and HBeAg-negative virological relapse were tenofovir treatment (hazard ratio [HR] = 5.411, p < 0.001; HR = 2.066, p = 0.006, respectively) and HBsAg at end of treatment (EOT) (HR = 1.461, p = 0.001; HR = 1.303, p = 0.019, respectively). The 5-year cumulative incidence of HBsAg loss in SVR patients was 13.7% and EOT HBsAg was the only associated factor (HR = 0.524, p = 0.024). Compared to that of ETV-treated patients, TDF-treated patients had a significantly higher 3-year cumulative incidence of virological relapse (87.3% vs. 62.8%, p < 0.001), earlier HBeAg-reversion virological relapse (2.9 vs. 7.8 months, p < 0.001), a higher rate of HBeAg-reversion virological relapse (53.2% vs. 26.7%) and a lower SVR rate (15.6% vs. 39.4%) (p < 0.001). In summary, the clinical outcomes after treatment cessation in HBeAg-positive patients with HBeAg loss were composed of HBeAg-reversion virological relapse, HBeAg-negative virological relapse and SVR. TDF was significantly associated with off-treatment virological relapse. EOT HBsAg plays an important role in HBsAg loss among SVR patients and posttreatment virological relapse.
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Affiliation(s)
- Yi-Cheng Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan City, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Chao-Wei Hsu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan City, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan City, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
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Hsu YC, Tseng CH, Kao JH. Safety considerations for withdrawal of nucleos(t)ide analogues in patients with chronic hepatitis B: First, do no harm. Clin Mol Hepatol 2023; 29:869-890. [PMID: 36916171 PMCID: PMC10577354 DOI: 10.3350/cmh.2022.0420] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 02/19/2023] [Accepted: 03/13/2023] [Indexed: 03/16/2023] Open
Abstract
Nucleos(t)ide analogues (NA) are widely used to treat hepatitis B virus (HBV) infection, but they cannot eradicate the virus and treatment duration can be lifelong if the endpoint is set at seroclearance of the hepatitis B surface antigen (HBsAg). As an alternative strategy, finite NA therapy without the prerequisite of HBsAg seroclearance has been proposed to allow treatment cessation in patients with sustained undetectable HBV viremia for two to three years. However, reactivation of viral replication almost always follows NA withdrawal. Whereas HBV reactivation might facilitate HBsAg seroclearance in some, it could lead to serious acute flare-ups in a certain proportion of patients. Occurrence and consequences of NA withdrawal flares are complicated with various factors involving the virus, host, and treatment. Accurate risk prediction for severe flares following NA cessation is essential to ensure patient safety. The risks of life-threatening flares in patients who discontinued NA according to the stopping rules of current guidelines or local reimbursement policies have recently been quantitatively estimated in large-scale studies, which also provided empirical evidence to help identify vulnerable patients at risk of devastating outcomes. Moreover, risk predictors were further explored and validated to hopefully aid in patient selection and management. In this narrative review with a focus on patient safety, we summarize and discuss current literature on the incidence of severe flares following NA cessation, risk stratification for candidate selection, rules of posttreatment monitoring, and indications for treatment resumption. We also share our thoughts on the limitations of existing knowledge and suggestions for future research.
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Affiliation(s)
- Yao-Chun Hsu
- Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan
- School of Medicine College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Department of Internal Medicine, Fu-Jen Catholic University Hospital, New Taipei, Taiwan
- Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan
| | - Cheng-Hao Tseng
- School of Medicine College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Division of Gastroenterology and Hepatology, E-Da Cancer Hospital, Kaohsiung, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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Chen CH, Peng CY, Hu TH, Wang JH, Hung CH, Lu SN. Higher rate of HBsAg loss after discontinuation of tenofovir than entecavir in patients with chronic hepatitis B. Aliment Pharmacol Ther 2023; 58:334-345. [PMID: 37265196 DOI: 10.1111/apt.17602] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 05/08/2023] [Accepted: 05/23/2023] [Indexed: 06/03/2023]
Abstract
BACKGROUND/AIMS To compare the rates of hepatitis B surface antigen (HBsAg) loss after discontinuation of entecavir versus tenofovir disoproxil fumarate (TDF) in patients with chronic hepatitis B (CHB) without cirrhosis. METHODS A total of 891 patients who received entecavir (n = 556) or TDF (n = 335) followed up post-treatment for at least 12 months were retrospectively assessed. A total of 677 patients who had continued entecavir or TDF therapy for at least 4 years were enrolled as the continued group. RESULTS Patients who discontinued TDF had higher rates of virological and clinical relapse and retreatment than patients who discontinued entecavir in both the HBeAg-positive and HBeAg-negative subgroups. In the entire discontinued cohort, the cumulative rates of HBsAg loss at 7 years were 22.6% and 35.4% in the entecavir and TDF groups respectively. Patients who discontinued TDF had significantly higher rates of HBsAg loss than patients who discontinued entecavir therapy in all (p = 0.019) and propensity score-matched (p = 0.015) patients, especially among the subgroups who achieved a sustained response (p < 0.001). Cox regression analysis revealed that TDF, longer treatment duration and lower HBsAg levels at end of treatment were independently associated with HBsAg loss in the entire discontinued group. The incidence of HBsAg loss was significantly higher in the discontinued group than in the continued group after propensity score matching (p < 0.001), including HBeAg-positive and HBeAg-negative patients. CONCLUSIONS Patients who discontinued TDF had significantly higher rates of HBsAg loss than patients who discontinued entecavir, especially among the subgroups without HBV relapse after cessation of therapy.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 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
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Broquetas T, Carrión JA. Past, present, and future of long-term treatment for hepatitis B virus. World J Gastroenterol 2023; 29:3964-3983. [PMID: 37476586 PMCID: PMC10354584 DOI: 10.3748/wjg.v29.i25.3964] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
The estimated world prevalence of hepatitis B virus (HBV) infection is 316 million. HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma (HCC) despite universal vaccination programs, and effective antiviral therapy. Long-term administration of nucleos(t)ide analogues (NA) has been the treatment of choice for chronic hepatitis B during the last decades. The NA has shown a good safety profile and high efficacy in controlling viral replication, improving histology, and decreasing the HCC incidence, decompensation, and mortality. However, the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment. The knowledge, in recent years, about the different phases of the viral cycle, and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches. Consequently, several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results. This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B, the present of NA treatment and withdrawal, and the future perspectives with combined molecules to achieve a functional cure.
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Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
- Universitat Pompeu Fabra, Facultat de Ciències de la Salut i de la Vida, Barcelona 08003, Spain
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Lin MJ, Su TH, Liu CJ, Yang HC, Chen CL, Liou JM, Tseng TC, Liu CH, Hong CM, Chen PJ, Kao JH. Serum cytokine profiles predict outcomes of chronic hepatitis B patients discontinuing entecavir or tenofovir therapy. J Formos Med Assoc 2023; 122:564-573. [PMID: 36872131 DOI: 10.1016/j.jfma.2023.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 02/07/2023] [Accepted: 02/10/2023] [Indexed: 03/06/2023] Open
Abstract
BACKGROUND/PURPOSE Distinct hepatitis relapse has been observed after discontinuing entecavir (ETV) or tenofovir disoproxil fumarate (TDF) therapy in chronic hepatitis B (CHB) patients. End-of-therapy (EOT) serum cytokines were compared and used for outcome prediction. METHODS A total of 80 non-cirrhotic CHB patients in a tertiary medical center in Taiwan who discontinued ETV (n = 51) or TDF (n = 29) therapy after fulfilling the APASL guidelines were prospectively enrolled. Serum cytokines were measured at EOT and 3rd month afterwards. Multivariable analysis was performed to predict virological relapse (VR, HBV DNA >2000 IU/mL), clinical relapse (CR, VR and alanine aminotransferase > 2-fold upper limit of normal) and hepatitis B surface antigen (HBsAg) seroclearance. RESULTS Compared with TDF group, ETV stoppers had greater interleukin 5 (IL-5), IL-12 p70, IL-13, IL-17 A and tumor necrosis factor alpha (TNF-alpha) (all P < 0.05) at EOT. Older age, TDF use, higher EOT HBsAg and IL-18 (Hazard ratio [HR], 1.01; 95% CI, 1.00-1.02) levels at EOT predicted VR, while older age, higher EOT HBsAg and IL-7 (HR, 1.25; 95% CI, 1.00-1.56) levels predicted CR. In TDF stoppers, higher IL-7 (HR, 1.29; 95% CI, 1.05-1.60) and IL-18 (HR, 1.02; 95% CI, 1.00-1.04) levels predicted VR, while IL-7 (HR, 1.34; 95% CI, 1.08-1.65) and interferon-gamma (IFN-gamma) (HR, 1.08; 95% CI, 1.02-1.14) levels predicted CR. A lower EOT HBsAg level was associated with HBsAg seroclearance. CONCLUSION Distinct cytokine profiles were observed after stopping ETV or TDF. Higher EOT IL-7, IL-18, and IFN-gamma could be probable predictors for VR and CR in patients discontinuing NA therapies.
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Affiliation(s)
- Meng-Ju Lin
- School of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hung-Chih Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jyh-Ming Liou
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Chung Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chen-Hua Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Ming Hong
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
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Hui RWH, Mak LY, Seto WK, Yuen MF, Fung J. Chronic hepatitis B: a scoping review on the guidelines for stopping nucleos(t)ide analogue therapy. Expert Rev Gastroenterol Hepatol 2023; 17:443-450. [PMID: 36972516 DOI: 10.1080/17474124.2023.2196405] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 03/24/2023] [Indexed: 03/29/2023]
Abstract
INTRODUCTION Nucleos(t)ide analogues (NAs) are effective in suppressing the replication of the hepatitis B virus. However, NAs cannot effectively induce hepatitis B surface antigen (HBsAg) seroclearance, which represents the optimal treatment endpoint in chronic hepatitis B (CHB). Hence, most CHB patients are advised for indefinite NA therapy, but recent data has supported the concept of finite NA therapy before HBsAg seroclearance. AREAS COVERED This article covered the latest evidence on stopping NAs in CHB, with a focused analysis on international guidelines. Articles were retrieved by a literature search on PubMed with the keywords 'chronic hepatitis B,' 'antiviral therapy,' 'nucleos(t)ide analogue,' 'cessation,' 'stopping', and 'finite.' Studies up till 1 December 2022 were included. EXPERT OPINION Finite NA therapy in CHB has the potential in enhancing HBsAg seroclearance, however it also carries rare but potentially severe risks. NA cessation before HBsAg seroclearance is only suitable for a highly selected group of patients, whereas the majority of CHB patients should be treated indefinitely or until HBsAg seroclearance. Current guidelines have provided recommendations on stopping NAs, but further research is required to optimize the monitoring and retreatment protocol after stopping NAs.
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Affiliation(s)
- Rex Wan-Hin Hui
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - James Fung
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
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Abstract
Hepatitis B virus (HBV) infection is a major public health problem, with an estimated 296 million people chronically infected and 820 000 deaths worldwide in 2019. Diagnosis of HBV infection requires serological testing for HBsAg and for acute infection additional testing for IgM hepatitis B core antibody (IgM anti-HBc, for the window period when neither HBsAg nor anti-HBs is detected). Assessment of HBV replication status to guide treatment decisions involves testing for HBV DNA, whereas assessment of liver disease activity and staging is mainly based on aminotransferases, platelet count, and elastography. Universal infant immunisation, including birth dose vaccination is the most effective means to prevent chronic HBV infection. Two vaccines with improved immunogenicity have recently been approved for adults in the USA and EU, with availability expected to expand. Current therapies, pegylated interferon, and nucleos(t)ide analogues can prevent development of cirrhosis and hepatocellular carcinoma, but do not eradicate the virus and rarely clear HBsAg. Treatment is recommended for patients with cirrhosis or with high HBV DNA levels and active or advanced liver disease. New antiviral and immunomodulatory therapies aiming to achieve functional cure (ie, clearance of HBsAg) are in clinical development. Improved vaccination coverage, increased screening, diagnosis and linkage to care, development of curative therapies, and removal of stigma are important in achieving WHO's goal of eliminating HBV infection by 2030.
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Affiliation(s)
- Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - George V Papatheodoridis
- Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Anna S F Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
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22
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Huang CW, Yang CT, Su PY, Chen YY, Huang SP, Yen HH. Chronic Hepatitis B Relapse Rates after Cessation of Tenofovir Alafenamide and Entecavir Therapy. Biomedicines 2023; 11:biomedicines11030752. [PMID: 36979731 PMCID: PMC10045269 DOI: 10.3390/biomedicines11030752] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 02/19/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Chronic hepatitis B (CHB) relapse occurs after the cessation of nucleos(t)ide analogues (NUC) therapy due to the waning of viral suppression. Few studies have investigated the viral relapse rate and clinical relapse rate after tenofovir alafenamide (TAF) therapy. We compared the CHB relapse rate between TAF and entecavir therapy. We enrolled patients with chronic hepatitis B who underwent TAF or entecavir therapy. NUC therapy was terminated after HBeAg loss for 1 year in HBeAg-positive patients and after undetectable serum HBV DNA on three separate tests each >6 months apart in HBeAg-negative patients. After cessation of NUC therapy, we followed alanine aminotransferase (ALT) levels at 12, 24, and 48 weeks. Serum HBV DNA levels were checked if patients showed a two-fold elevation from the upper limit of normal ALT levels (41 IU/mL). Clinical relapse (CR) was defined as a two-fold elevation in ALT levels and HBV DNA levels > 2000 IU/mL. We then investigated the CR rate of HBV after cessation of TAF and entecavir therapy at 12, 24, and 48 weeks. Of the 117 patients enrolled, 78 were in the entecavir group and 39 were in the TAF group. At 12 weeks after cessation of NUC therapy, no patients had HBV CR in the entecavir group. However, three patients (CR cumulative rate 7.9%) had CR in the TAF group. At 24 weeks, the CR cumulative rate in the entecavir and TAF groups were 1.3% and 13.2%, respectively (p < 0.05). At 48 weeks, the CR cumulative rates were 9.2% and 24.2%, respectively (p = 0.055). Patients in the TAF group had a higher cumulative rate of CR than those in the entecavir group (log-rank p = 0.023). Furthermore, patients in the TAF group had earlier CR times than those in the entecavir group, especially in the first 24 weeks after cessation of therapies (p < 0.05). The cessation of TAF therapy had significantly earlier and higher CR rates than that of entecavir therapy. Close monitoring of liver function and HBV DNA levels may be necessary, especially within 24 weeks after cessation of TAF therapy.
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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
| | - Pei-Yuan Su
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan
- College of Medicine, National Chung Hsing University, Taichung 400, Taiwan
| | - Yang-Yuan Chen
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan
- College of Medicine, National Chung Hsing University, Taichung 400, 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
- College of Medicine, National Chung Hsing University, Taichung 400, Taiwan
- Correspondence:
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23
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Chen CH, Jeng WJ, Hu TH, Liu YC, Wang JH, Hung CH, Lu SN, Chien RN. HBV relapse rates in patients who discontinue tenofovir disoproxil fumarate with or without switching to tenofovir alafenamide. Dig Liver Dis 2023; 55:771-777. [PMID: 36737315 DOI: 10.1016/j.dld.2023.01.154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 01/16/2023] [Accepted: 01/19/2023] [Indexed: 02/05/2023]
Abstract
BACKGROUND/AIMS The incidence and relapse pattern in patients stopping tenofovir alafenamide (TAF), a prodrug of tenofovir which is more concentrated in hepatocytes, is unknown. METHODS HBeAg-negative CHB patients stopping tenofovir disoproxil fumarate (TDF) (off-TDF) or who had switched to TAF more than 3 months before discontinuation (off-TAF) were recruited. The propensity score-matching method (PSM) was used, creating a ratio of 1:3 between the off-TAF versus the off-TDF groups to adjust for associated factors. RESULTS After PSM, 180 off-TDF and 60 off-TAF patients were analyzed. The cumulative rates of virological and clinical relapse at 52 weeks were 75.1% and 58.5% respectively in the off-TDF group and 91.1% and 61.6% in the off-TAF group. Patients in the off-TAF group had significantly higher rates of virological relapse than those in the off-TDF group (p = 0.021), but not clinical relapse (p = 0.785). Multivariate cox regression analysis showed that off-TAF group was an independent factor for virological relapse, but not clinical relapse. Severity of clinical relapse and hepatic decompensation rate were comparable between off-TDF and off-TAF groups CONCLUSIONS: The off-TAF group had a higher virological relapse rate than the off-TDF group. The difference in clinical relapse pattern and severity was not clinically important between the two groups.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan.
| | - Wen-Juei Jeng
- Division of Hepatogastroenterology, Department of Internal Medicine, Linkuo Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Yen-Chun Liu
- Division of Hepatogastroenterology, Department of Internal Medicine, Linkuo Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Rong-Nan Chien
- Division of Hepatogastroenterology, Department of Internal Medicine, Linkuo Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
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Chiu SM, Chang KC, Hu TH, Hung CH, Wang JH, Lu SN, Chen CH. Retreatment Efficacy and Renal Safety of Tenofovir Alafenamide, Entecavir, and Tenofovir Disoproxil Fumarate After Entecavir or Tenofovir Cessation. Dig Dis Sci 2023; 68:665-675. [PMID: 35976597 DOI: 10.1007/s10620-022-07657-8] [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: 12/20/2021] [Accepted: 07/31/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND We aimed to compare the one-year retreatment efficacy and renal safety of entecavir, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) after HBV relapse in patients who discontinued entecavir or TDF. METHODS This retrospective study included 289 chronic hepatitis B (CHB) patients without cirrhosis who received entecavir (n = 93), TDF (n = 103), or TAF (n = 86) retreatment for at least 12 months after entecavir or TDF cessation. RESULTS The rate of virological response (HBV DNA < 20 IU/mL) at 12 months of retreatment was 79/93 (84.9%) in the entecavir group, 92/103 (89.3%) in the TDF group, and 72/86 (83.7%) in the TAF group. The rate of ALT normalization (ALT ≤ 40 U/L) after 12 months of retreatment was 76/93 (81.7%) in the entecavir group, 77/103 (74.7%) in the TDF group , and 73/86 (84.9%) in the TAF group. There was no significant difference in the rates of virological response (p = 0.495) and ALT normalization (p = 0.198) among the three groups. Multivariate analysis showed that lower HBV DNA and HBsAg levels at baseline were independently associated with virological response at 12 months of retreatment. The TDF group (37.8 ± 34.8 U/L) had higher ALT levels at 12 months of retreatment than the TAF (27. ± 17.9 U/L, p = 0.015) and entecavir (28.3 ± 19.3 U/L, p = 0.022) groups. In patients with eGFR 60-90 mL/min/1.73 m2, eGFR change between baseline and 12 months of retreatment increased in the entecavir and TAF groups and decreased in the TDF group. CONCLUSIONS TAF could be one of the retreatment options for retreatment of HBV relapse after entecavir or TDF cessation.
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Affiliation(s)
- Shao-Ming Chiu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Kuo-Chin Chang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan.
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Peng CW, Jeng WJ, Yang HI, Liu YC, Chien RN, Liaw YF. A switch from tenofovir to entecavir prior to hepatitis B treatment cessation is associated with a reduced risk of off-therapy relapse: An observational study. J Gastroenterol Hepatol 2022; 37:2164-2172. [PMID: 35869752 DOI: 10.1111/jgh.15966] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 07/11/2022] [Accepted: 07/13/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM In HBeAg negative chronic hepatitis B (CHB) patients, clinical relapse (CR) occurs more frequently, much earlier and often more severely after stopping tenofovir (TDF) and other nucleos(t)ide analogues (Nucs) than after stopping entecavir (ETV). It is unknown whether off-Nuc hepatitis flare can be alleviated by switching from one Nuc to another. METHODS HBeAg-negative CHB patients who had stopped Nuc according to the APASL stopping rule and had been followed-up for > 48 weeks after Nuc cessation were recruited. Patients were classified as four groups: ETV monotherapy (mono-ETV), TDF monotherapy (mono-TDF), switched to ETV (switch-ETV), and switched to TDF (switch-TDF). Both switch groups had switched to the replacement Nuc > 12 weeks prior to end of therapy. Propensity score matching (PSM) was performed to minimize confounders among groups. Cox regression analysis was used to identify risks factors for off-Nuc CR and flares. RESULTS A total of 1309 patients (1022 mono-ETV, 219 mono-TDF, 40 switch-ETV and 28 switch-TDF) were enrolled. The median time to CR was 39, 13, 38 and 14 weeks in mono-ETV, mono-TDF, switch-ETV and switch-TDF respectively (P < 0.001). After PSM, the mono-ETV (adjusted HR: 0.39, P < 0.001) and switch-ETV patients (adjusted HR: 0.41, P = 0.003) had both significantly later occurrence and lower rates of CR and flare. CONCLUSION In summary, the incidence and timing of CR was determined by ETV or TDF in the last 3 months prior to end of treatment. Patients treated with non-ETV-Nuc switched to ETV > 12 weeks before end of the original Nuc therapy may reduce/defer CR.
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Affiliation(s)
- Chien-Wei Peng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hwai-I Yang
- Genomic Research Center, Academia Sinica, Taipei, Taiwan
| | - Yen-Chun Liu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Linkou branch, Taoyuan, Taiwan
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Serious adverse events after cessation of nucleos(t)ide analogues in individuals with chronic hepatitis B: A systematic review and meta-analysis. JHEP Rep 2022; 5:100617. [DOI: 10.1016/j.jhepr.2022.100617] [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: 08/28/2022] [Revised: 10/12/2022] [Accepted: 10/15/2022] [Indexed: 11/30/2022] Open
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Zhu M, Wang H, Lou T, Xiong P, Zhang J, Li L, Sun Y, Wu Y. Current treatment of chronic hepatitis B: Clinical aspects and future directions. Front Microbiol 2022; 13:975584. [PMID: 36160238 PMCID: PMC9493448 DOI: 10.3389/fmicb.2022.975584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 07/26/2022] [Indexed: 11/23/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a public health threat worldwide, and there is no direct treatment yet available. In the event of infection, patients may present liver cirrhosis and cancer, which threaten the patients’ health globally, especially in the Asia-Pacific region and China. In 2019, Chinese hepatopathologists updated the 2015 Guidelines for the Prevention and Treatment of Chronic Hepatitis B as the clinical reference. The other versions formulated by the American Association for the Study of Liver Diseases (2018 AASLD guidelines) (AASLD, 2018), European Association for the Study of the Liver (2017 EASL guidelines) (EASL, 2017), and Asian-Pacific Association for the Study of the Liver (2015 APASL guidelines) (APASL, 2015) also provide clinical guidance. However, there are still some issues that need to be addressed. In the present study, the following aspects will be introduced successively: (1) Who should be treated in the general population according to the guidelines; (2) Treatment of specific populations infected with HBV; (3) Controversial issues in clinical practice; (4) Perspective.
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Affiliation(s)
- Minmin Zhu
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Hui Wang
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Tao Lou
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Pian Xiong
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Jiebing Zhang
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Lele Li
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Yuchao Sun
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
- International Institutes of Medicine, Zhejiang University, Jinhua, China
| | - Yingping Wu
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
- International Institutes of Medicine, Zhejiang University, Jinhua, China
- *Correspondence: Yingping Wu,
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Upadhyay P, Lal BB, Sood V, Khanna R, Gupta E, Rastogi A, Alam S. Incidence and Predictors of Relapse After Stopping Antiviral Therapy in Pediatric Chronic Hepatitis B. Pediatr Infect Dis J 2022; 41:714-719. [PMID: 35703278 DOI: 10.1097/inf.0000000000003602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
BACKGROUND There are no definite end-points for stopping therapy in pediatric chronic hepatitis B (CHB). The study objective was to evaluate the incidence of relapse after stopping antiviral therapy and to identify its predictors. METHODS All hepatitis B surface antigen (HBsAg) positive children presenting to our hospital, who had been on antivirals for at least 2 years with undetectable hepatitis B virus-deoxyribonucleic acid (HBV-DNA) and normal alanine aminotransferase (ALT) on 3 consecutive occasions over last 12 months were included. Antivirals were stopped if liver biopsy showed histological activity index <5 and fibrosis (Ishak) <3. Virological relapse was defined as the elevation of HBV-DNA (>2000 IU/mL) and biochemical relapse as a rise in ALT levels to >2 times the upper limit of normal. Those having biochemical relapse were started on pegylated interferon alpha-2b-based sequential therapy. RESULTS Of the 114 children with CHB screened, 31 HBsAg-positive children fulfilled inclusion criteria and antivirals were stopped in them. Virological and biochemical relapse was seen in 12 (38.7%) and 5 (16.1%) children within 12 months of stopping antiviral treatment. On Cox regression, hepatitis B e antigen (HBeAg) positive status at the time of stopping antiviral therapy (HR: 6.208, 95% CI: 1.630-23.638) and longer time taken for HBV-DNA to become undetectable while on antivirals (HR: 1.027, 95% CI: 1.000-1.055) were the independent predictors of relapse. CONCLUSION Discontinuation of antiviral treatment in children with CHB resulted in relapse in one-third of the patients. Relapse was frequent in those who were HBeAg-positive at the time of stopping therapy and in those who required longer therapy for HBV-DNA to become undetectable.
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Affiliation(s)
- Piyush Upadhyay
- From the Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Bikrant Bihari Lal
- From the Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vikrant Sood
- From the Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rajeev Khanna
- From the Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ekta Gupta
- Department of Virology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Seema Alam
- From the Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Liu YC, Liaw YF. Distinct Relapse Patterns Between HBeAg-Negative Patients Stopping Tenofovir and Entecavir. Clin Gastroenterol Hepatol 2022; 21:1380. [PMID: 35985637 DOI: 10.1016/j.cgh.2022.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/08/2022] [Accepted: 08/09/2022] [Indexed: 02/07/2023]
Affiliation(s)
- Yen-Chun Liu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taoyuan, Taiwan; and, Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan
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Hall SAL, Vogrin S, Wawryk O, Burns GS, Visvanathan K, Sundararajan V, Thompson A. Discontinuation of nucleot(s)ide analogue therapy in HBeAg-negative chronic hepatitis B: a meta-analysis. Gut 2022; 71:1629-1641. [PMID: 34493592 DOI: 10.1136/gutjnl-2020-323979] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 08/25/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Sustained virological suppression and hepatitis B surface antigen (HBsAg) loss have been described after nucleot(s)ide analogue (NA) discontinuation for patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). We performed a meta-analysis of the clinical outcomes after NA discontinuation for HBeAg-negative CHB. METHODS Studies involving NA cessation in HBeAg-negative CHB individuals with a median follow-up of ≥12 months were included. Participants were HBeAg-negative at the time of NA initiation. Random effects meta-analyses were performed for the following clinical outcomes: (1) virological relapse (VR) at 6 and 12 months; (2) clinical relapse (CR) at 6 and 12 months and (3) HBsAg loss. Effect of other variables was estimated using subgroup analysis and meta-regression. Studies including patients stopping entecavir (ETV) and/or tenofovir disoproxil fumarate (TDF) were considered separately to studies including patients stopping older generation NA. RESULTS N=37 studies met inclusion criteria. Cumulative incidence of VR and CR after stopping ETV/TDF was 44% and 17% at 6 months and 63% and 35% at 12 months. Similar relapse rates were observed after stopping older NAs. Among patients stopping ETV/TDF, TDF cessation was associated with increased CR rates at 6 months versus ETV. There was an association between follow-up ≥4 years and HBsAg loss rates when stopping older NAs. Hepatic decompensation and hepatocellular carcinoma were rare but occurred more frequently in studies including cirrhotic individuals. CONCLUSION VR is common after NA discontinuation, however, CR was only seen in one-third of patients at 12 months. Stopping NA therapy can be followed by HBsAg clearance, and rates are higher with longer follow-up.
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Affiliation(s)
| | - Sara Vogrin
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Olivia Wawryk
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Gareth S Burns
- Gastroenterology Department, St Vincent's Hospital Melbourne Pty Ltd, Fitzroy, Victoria, Australia
| | - Kumar Visvanathan
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.,Infectious Diseases Department, St Vincent's Hospital Melbourne Pty Ltd, Fitzroy, Victoria, Australia
| | - Vijaya Sundararajan
- Department of Public Health, La Trobe University, Melbourne, Victoria, Australia
| | - Alexander Thompson
- Gastroenterology Department, St Vincent's Hospital Melbourne Pty Ltd, Fitzroy, Victoria, Australia.,Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
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Broquetas T, Hernandez JJ, Garcia-Retortillo M, Canillas L, Puigvehí M, Cañete N, Coll S, Viu A, Garrido E, Mico M, Bessa X, Carrión JA. On-therapy HBsAg kinetics can predict HBsAg loss after nucleos(t)ide analogues interruption in HBeAg-negative patients. The cup is half full and half empty. Dig Liver Dis 2022; 54:1044-1051. [PMID: 35063365 DOI: 10.1016/j.dld.2021.12.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 11/25/2021] [Accepted: 12/29/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND Nucleos(t)ide analogues withdrawal may improve HBsAg loss rates. However, conditions to select patients are not well established. AIMS to evaluate the impact of HBsAg kinetics before treatment interruption on post-treatment response. METHODS Longitudinal, ambispective study in non-cirrhotic chronic hepatitis B HBeAg-negative patients, analysing on-treatment and post-treatment HBsAg kinetics. On-treatment HBsAg kinetics diagnostic accuracy (AUROC) to identify HBsAg loss was evaluated. RESULTS 52 HBeAg-negative patients stopped treatment after 8.2 years, and 6 (11.5%) achieved HBsAg loss one year after withdrawal. Multivariate analysis showed that on-treatment HBsAg kinetics was related to HBsAg loss (OR=0.10; 95%CI=0.016-0.632; p = 0.014) with a high diagnostic accuracy (AUROC=0.935). A significant HBsAg decline ≥1 log10 IU/mL showed a positive and negative predictive value of 50% and of 97.6%, respectively. After treatment interruption, HBsAg decline speed (log10 IU/mL/year) accelerated in patients treated >6 years (from -0.06 to -0.20, p<0.05) and remained stable in treated <6 years (from -0.12 to -0.12 p=ns). CONCLUSIONS On-treatment HBsAg kinetics can predict post-treatment HBsAg loss rate. Half of patients with a significant HBsAg decline can eliminate HBsAg the first year after withdrawal. Post-treatment HBsAg decline is faster not only in patients who lost the HBsAg but also in those who remain HBsAg-positive.
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Affiliation(s)
- Teresa Broquetas
- Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; Liver Section, Gastroenterology Department, Hospital del Mar, 25-29 Passeig Marítim, Barcelona 08003, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | | | - Montserrat Garcia-Retortillo
- Liver Section, Gastroenterology Department, Hospital del Mar, 25-29 Passeig Marítim, Barcelona 08003, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Lidia Canillas
- Liver Section, Gastroenterology Department, Hospital del Mar, 25-29 Passeig Marítim, Barcelona 08003, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Marc Puigvehí
- Liver Section, Gastroenterology Department, Hospital del Mar, 25-29 Passeig Marítim, Barcelona 08003, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Nuria Cañete
- Liver Section, Gastroenterology Department, Hospital del Mar, 25-29 Passeig Marítim, Barcelona 08003, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Susanna Coll
- Liver Section, Gastroenterology Department, Hospital del Mar, 25-29 Passeig Marítim, Barcelona 08003, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Ana Viu
- Liver Section, Gastroenterology Department, Hospital del Mar, 25-29 Passeig Marítim, Barcelona 08003, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Esther Garrido
- Liver Section, Gastroenterology Department, Hospital del Mar, 25-29 Passeig Marítim, Barcelona 08003, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Miquel Mico
- Laboratori de Referència de Catalunya, El Prat de Llobregat, Spain
| | - Xavier Bessa
- Liver Section, Gastroenterology Department, Hospital del Mar, 25-29 Passeig Marítim, Barcelona 08003, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - José A Carrión
- Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; Liver Section, Gastroenterology Department, Hospital del Mar, 25-29 Passeig Marítim, Barcelona 08003, Spain.
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Liu YC, Jeng WJ, Chen CH. Keystone to Secure Safety After Stopping Nucleos(t)ide Analogue Therapy in Chronic Hepatitis B Patients. Clin Gastroenterol Hepatol 2022; 20:1890-1891. [PMID: 34583016 DOI: 10.1016/j.cgh.2021.09.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 09/22/2021] [Indexed: 02/07/2023]
Affiliation(s)
- Yen-Chun Liu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City; College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City; College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Chien-Hung Chen
- Department of Gastroenterology and Hepatology, Kaohsiung Chang Gung Memorial Hospital, Taoyuan City; College of Medicine, Chang Gung University, Taoyuan City, Taiwan
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Choi HSJ, Hirode G, Chen CH, Su TH, Seto WK, Van Hees S, Papatheodoridi M, Lens S, Wong GLH, Brakenhoff SM, Chien RN, Feld JJ, Sonneveld MJ, Chan HLY, Forns X, Papatheodoridis GV, Vanwolleghem T, Yuen MF, Hsu YC, Kao JH, Cornberg M, Hansen BE, Jeng WJ, Janssen HLA. Differential Relapse Patterns After Discontinuation of Entecavir vs Tenofovir Disoproxil Fumarate in Chronic Hepatitis B. Clin Gastroenterol Hepatol 2022; 21:1513-1522.e4. [PMID: 35863683 DOI: 10.1016/j.cgh.2022.07.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 06/27/2022] [Accepted: 07/03/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) differentially affect relapse and outcomes following treatment discontinuation across different patient subpopulations remains unclear. We aimed to compare rates of off-therapy hepatitis B surface antigen (HBsAg) loss, virological and clinical relapse, and retreatment between chronic hepatitis B (CHB) patients who discontinued TDF or ETV therapy. METHODS This study included 1402 virally suppressed CHB patients who stopped either ETV (n = 981) or TDF (n = 421) therapy between 2001 and 2020 from 13 participating centers across North America, Europe, and Asia. All patients were hepatitis B e antigen-negative at treatment discontinuation. Inverse probability of treatment weighting was used to balance the treatment groups. Outcomes were analyzed using survival methods. RESULTS During a median off-treatment follow-up of 18 months, HBsAg loss occurred in 96 (6.8%) patients overall. Compared with ETV, TDF was associated with a higher rate of HBsAg loss (P = .03); however, the association was no longer significant after statistical adjustment (P = .61). Virological relapse occurred earlier among TDF-treated patients (P < .01); nonetheless, rates became comparable after the first year off therapy (P = .49). TDF was significantly associated with a higher clinical relapse rate than ETV throughout follow-up (P < .01). The development of a virological or clinical relapse did not affect the rate of HBsAg loss. Retreatment rates were not significantly different between the treatment groups. CONCLUSIONS TDF and ETV have differential relapse patterns but are associated with similar rates of HBsAg loss and retreatment following discontinuation. Finite therapy can be considered for CHB patients on either TDF or ETV therapy.
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Affiliation(s)
- Hannah S J Choi
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Grishma Hirode
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Toronto Viral Hepatitis Care Network, University Health Network, Toronto, Ontario, Canada
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan
| | - Tung-Hung Su
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
| | - Stijn Van Hees
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Margarita Papatheodoridi
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Sabela Lens
- Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Grace L H Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - Sylvia M Brakenhoff
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Linkou, Taiwan
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Toronto Viral Hepatitis Care Network, University Health Network, Toronto, Ontario, Canada
| | - Milan J Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Henry L Y Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - Xavier Forns
- Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - George V Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Thomas Vanwolleghem
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
| | - Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Centre for Individualized Infection Medicine, Helmholtz Centre for Infection Research and Hannover Medical School, Hannover, Germany
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada; Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Linkou, Taiwan
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada; Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
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Finite versus Indefinite Nucleos(t)ide Analogue Therapy of Patients with Chronic Hepatitis B Exhibiting Negative HBsAg Levels after Treatment. BIOMED RESEARCH INTERNATIONAL 2022; 2022:6069781. [PMID: 35872855 PMCID: PMC9307367 DOI: 10.1155/2022/6069781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 12/14/2021] [Accepted: 12/17/2021] [Indexed: 11/17/2022]
Abstract
Aim To determine whether a decrease in HBsAg to <0.05 IU/mL could be a criterion for cessation of finite nucleos(t)ide analogue (NUC) therapy in patients with chronic hepatitis B (CHB). Methods This was a retrospective analysis of 6715 patients with CHB between January 1998 and May 2016. Patients were followed up every 12–24 weeks. Among 104 patients achieving HBsAg levels < 0.05 IU/mL, 71 were eligible for inclusion in the analysis: 31 received finite NUC therapy, and 40 received indefinite NUC therapy. In the finite therapy group, 9 patients received no NUC consolidation therapy, 6 received short-term (<1 year) consolidation, and 16 received long-term (>1 year) consolidation. The outcome measures were alanine aminotransferase (ALT), total bilirubin, albumin, hepatitis B virus DNA, and HBsAg levels. Results Baseline parameters and characteristics at the time when HBsAg levels had fallen to <0.05 IU/mL were similar between the finite and indefinite therapy groups. No patients experienced viral breakthrough/relapse during a median follow-up of 120 weeks. There were little or no differences in long-term outcomes between the finite and indefinite therapy groups and between the short-term and long-term consolidation groups. Conclusions Discontinuation of NUCs may be acceptable in patients whose HBsAg levels fall to <0.05 IU/mL. Consolidation therapy lasting <1 year appears adequate to prevent poor long-term prognosis.
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Clinical Efficacy and Safety of Tenofovir in the Treatment of Patients with Chronic Hepatitis B. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:1673453. [PMID: 35774746 PMCID: PMC9239785 DOI: 10.1155/2022/1673453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/22/2022] [Accepted: 05/26/2022] [Indexed: 11/24/2022]
Abstract
The negative rate of serum HBV DNA, HBeAg, and ALT in the tenofovir group was significantly higher than that in the entecavir group (86.67%, 3.33%, and 80.00%) (all P < 0.05). In the tenofovir group, 2cases were considered. Objective. The aim of this study is to analyze the clinical effect and safety of tenofovir in the treatment of chronic hepatitis B (CHB) patients. Methods. A total of 60 patients with CHB who were admitted and treated in Anqing First People's Hospital Affiliated to Anhui Medical University from January 2019 to July 2020 were randomly assigned at a ratio of 1 : 1 into the tenofovir group (treated with tenofovir) and the entecavir group (treated with entecavir) via the random number table method. The clinical therapeutic effect and safety of the two groups were compared. Results. The serum hepatitis B virus (HBV) DNA levels in the two groups decreased after treatment, but there was no significant difference. Ths (2.50%) had nausea, 1 (1.25%) had headache, and 0 had an elevated creatine kinase. In the tenofovir group,1(3.33%) had nausea, 0 had headache, and 0 had an elevated creatine kinase. In the entecavir group, there were 3 (10.00%) cases of nausea, 2 (6.67%) cases of headache, and 1 (3.33%) case of elevated creatine kinase. The overall incidence of adverse reactions in the tenofovir group (3.33%) was significantly lower than that in the entecavir group (20.00%) (all P < 0.05). Conclusion. Tenofovir is more effective than entecavir in the treatment of patients with CHB due to low incidence of adverse events and a good safety profile.
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Fang HW, Yen YH, Hung CH, Wang JH, Hu TH, Lu SN, Chen CH. Predictors of Virological Suppression After Clinical Relapse in Patients Who Discontinued Entecavir or Tenofovir. Dig Dis Sci 2022; 67:3402-3411. [PMID: 34241753 DOI: 10.1007/s10620-021-07128-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 06/20/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND The predictors of persistent virological suppression after clinical relapse remain unclear. AIMS To investigate the predictors of retreatment or persistent virological suppression after clinical relapse in chronic hepatitis B (CHB) patients who discontinued entecavir or tenofovir disoproxil fumarate (TDF). METHODS A total of 243 hepatitis B e antigen-negative CHB patients without cirrhosis who experienced clinical relapse after entecavir or TDF cessation were enrolled. RESULTS Of the 243 CHB patients, 192 received retreatment and 51 did not receive retreatment after clinical relapse. Of the 51 patients without retreatment, 23 achieved persistent virological suppression (persistent HBV DNA < 2000 IU/mL at least 2 years) and 10 experienced hepatitis B surface antigen (HBsAg) loss. The Cox regression analysis showed that short consolidation duration, short duration of the first clinical relapse from the end of treatment (EOT), and high bilirubin and HBV DNA levels at the first clinical relapse were independent predictors of retreatment. Long duration of the first clinical relapse from the EOT and low HBsAg levels at the first clinical relapse were independent factors of patients with persistent virological suppression. The rates of persistent virological suppression at the first clinical relapse among patients with HBsAg < 100 and ≥ 100 IU/mL were 44.4% (12/27) and 5.1% (11/216) (P < 0.001), respectively. Baseline HBsAg levels and no retreatment requirement were independent factors associated with HBsAg loss. CONCLUSIONS The HBsAg of 100 IU/mL at the first clinical relapse could predict persistent virological suppression after clinical relapse in patients who discontinued entecavir or TDF therapy.
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Affiliation(s)
- Hsin-Wei Fang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Yi-Hao Yen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan.
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Liu YC, Jeng WJ, Peng CW, Chien RN, Liaw YF. Off-tenofovir hepatitis flares in HBeAg-negative patients occur earlier, more frequent and severe than those off-entecavir therapies. Liver Int 2022; 42:551-560. [PMID: 34936719 DOI: 10.1111/liv.15140] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 11/23/2021] [Accepted: 12/19/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Clinical relapse occurs much earlier and more frequently in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients after stopping tenofovir (TDF) therapy than those off-entecavir (ETV). Clinical relapse may subside or progress to hepatitis flare which poses a safety concern. This study compared the incidence, timing and severity of hepatitis flares after stopping TDF and ETV. METHODS HBeAg-negative CHB patients who had stopped ETV or TDF were included in the study. Off-therapy hepatitis flare patterns were compared between off-ETV and off-TDF patients before and after propensity score matching (PSM). RESULTS The off-therapy hepatitis flares occurred more frequently (2-year: 58% vs 38%, P < .001) and much earlier (12 vs. 38 weeks, P < .001) in TDF group, with higher alanine aminotransferase (ALT) levels (after PSM: 536 vs. 419 U/L, P = .020) and two times rate of hepatic decompensation (4.0% vs. 2.1%, P = .322). The cirrhotic status [aHR: 20.531 (2.645-159.365), P = .004] and off-TDF [aHR: 5.530 (1.728-17.694), P = .004] were two independent predictors for hepatic decompensation. CONCLUSIONS Hepatitis flare occurred more frequently, earlier, and more severe in off-TDF than off-ETV patients. More stringent off-therapy monitoring within 6 months off-TDF is mandatory whereas more attention is needed after 6 months off-ETV.
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Affiliation(s)
- Yen-Chun Liu
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wen-Juei Jeng
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chien-Wei Peng
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Rong-Nan Chien
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yun-Fan Liaw
- College of Medicine, Chang Gung University, Taipei, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan
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Chien-Hung C, Peng CY, Kuo YH, Hu TH, Hung CH, Wang JH, Lu SN. Earlier and higher rate of hepatitis B virus relapse after discontinuing tenofovir versus entecavir in HBeAg-positive patients. J Infect Dis 2021; 225:1974-1981. [PMID: 34894128 DOI: 10.1093/infdis/jiab596] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 12/09/2021] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND This study investigated the incidence and predictors of hepatitis B virus (HBV) relapse in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) who discontinued entecavir or tenofovir disoproxil fumarate (TDF). METHODS A total of 205 and 111 HBeAg-positive patients without cirrhosis who had stopped entecavir or TDF treatment, respectively, for at least 6 months were recruited. RESULTS In the entire cohort, patients with HBeAg seroconversion during treatment and propensity score (PS)-matched patients, patients who discontinued TDF had significantly higher rates of virological and clinical relapse than patients who discontinued entecavir therapy. Multivariate analysis identified TDF were independently associated with virological and clinical relapse in the entire cohort and subgroups analysis. Patients with HBeAg loss without anti-HBe antibody formation during treatment had significantly higher rates of off-therapy HBV relapse and HBeAg seroreversion than patients with HBeAg seroconversion during treatment. The HBcrAg level at end of treatment (EOT) was independently associated with HBV relapse and HBeAg seroreversion in all patients and patients with HBeAg seroconversion during treatment. CONCLUSIONS TDF therapy, HBeAg loss without seroconversion during treatment and higher HBcrAg levels at EOT are significant predictors of HBV relapse in HBeAg-positive patients who discontinued entecavir or TDF.
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Affiliation(s)
- Chen Chien-Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung.,School of Medicine, China Medical University, Taichung, Taiwan
| | - Yuan-Hung Kuo
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- 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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39
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Lai CY, Yang SS, Lee SW, Tsai HJ, Lee TY. Cessation of Nucleos(t)ide Analogue Therapy in Non-Cirrhotic Hepatitis B Patients with Prior Severe Acute Exacerbation. J Clin Med 2021; 10:4883. [PMID: 34768403 PMCID: PMC8584579 DOI: 10.3390/jcm10214883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/20/2021] [Accepted: 10/20/2021] [Indexed: 11/16/2022] Open
Abstract
UNLABELLED Chronic hepatitis B (CHB) with severe acute exacerbation (SAE) is an urgent problem requiring nucleos(t)ide analogue (NA) therapy. We aim to evaluate the clinical relapse (CR) risk after discontinuing NA in patients with prior SAE. METHODS In this retrospective cohort study, CHB patients who discontinued NA therapy were screened between October, 2003 and January, 2019. A total of 78 non-cirrhotic patients who had received NA therapy for CHB with SAE, i.e., bilirubin ≥ 2 mg/dL and/or prothrombin time prolongation ≥3 s, (SAE group) were matched 1:2 with 156 controls without SAE (non-SAE group) by means of propensity scores (age, gender, NA categories, NA therapy duration, and HBeAg status). RESULTS The 5-year cumulative incidences of severe CR, i.e., ALT > 10X ULN, (42.78%, 95% CI: 27.84-57.73% vs. 25.42%, 95% CI: 16.26-34.58%; p = 0.045) and SAE recurrence (25.91%, 95% CI: 10.91-40.91% vs. 1.04%, 95% CI: 0-3.07%; p < 0.001) were significantly higher in the SAE group. Prior SAE history (HR 1.79, 95% CI: 1.04-3.06) was an independent factor for severe CR. The 5-year cumulative incidence of HBsAg seroclearance was significantly higher in the SAE group than that in the non-SAE group (16.82%, 95% CI: 2.34-31.30% vs. 6.02%, 95% CI: 0-13.23%; p = 0.049). CONCLUSIONS Even though it creates a greater chance of HBsAg seroclearance, NA therapy cessation may result in a high risk of severe CR in non-cirrhotic CHB patients with prior SAE.
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Affiliation(s)
- Chia-Yeh Lai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-Y.L.); (S.-S.Y.); (S.-W.L.); (H.-J.T.)
| | - Sheng-Shun Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-Y.L.); (S.-S.Y.); (S.-W.L.); (H.-J.T.)
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
- Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 40227, Taiwan
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan
| | - Shou-Wu Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-Y.L.); (S.-S.Y.); (S.-W.L.); (H.-J.T.)
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Hsin-Ju Tsai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-Y.L.); (S.-S.Y.); (S.-W.L.); (H.-J.T.)
| | - Teng-Yu Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (C.-Y.L.); (S.-S.Y.); (S.-W.L.); (H.-J.T.)
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
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40
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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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41
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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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42
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Abstract
Antiviral therapy has greatly improved the survival and reduced the incidence of adverse liver events such as hepatic decompensation and hepatocellular carcinoma in chronic hepatitis B patients with cirrhosis (hepatitis B virus [HBV]-cirrhosis). However, hepatitis B surface antigen loss, regarded as the ultimate goal of therapy or functional cure, was rarely achieved during long-term indefinite nucleos(t)ide analogues (Nuc) treatment. Emerging issues such as medication adherence and loss-to-follow-up may lead to increased risk of hepatic decompensation, even catastrophic life-threatening events. Studies have shown that finite therapy is feasible and reasonably safe, even in patients with HBV-cirrhosis. This review critically assesses the scientific evidence of the pros and cons for finite Nuc therapy in HBV-cirrhosis and proposes how to stop Nuc therapy and monitor the off-therapy patients. It also proposes the perspective and unsolved issues to be investigated in the future.
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Affiliation(s)
- Wen-Juei Jeng
- Liver Research Unit, Linkou Medical Center, Chang Gung University, Chang Gung Memorial Hospital, College of Medicine, Taoyuan, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Linkou Medical Center, Chang Gung University, Chang Gung Memorial Hospital, College of Medicine, Taoyuan, Taiwan
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43
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APASL guidance on stopping nucleos(t)ide analogues in chronic hepatitis B patients. Hepatol Int 2021; 15:833-851. [PMID: 34297329 DOI: 10.1007/s12072-021-10223-5] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 06/21/2021] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is currently incurable. Long-term treatment with potent and safe nucleos(t)ide analogs (NAs) can reduce hepatocellular carcinoma (HCC) and cirrhosis-related complications through profound viral suppression. However, indefinite therapy raises several crucial issues with pros and cons. Because seroclearance of hepatitis B surface (HBsAg) as functional cure is not easily achievable, a finite therapy including sequential 48-week pegylated interferon therapy may provide an opportunity to facilitate HBsAg seroclearance by the rejuvenation of exhausted immune cells. However, the cost of stopping NA is the high incidence of virological relapse and surge of alanine aminotransferase (ALT) levels, which may increase the risk of adverse outcomes (e.g., decompensation, fibrosis progression, HCC, or liver-related mortality). So far, the APASL criteria to stop NA treatment is undetectable HBV DNA levels with normalization of ALT; however, this criterion for cessation of treatment is associated with various incidence rates of virological/clinical relapse and more than 40% of NA-stoppers eventually receive retreatment. A very intensive follow-up strategy and identification of low-risk patients for virological/clinical relapse by different biomarkers are the keys to stop the NA treatment safely. Recent studies suggested that decreasing HBsAg level at the end-of-treatment to < 100-200 IU/mL seems to be a useful marker for deciding when to discontinue NAs therapy. In addition, several viral and host factors have been reviewed for their potential roles in predicting clinical relapse. Finally, the APASL guidance has proposed rules to stop NA and the subsequent follow-up strategy to achieve a better prognosis after stopping NA. In general, for both HBeAg-positive and HBeAg-negative patients who have stopped treatment, these measurements should be done every 1-3 months at the minimum until 12 months.
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Cornberg M, Sandmann L, Protzer U, Niederau C, Tacke F, Berg T, Glebe D, Jilg W, Wedemeyer H, Wirth S, Höner Zu Siederdissen C, Lynen-Jansen P, van Leeuwen P, Petersen J. S3-Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) zur Prophylaxe, Diagnostik und Therapie der Hepatitis-B-Virusinfektion – (AWMF-Register-Nr. 021-11). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 59:691-776. [PMID: 34255317 DOI: 10.1055/a-1498-2512] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Markus Cornberg
- Deutsches Zentrum für Infektionsforschung (DZIF), Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover; Centre for individualised infection Medicine (CiiM), Hannover.,Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Lisa Sandmann
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Ulrike Protzer
- Institut für Virologie, Technische Universität München/Helmholtz Zentrum München, München
| | | | - Frank Tacke
- Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charité Universitätsmedizin Berlin, Berlin
| | - Thomas Berg
- Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig
| | - Dieter Glebe
- Institut für Medizinische Virologie, Nationales Referenzzentrum für Hepatitis-B-Viren und Hepatitis-D-Viren, Justus-Liebig-Universität Gießen, Gießen
| | - Wolfgang Jilg
- Institut für Medizinische Mikrobiologie und Hygiene, Universität Regensberg, Regensburg
| | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Stefan Wirth
- Zentrum für Kinder- und Jugendmedizin, Helios Universitätsklinikum Wuppertal, Wuppertal
| | | | - Petra Lynen-Jansen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin
| | - Pia van Leeuwen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin
| | - Jörg Petersen
- IFI Institut für Interdisziplinäre Medizin an der Asklepios Klinik St. Georg, Hamburg
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Cost-effectiveness analysis of first-line treatment for chronic hepatitis B in China. Clin Microbiol Infect 2021; 28:300.e1-300.e8. [PMID: 34197929 DOI: 10.1016/j.cmi.2021.06.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 06/07/2021] [Accepted: 06/12/2021] [Indexed: 11/21/2022]
Abstract
OBJECTIVES Hepatitis B virus infection is an important public health problem. We analysed the cost-effectiveness of the first-line therapies, including nucleotide analogues (namely tenofovir alafenamide fumarate (TAF), tenofovir disoproxil fumarate (TDF) and entecavir) and pegylated interferon (Peg-IFN) for patients with chronic hepatitis B (CHB) in China. METHODS A Markov model describing CHB disease progression was constructed to compare the cost-effectiveness of the first-line therapies, considering both satisfactory (HBeAg seroconversion) and optimal (HBsAg seroclearance) treatment goals. We examined the main outcomes, including cumulative lifetime cost per patient, incremental quality-adjusted life years (QALYs), incremental cost-effectiveness ratio and net monetary benefit. Uncertainty analysis was conducted to identify key influential parameters. RESULTS Compared with the baseline strategy, Peg-IFN had the highest QALY gain for HBeAg-positive (HBeAg+) CHB patients achieving a satisfactory goal and an optimal goal (3.19 and 6.32 respectively), and TDF was the most cost-effective therapy for HBeAg-negative CHB patients ($1418/QALY) achieving a satisfactory goal. Among nucleotide analogues, TAF was the most-effective strategy and had higher acceptability to achieve an optimal goal in the Eastern region of China (under 1 x GDP per capita threshold). CONCLUSIONS Among nucleotide analogues, TDF was the most cost-effective treatment in China for CHB patients to achieve satisfactory and optimal treatment goals, whereas TAF was cost-effective and more effective in the wealthier region. Peg-IFN was most cost-effective among HBeAg+ CHB patients to achieve both goals, with better clinical outcomes. Our findings also indicate the importance of regular monitoring during and after CHB treatment, and could inform treatment strategies in China and other countries.
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46
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Li ZB, Li L, Niu XX, Chen SH, Fu YM, Wang CY, Liu Y, Shao Q, Chen G, Ji D. Switching from entecavir to tenofovir alafenamide for chronic hepatitis B patients with low-level viraemia. Liver Int 2021; 41:1254-1264. [PMID: 33404182 DOI: 10.1111/liv.14786] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/13/2020] [Accepted: 01/03/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS About 20% of patients receiving nucleos(t)ide analogues treatment experienced low-level viraemia (LLV), which is associated with progression of liver fibrosis and high risk of hepatocellular carcinoma. We aimed to evaluate the effectiveness and safety of switching from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) in ETV-treated patients with LLV. METHODS In this prospective study, ETV-treated patients with LLV, presented to our hospital from December 2018 to October 2019, were enrolled. Switching to TAF or continuing ETV was given. The primary effectiveness endpoint was complete virological response (CVR) at 24 weeks, and the safety endpoint was the first occurrence of any clinical adverse event during the treatment. RESULTS Totally, 211 patients were recruited and propensity score matching (PSM) generated 75 patients in either TAF or ETV group. After PSM, baseline characteristics were balanced in two groups. After 24-week treatment, the CVR and ALT normalization in TAF group were 62.7% and 47.6%, which were higher than 9.3% and 10.5% in ETV group (OR 16.4, 95% CI 6.6-40.0, P < .001) respectively. Subgroup analysis showed that switching to TAF achieved favours CVR regardless of the status of sex, age, CHB family history, HBV DNA, HBeAg and cirrhosis, whereas alcohol consumption and diabetes mellitus might compromise the CVR of switching to TAF. Both therapies were well tolerated and had satisfying renal safety. CONCLUSIONS For ETV-treated patients with LLV, switching to TAF is safe enough and superior compared with continuing ETV monotherapy regarding both virological and biochemical benefits.
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Affiliation(s)
- Zhong-Bin Li
- Department of Liver Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Le Li
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xiao-Xia Niu
- Department of Liver Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Song-Hai Chen
- Department of Liver Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yi-Ming Fu
- Department of Liver Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Chun-Yan Wang
- Department of Liver Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yan Liu
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Qing Shao
- Department of Liver Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Guofeng Chen
- Department of Liver Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Dong Ji
- Department of Liver Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
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Chotiyaputta W, Poosanasuwansri K, Kiattisunthorn K, Chainuvati S, Tanwandee T. Comparison of viral control between two tenofovir dose reduction regimens (300 mg every 48 hours versus 300 mg every 72 hours) in chronic hepatitis B patients with moderate renal impairment from tenofovir-induced renal dysfunction. J Viral Hepat 2021; 28:364-372. [PMID: 33047455 DOI: 10.1111/jvh.13420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 08/05/2020] [Accepted: 09/20/2020] [Indexed: 01/09/2023]
Abstract
Long-term use of tenofovir disoproxil fumarate (TDF) can induce renal dysfunction that requires TDF dose reduction. Previous studies showed that systemic drug use exerts a threefold higher risk of moderate renal impairment. This study aimed to compare viral control between two tenofovir dose reduction regimens in chronic hepatitis B (CHB) patients with moderate renal impairment from TDF-induced renal dysfunction. This noninferiority, randomized controlled study was conducted at the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Virologically suppressed CHB patients treated with TDF who had moderate renal impairment were randomly allocated to receive TDF 300 mg either every 48 or 72 hours. Forty-six patients (67.4% male) with a mean age of 62.8 ± 7.8 years were enrolled. Among all patients, 34.8% were HBeAg-positive, and 23.9% had cirrhosis. All included patients completed 12 months of follow-up. No patients had virological breakthrough. After dose reduction, estimated glomerular filtration rate (eGFR) was improved in both groups, but a higher proportion of patients had an eGFR > 60 mL/min/1.73 m2 in the TDF every 72 hours group. Other renal parameters, including serum phosphate, tubular maximal reabsorption for phosphate per GFR, urine protein-to-creatinine ratio, urine sugar and urine neutrophil gelatinase-associated lipocalin, were not significantly different between groups. Among TDF-treated CHB patients with TDF-induced moderate renal impairment, more aggressive dose reduction in TDF from every 48 hours to every 72 hours did not affect virological breakthrough. A higher proportion of patients in the TDF every 72 hours group had improvement in renal function.
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Affiliation(s)
- Watcharasak Chotiyaputta
- Faculty of Medicine Siriraj Hospital, Division of Gastroenterology, Department of Medicine, Mahidol University, Bangkok, Thailand
| | - Karn Poosanasuwansri
- Faculty of Medicine Siriraj Hospital, Division of Gastroenterology, Department of Medicine, Mahidol University, Bangkok, Thailand
| | - Kraiwiporn Kiattisunthorn
- Faculty of Medicine Siriraj Hospital, Division of Nephrology, Department of Medicine, Mahidol University, Bangkok, Thailand
| | - Siwaporn Chainuvati
- Faculty of Medicine Siriraj Hospital, Division of Gastroenterology, Department of Medicine, Mahidol University, Bangkok, Thailand
| | - Tawesak Tanwandee
- Faculty of Medicine Siriraj Hospital, Division of Gastroenterology, Department of Medicine, Mahidol University, Bangkok, Thailand
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48
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Liaw YF. Hepatitis B Flare After Cessation of Nucleos(t)ide Analogue Therapy in HBeAg-Negative Chronic Hepatitis B: To Retreat or Not to Retreat. Hepatology 2021; 73:843-852. [PMID: 32810321 DOI: 10.1002/hep.31525] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 07/14/2020] [Accepted: 08/03/2020] [Indexed: 12/17/2022]
Affiliation(s)
- Yun-Fan Liaw
- Liver Research UnitChang Gung Memorial HospitalChang Gung University College of MedicineTaipeiTaiwan
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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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Chiu SM, Kuo YH, Wang JH, Hung CH, Hu TH, Lu SN, Chen CH. Associations of HBV Genotype B vs C Infection With Relapse After Cessation of Entecavir or Tenofovir Therapy. Clin Gastroenterol Hepatol 2020; 18:2989-2997.e3. [PMID: 32353534 DOI: 10.1016/j.cgh.2020.04.048] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 03/26/2020] [Accepted: 04/17/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We compared rates of relapse of hepatitis B virus (HBV) infection between patients with HBV genotype B vs genotype C infection after cessation of entecavir or tenofovir disoproxil fumarate (TDF) therapy. All patients included in the study were HB e antigen (HBeAg)-negative. METHODS We performed a retrospective study of 460 HBeAg-negative patients without cirrhosis in Taiwan who had stopped entecavir or TDF treatment for at least 12 months; data were collected from 2007 through 2016. All patients fulfilled the stopping criteria proposed by the APASL 2012 guidelines. Patients were evaluated every 1-3 months during the first 6 months after stopping therapy and then every 3 months until their last hospital visit; HB surface antigen (HBsAg) was measured in serum samples collected before treatment, after 12 months of treatment, and at the end of treatment. Virologic relapse was defined as a serum level of HBV DNA >2000 IU/mL after the cessation of treatment; clinical relapse was defined as increase in alanine aminotransferase more than 2-fold the upper limit of normal (40 U/L) and level of HBV DNA >2000 IU/mL after stopping treatment. RESULTS Significantly higher proportions of patients with HBV genotype B infection had virologic and clinical relapse and retreatment than patients with HBV genotype C infection, among all patients and among patients matched by propensity sore. Patients who discontinued TDF therapy had significantly higher rates and earlier times of virologic and clinical relapse than patients who discontinued entecavir therapy, among all patients and propensity score-matched patients. Multivariate analysis showed that TDF therapy, old age, HBV genotype B, and higher end of treatment HBsAg level were independently associated with virologic and clinical relapse. Five-year rates of virologic and clinical relapse were low (19.2% and 15.4%, respectively) in patients with a combination of end of treatment level of HBsAg of 100 IU/mL or less and HBV genotype C infection. Rates of off-therapy HBsAg loss, development of hepatocellular carcinoma, and hepatic decompensation did not differ significantly between patients with HBV genotypes B vs C infection or between the entecavir vs TDF groups. CONCLUSIONS Higher proportions of HBeAg-negative patients with HBV genotype B infection have virologic and clinical relapse and retreatment than patients with HBV genotype C infection, after cessation of entecavir or TDF therapy.
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Affiliation(s)
- Shao-Ming Chiu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Yuan-Hung Kuo
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Chiyai Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Chiyai Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
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