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Maung ST, Chaiteerakij R. Scoping Review on Strategies for Safe Nucleot(s)ide Analogue Discontinuation and Optimising Functional Cure in Chronic Hepatitis B. J Viral Hepat 2025; 32:e70040. [PMID: 40478218 DOI: 10.1111/jvh.70040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2025] [Revised: 05/05/2025] [Accepted: 05/22/2025] [Indexed: 06/11/2025]
Abstract
Chronic hepatitis B (CHB) remains a global health challenge, contributing to significant morbidity and mortality. While long-term nucleos(t)ide analogue (NA) therapy effectively suppresses viral replication, achieving a functional cure remains rare. Current treatment guidelines primarily recommend indefinite therapy. However, long-term NA use poses many challenges, prompting interest in finite therapy. Recent studies suggest that carefully selected patients may safely discontinue NAs, leading to a functional cure in some cases. This review evaluates the latest evidence on NA discontinuation, highlighting key factors influencing outcomes. This review synthesises established and emerging evidence on NA discontinuation in CHB. It explores early studies that identified quantitative HBsAg (qHBsAg) as a predictor of sustained response and HBsAg seroclearance, followed by systematic reviews and meta-analyses reinforcing finite therapy as a feasible approach. Advances in predictive modelling, incorporating biomarkers, have refined patient selection for safe NA withdrawal. Additionally, this review assesses the risks associated with NA discontinuation, highlighting the importance of identifying high-risk patients for hepatic decompensation. Ethnicity-specific qHBsAg cut-offs are also discussed, recognising variations in treatment response between Asian and Caucasian populations. Finite NA therapy is emerging as a viable approach for achieving functional cure. Future strategies should integrate liver fibrosis assessment to enhance patient selection before NA discontinuation. Optimising re-treatment approaches requires balancing timing, immune response, and qHBsAg kinetics to maximise HBsAg seroclearance. Clinical perspectives on NA discontinuation remain a key research priority, necessitating standardised guidelines and improved post-NA monitoring strategies to ensure safe and effective finite therapy in CHB management.
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Affiliation(s)
- Soe Thiha Maung
- Division of Graduate Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Ma Har Myaing Hospital, Yangon, Myanmar
| | - Roongruedee Chaiteerakij
- Integrated Innovation and Digital Technologies Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Maung ST, Decharatanachart P, Chaiteerakij R. Hepatitis B Surface Antigen Seroclearance Rate After Stopping Nucleos(t)ide Analogues in Chronic Hepatitis B-A Systematic Review and Meta-Analysis. J Gastroenterol Hepatol 2025; 40:1079-1104. [PMID: 40041970 DOI: 10.1111/jgh.16920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 02/12/2025] [Accepted: 02/17/2025] [Indexed: 05/11/2025]
Abstract
AIM To identify factors influencing HBsAg seroclearance rates after stopping nucleos(t)ide analogue (NA) therapy in patients with chronic hepatitis B (CHB). METHODS We conducted a comprehensive literature search in databases from inception to July 2024. Subgroup analyses and meta-regression were performed to determine factors associated with HBsAg seroclearance, including ethnicity, HBV genotype, NA therapy duration, end-of-treatment (EOT) qHBsAg levels, HBeAg status, cirrhosis status, and follow-up duration. RESULTS The meta-analysis included 62 studies (n = 9867) with a pooled HBsAg seroclearance rate of 10% (95%CI: 8%-12%, I2 = 92%) after NA cessation. HBeAg-negative patients showed significantly higher rates than HBeAg-positive patients (11% vs. 5%, p = 0.030). Subgroup analysis revealed higher seroclearance with follow-up of >5 years (18%, p = 0.004), showing significantly higher rates were observed in studies with longer follow-up periods. Caucasians showed a higher rate (12%) than Asians (9%, p = 0.067). Studies adhering to AASLD, EASL, or APASL stopping rules showed no significant differences in rates. Patients with EOT qHBsAg ≤2.0 log IU/mL had higher rates (23%) than those with >2.0 log IU/mL (11%). Re-treated patients had lower seroclearance (6%) compared to those not re-treated (17%, p = 0.178). Meta-regression identified ethnicity, HBeAg status, and follow-up duration as significant contributors to heterogeneity. Egger's test showed no evidence of publication bias (p = 0.1928). CONCLUSION Our meta-analysis highlights the role of ethnicity, EOT qHBsAg levels, HBeAg-status, and follow-up duration in determining HBsAg seroclearance rates. These findings stress the need for personalized NA discontinuation strategies and further research on HBV genotypes and biomarkers to improve treatment outcomes and predict seroclearance more accurately.
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Affiliation(s)
- Soe Thiha Maung
- Division of Gastroenterology, Department of Medicine, King Chulalongkorn Memorial Hospital and Thai Red Cross Society, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Ma Har Myaing Hospital, Yangon, Myanmar
| | - Pakanat Decharatanachart
- Division of Gastroenterology, Department of Medicine, King Chulalongkorn Memorial Hospital and Thai Red Cross Society, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Division of Academic Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Roongruedee Chaiteerakij
- Division of Gastroenterology, Department of Medicine, King Chulalongkorn Memorial Hospital and Thai Red Cross Society, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence for Innovation and Endoscopy in Gastrointestinal Oncology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Franzè MS, Saitta C, Lombardo D, Musolino C, Caccamo G, Filomia R, Pitrone C, Cacciola I, Pollicino T, Raimondo G. Long-term virological and clinical evaluation of chronic hepatitis B patients under nucleos(t)ide analogues therapy. Clin Res Hepatol Gastroenterol 2025; 49:102566. [PMID: 40043798 DOI: 10.1016/j.clinre.2025.102566] [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: 01/09/2025] [Accepted: 03/02/2025] [Indexed: 04/06/2025]
Abstract
INTRODUCTION AND OBJECTIVES Identifying hepatitis B virus (HBV) patients eligible for safe nucleos(t)ide analogues (NAs) discontinuation remains challenging. Discrepant data on combined HBV DNA and quantitative HBV surface antigen (qHBsAg) assessments are available. This study aimed to identify potential predictors for safe treatment discontinuation by evaluating clinical/virological outcomes in patients on long-term NA therapy. PATIENTS AND METHODS A retrospective cohort of 139 chronic hepatitis B (CHB) patients - who consecutively started Entecavir or Tenofovir from 2007 to 2011 - was evaluated. The study population was selected based on anti-HBe positivity, absence of prior antiviral treatment, absence of non-HBV-related liver diseases or hepatocellular carcinoma (HCC), and long-term clinical/ultrasonographic/laboratory evaluations post-NA initiation. Serum samples collected before starting NA (T0) and over ten years (T1-T10) were tested for HBV DNA and qHBsAg. RESULTS Twenty-two/139 (15.8 %) CHB patients (12 chronic hepatitis, 10 cirrhosis) met the inclusion criteria. All patients showed a significant decrease in liver stiffness values in the ten years of follow-up (p = 0.001), and no hepatic decompensation occurred. Three/22 (13.6 %) patients developed HCC. Ten/22 patients (45.5 %; group-A) had fluctuating HBV DNA, while other 10/22 (45.5 %; group-B) showed undetectable HBV DNA for 5-9 years with more significant qHBsAg decline (p = 0.04) than group-A. Two/22 (9.1 %) patients showed a critical qHBsAg decline up to seroconversion together with undetectable HBV DNA. CONCLUSIONS Persistent undetectable HBV DNA levels correlate with qHBsAg reduction and the potential HBsAg seroclearance, suggesting that long-term HBV DNA monitoring in NA-treated CHB patients might help identify candidates for treatment discontinuation.
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Affiliation(s)
- Maria Stella Franzè
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Carlo Saitta
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Daniele Lombardo
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Cristina Musolino
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Gaia Caccamo
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Roberto Filomia
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Concetta Pitrone
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Irene Cacciola
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Teresa Pollicino
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Laboratory of Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Giovanni Raimondo
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy.
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Lim SG, Teo AED, Chan ESY, Phyo WW, Chen DHY, Hargreaves CA. Stopping Nucleos(t)ide Analogues in Chronic Hepatitis B Using HBsAg Thresholds: A Meta-Analysis and Meta-Regression. Clin Gastroenterol Hepatol 2024; 22:2403-2412. [PMID: 38871150 DOI: 10.1016/j.cgh.2024.05.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 04/30/2024] [Accepted: 05/28/2024] [Indexed: 06/15/2024]
Abstract
BACKGROUND AND AIMS Recommendations for stopping nucleoside analogue (NA) therapy in hepatitis B e antigen-negative chronic hepatitis B (CHB) are unclear. End-of-treatment quantitative hepatitis B serum antigen (EOTqHBsAg) thresholds <100 IU/mL or <1000 IU/mL have been proposed as stopping criteria, which we assessed by meta-analysis and meta-regression. METHODS We searched PubMed, EMBASE, and conference abstracts for studies of hepatitis B e antigen-negative CHB NA discontinuation. Extracted studies were analyzed for risk of bias, pooled risk of hepatitis B serum antigen (HBsAg) loss, virological relapse (VR), and biochemical relapse (BR). Significant heterogeneity (I2) was addressed by subgroup analysis and random-effects meta-regression with known important covariates, including EOTqHBsAg thresholds, ethnicity, duration of therapy, and follow-up. RESULTS We found 24 articles (3732 subjects); 16 had low and 8 had moderate risk of bias. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <100 IU/mL were 41.8%, 33.4%, and 17.3%, respectively, vs 4.6%, 72.1%, and 34.6%, respectively, for EOTqHBsAg ≥100 IU/mL. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <1000 IU/mL were 22.0%, 52.7%, and 15.9%, respectively, vs 3.4%, 63.8%, and 26.4%, respectively, for EOTqHBsAg ≥1000 IU/mL. Multivariable analysis for HBsAg loss showed that ethnicity, follow-up duration, and EOTqHBsAg <100 IU/mL and ≥100 IU/mL explained 85% of the variance in heterogeneity; Asians with EOTqHBsAg <100 IU/mL had 28.2%, while non-Asians with EOTqHBsAg <1000 IU/mL had 38.4% HBsAg loss. Multivariable analysis showed EOTqHBsAg <100 IU/mL and ≥100 IU/mL and other covariates only explained 43% and 63% of the variance in heterogeneity for VR and BR, respectively, suggesting that other factors are also important for relapse. CONCLUSIONS While EOTqHBsAg thresholds, ethnicity, and follow-up duration strongly predict HBsAg loss, this is not true for VR and BR, hence stopping NA therapy should be considered cautiously.
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Affiliation(s)
- Seng Gee Lim
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, National University Health System, Singapore.
| | - Ada Ee Der Teo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Edwin Shih-Yen Chan
- Singapore Clinical Research Institute, Consortium for Clinical Research and Innovation Singapore, Singapore; Cochrane Singapore, Singapore; Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore
| | - Wah Wah Phyo
- Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - David Hsing Yu Chen
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Carol Anne Hargreaves
- Data Analytics Consulting Centre, Faculty of Science, National University of Singapore, Singapore
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Lazarevic I, Miljanovic D, Banko A, Cupic M, Cirkovic A. Quantitative HBV Core Antibodies as a Prognostic Marker for HBeAg Seroclearance: A Systematic Review with Meta-Analysis. Viruses 2024; 16:1121. [PMID: 39066283 PMCID: PMC11281513 DOI: 10.3390/v16071121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 07/07/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
During chronic hepatitis B virus (HBV) infection, the seroclearance of hepatitis B e antigen (HBeAg) is an important event and a significant surrogate endpoint of all current therapeutic strategies. The prediction of HBeAg seroclearance can help assess the benefits of therapy in patients during or before therapy initiation. The quantitation of HBV core antibodies (qAnti-HBc) is a new non-invasive biomarker for solving multiple diagnostic dilemmas. A systematic review and meta-analysis of studies that measured qAnti-HBc in patients who achieved HBeAg seroclearance were performed through PubMed, Web of Science (WoS) and SCOPUS electronic database searches. Nineteen articles were included in the systematic review, comprising 3434 chronically infected patients (1014 with and 2420 without HBeAg seroclearance). Sixteen publications with data regarding qAnti-HBc levels were included in the meta-analysis. The baseline level of qAnti-HBc antibodies was significantly higher in patients with than without HBeAg seroclearance (SMD = 0.88, 95%CI SMD = 0.56-1.2, p < 0.001). The same conclusion was reached for patients originating from Asia (SMD = 0.94, 95%CI SMD = 0.55-1.33) and for the qAnti-HBc antibodies among adult HBV patients with therapy-induced HBeAg seroclearance (SMD = 0.90, 95%CI SMD = 0.54-1.25, p < 0.001). The systematic review and meta-analysis provide evidence of the role of qAnti-HBc as a promising biomarker for predicting HBeAg seroclearance in chronically infected patients.
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Affiliation(s)
- Ivana Lazarevic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (D.M.); (A.B.); (M.C.)
| | - Danijela Miljanovic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (D.M.); (A.B.); (M.C.)
| | - Ana Banko
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (D.M.); (A.B.); (M.C.)
| | - Maja Cupic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (D.M.); (A.B.); (M.C.)
| | - Andja Cirkovic
- Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
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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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7
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Papatheodoridi M, Papatheodoridis G. Finite therapy of chronic hepatitis B infection: Pros. Clin Liver Dis (Hoboken) 2024; 23:e0148. [PMID: 38707241 PMCID: PMC11068136 DOI: 10.1097/cld.0000000000000148] [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: 11/18/2023] [Accepted: 01/09/2024] [Indexed: 05/07/2024] Open
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Papatheodoridi M, Papachristou E, Moschidis Z, Hadziyannis E, Rigopoulou E, Zachou K, Villeret F, Magiorkinis G, Lyberopoulou A, Gatselis N, Vlachogiannakos I, Manolakopoulos S, Dalekos GN, Zoulim F, Paraskevis D, Papatheodoridis GV. Significance of serum HBV RNA in non-cirrhotic HBeAg-negative chronic hepatitis B patients who discontinue effective antiviral therapy. J Viral Hepat 2022; 29:948-957. [PMID: 35789515 DOI: 10.1111/jvh.13729] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/13/2022] [Accepted: 06/20/2022] [Indexed: 12/30/2022]
Abstract
HBV RNA is considered as a promising predictor in patients who discontinue nucleos(t)ide analogues (NAs). We determined HBV RNA levels in non-cirrhotic HBeAg-negative patients who discontinued NAs and assessed their predictability for 12-month outcomes. Fifty-seven patients of DARING-B study were included. HBV RNA levels were determined in stored monthly serum samples drawn at 0-3 months after end of therapy (EOT). Other markers previously determined in the same cohort including hepatitis B core-related antigen (HBcrAg) were also assessed. HBV RNA at EOT was detectable in 7% of patients, who developed virological/clinical relapse and required retreatment at month 2; in patients with undetectable EOT HBV RNA, 12-month cumulative rates of virological relapse, clinical relapse and retreatment were 68%, 28% and 21%, respectively (p ≤ 0.008). HBV RNA at month-1 after EOT was detectable in 19% of patients being associated with higher probability only of virological relapse (p = 0.001). HBV RNA levels correlated significantly to HBV DNA, HBcrAg, ALT and interferon-induced protein-10, but not HBsAg levels. Combined EOT HBV RNA and HBcrAg detection and/or HBsAg >1000 IU/ml was associated only with higher probability of retreatment having higher sensitivity and lower specificity than HBV RNA alone. In conclusion, serum HBV RNA is detectable in a minority of non-cirrhotic HBeAg-negative patients under effective long-term NAs therapy offering low sensitivity but 100% specificity for early retreatment due to severe clinical relapses after NA discontinuation. The combinations of EOT HBV RNA with HBcrAg and/or high HBsAg levels increase sensitivity but decrease specificity for prediction of retreatment after NAs withdrawal.
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Affiliation(s)
- Margarita Papatheodoridi
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.,Institute of Liver and Digestive Health, University College of London, London, UK
| | - Eleni Papachristou
- Department of Hygiene and Epidemiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Zissis Moschidis
- Department of Hygiene and Epidemiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Emilia Hadziyannis
- 2nd Department of Internal Medicine, National and Kapodistrian University of Athens School of Health Sciences, General Hospital of Athens "Hippokratio", Athens, Greece
| | - Eirini Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | | | - Gkikas Magiorkinis
- Department of Hygiene and Epidemiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Nikolaos Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Ioannis Vlachogiannakos
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Spilios Manolakopoulos
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Fabien Zoulim
- INSERM U1052 - Cancer Research Center of Lyon (CRCL), Lyon, France
| | - Dimitrios Paraskevis
- Department of Hygiene and Epidemiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - George V Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
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Piermatteo L, Scutari R, Chirichiello R, Alkhatib M, Malagnino V, Bertoli A, Iapadre N, Ciotti M, Sarmati L, Andreoni M, Ceccherini-Silberstein F, Salpini R, Svicher V. Droplet digital PCR assay as an innovative and promising highly sensitive assay to unveil residual and cryptic HBV replication in peripheral compartment. Methods 2022; 201:74-81. [PMID: 34000391 DOI: 10.1016/j.ymeth.2021.05.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/29/2021] [Accepted: 05/12/2021] [Indexed: 02/07/2023] Open
Abstract
Droplet digital PCR is an innovative and promising approach for highly sensitive quantification of nucleic acids that is being increasingly used in the field of clinical virology, including the setting of hepatitis B virus (HBV). Here, we comprehensively report a robust and reproducible ddPCR assay for the highly sensitive quantification of serum HBV-DNA. The assay showed a limit of detection of 4 copies/ml (<1IU/ml) by Probit analysis, showed a good linearity (R2 = 0.94) and a high intra- and inter-run reproducibility with differences between the values obtained in the same run or in two independent runs never exceeding 0.14logcopies/mL and 0.21logcopies/mL, respectively. By analysing serum samples from chronically HBV infected patients (mostly under antiviral treatment), ddPCR successfully quantified serum HBV-DNA in 89.8% of patients with detectable serum HBV-DNA < 20 IU/mL [equivalent to <112copies/ml] by classical Real-Time PCR assay, with a median (IQR) of 8(5-14)IU/mL [45(28-78)copies/ml], and in 66.7% of patients with undetectable serum HBV-DNA, with a median (IQR) of 5(4-9)IU/mL [28(20-50)copies/ml]. Similarly, by analysing serum samples from patients with a serological profile compatible with occult HBV infection (anti-HBc+/HBsAg-), ddPCR successfully quantified serum HBV-DNA in 40% of patients with a median (IQR) value of 1(1-2)IU/mL [5(5-11)copies/ml], in line with the extremely limited viral replication typically observed in occult HBV infection. Overall, the availability of assays for the highly sensitive quantification of serum HBV-DNA can provide an added value in optimizing the diagnosis of occult hepatitis B infection, improving the therapeutic management of chronically HBV infected patients, also in the light of innovative drugs (upcoming in clinical practise) aimed at achieving HBV functional cure.
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Affiliation(s)
- Lorenzo Piermatteo
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Rossana Scutari
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | | | - Mohammad Alkhatib
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Vincenzo Malagnino
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Ada Bertoli
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy; Laboratory of Clinical Microbiology and Virology, Polyclinic Tor Vergata Foundation, Rome, Italy
| | - Nerio Iapadre
- Infectious Diseases Unit, "San Salvatore Hospital", L' Aquila, Italy
| | - Marco Ciotti
- Laboratory of Clinical Microbiology and Virology, Polyclinic Tor Vergata Foundation, Rome, Italy
| | - Loredana Sarmati
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Massimo Andreoni
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | | | - Romina Salpini
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.
| | - Valentina Svicher
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
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10
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Papatheodoridi M, Su TH, Hadziyannis E, Liao CH, Orfanidou Α, Yang HC, Zachou K, Liu CJ, Kourikou A, Gatselis N, Manolakopoulos S, Dalekos G, Kao JH, Hadziyannis S, Papatheodoridis GV. Hepatocellular carcinoma after treatment cessation in non-cirrhotic HBeAg-negative chronic hepatitis B: A multicentre cohort study. Liver Int 2022; 42:541-550. [PMID: 34890120 DOI: 10.1111/liv.15128] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 12/06/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Scarce data exist on the effect of nucleos(t)ide analogue (NA) discontinuation on hepatocellular carcinoma (HCC) risk in HBeAg-negative chronic hepatitis B (CHBe-). Therefore, we assessed whether HCC risk is increased in non-cirrhotic CHBe- patients who discontinue compared to those remaining on NAs. METHODS This cohort study included 650 consecutive non-cirrhotic Caucasian or Asian patients with CHBe- without a history of HCC who discontinued NAs after a median of 5 or 3 years (cases, n = 325; Caucasians: 143, Asians: 182) or remained on NA therapy beyond 5 or 3 years respectively (controls, n = 325; Caucasians: 223, Asians: 102). Propensity score (PS) 1:1 matching was applied to adjust for patients' origin, age and sex. RESULTS During a median follow-up of 44 months, HCC developed in 7/325 cases and 9/325 controls or 7/245 PS-matched cases and 7/245 PS-matched controls with 5-year cumulative HCC incidence of 5.1% and 4.9% respectively (log-rank, P = .836). No difference in 5-year HCC risk was observed between cases and controls of Caucasian (3.0% vs 4.8%; log-rank, P = .510) or Asian origin (1.3% vs 2.2%; log-rank, P = .873). In both cases and controls, HCC incidence was independently associated with age and PAGE-B score. In cases alone, HCC development after NA discontinuation was associated only with pretreatment platelet counts and PAGE-B score, but not with any type of relapse or HBsAg loss. CONCLUSIONS Our findings suggest that discontinuation of effective long-term NA therapy in non-cirrhotic CHBe- patients are not associated with increased HCC risk, which is not affected by post-NA relapses and/or HBsAg loss.
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Affiliation(s)
- Margarita Papatheodoridi
- Department of Gastroenterology, National and Kapodistrian University of Athens School of Health Sciences, General Hospital of Athens "Laiko", Athens, Greece
| | - Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Emilia Hadziyannis
- 2nd Department of Internal Medicine, National and Kapodistrian University of Athens School of Health Sciences, General Hospital of Athens "Hippokratio", Athens, Greece
| | - Chun-Hsun Liao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Αfroditi Orfanidou
- Department of Gastroenterology, National and Kapodistrian University of Athens School of Health Sciences, General Hospital of Athens "Laiko", Athens, Greece
| | - Hung-Chi Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Anastasia Kourikou
- 2nd Department of Internal Medicine, National and Kapodistrian University of Athens School of Health Sciences, General Hospital of Athens "Hippokratio", Athens, Greece
| | - Nikolaos Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Spilios Manolakopoulos
- Department of Gastroenterology, National and Kapodistrian University of Athens School of Health Sciences, General Hospital of Athens "Laiko", Athens, Greece.,2nd Department of Internal Medicine, National and Kapodistrian University of Athens School of Health Sciences, General Hospital of Athens "Hippokratio", Athens, Greece
| | - George Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Stephanos Hadziyannis
- 2nd Department of Internal Medicine, National and Kapodistrian University of Athens School of Health Sciences, General Hospital of Athens "Hippokratio", Athens, Greece
| | - George V Papatheodoridis
- Department of Gastroenterology, National and Kapodistrian University of Athens School of Health Sciences, General Hospital of Athens "Laiko", Athens, Greece
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11
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Recent Progress and Future Prospective in HBV Cure by CRISPR/Cas. Viruses 2021; 14:v14010004. [PMID: 35062208 PMCID: PMC8781244 DOI: 10.3390/v14010004] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 12/09/2021] [Accepted: 12/17/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) infection remains an important issue of global public health. Although current antiviral therapy has dramatically reduced the mortality and morbidity of chronic hepatitis B (CHB), it fails to cure it. Rebound viremia often occurs after stopping antiviral therapy. Persistent HBV covalently closed circular DNA (cccDNA) and integrated DNA under antiviral therapy form the major barrier to eradication of HBV infection. CRISPR-mediated genome editing has emerged as a promising therapeutic approach to specifically destroy persistent HBV genomes, both cccDNA and integrated DNA, for HBV cure. However, the cleavage of integrated HBV DNA by CRISPR-Cas9 will cause double-strand break (DSB) of host genome, raising a serious safety concern about genome instability and carcinogenesis. The newly developed CRISPR-derived base editors (BEs), which fuse a catalytically disabled nuclease with a nucleobase deaminase enzyme, can be used to permanently inactivate HBV genome by introducing irreversible point mutations for generation of premature stop codons without DSBs of host genome. Although promising, CRISPR-mediated base editing still faces daunting challenges before its clinical application, including the base-editing efficacy, the off-target effect, the difficulty in finding conserved target HBV sequences, and in vivo delivery efficiency. Several strategies have been adopted to optimize the efficiency and specificity of CRISPR-BEs and to improve in vivo delivery efficacy through novel viral and non-viral delivery approaches. Particularly, the non-viral delivery of Cas9 mRNA and ribonucleoprotein by lipid nanoparticles exhibits attractive potential for liver-targeted delivery in clinical. Along with all progress above, the CRISPR-mediated gene therapy will ultimately achieve HBV cure.
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12
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Zuccaro V, Asperges E, Colaneri M, Marvulli LN, Bruno R. HBV and HDV: New Treatments on the Horizon. J Clin Med 2021; 10:jcm10184054. [PMID: 34575165 PMCID: PMC8471459 DOI: 10.3390/jcm10184054] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/06/2021] [Accepted: 09/06/2021] [Indexed: 12/23/2022] Open
Abstract
Despite the accumulating knowledge, chronic hepatitis B (CHB) and HDV infection represent a global health problem, and there are still several critical issues, which frequently remain uncovered. In this paper, we provided an overview of the current therapeutic options and summarized the investigational therapies in the pipeline. Furthermore, we discussed some critical issues such as a “functional cure” approach, the futility of long-term NA therapy and the relevance of understanding drug actions and safety of antivirals, especially in special populations.
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Affiliation(s)
- Valentina Zuccaro
- U.O.C. Malattie Infettive I Fondazione IRCCS Policlinico San Matteo–Università di Pavia, 27100 Pavia, Italy; (E.A.); (M.C.); (L.N.M.); (R.B.)
- Correspondence: ; Tel.: +39-0382502660
| | - Erika Asperges
- U.O.C. Malattie Infettive I Fondazione IRCCS Policlinico San Matteo–Università di Pavia, 27100 Pavia, Italy; (E.A.); (M.C.); (L.N.M.); (R.B.)
| | - Marta Colaneri
- U.O.C. Malattie Infettive I Fondazione IRCCS Policlinico San Matteo–Università di Pavia, 27100 Pavia, Italy; (E.A.); (M.C.); (L.N.M.); (R.B.)
| | - Lea Nadia Marvulli
- U.O.C. Malattie Infettive I Fondazione IRCCS Policlinico San Matteo–Università di Pavia, 27100 Pavia, Italy; (E.A.); (M.C.); (L.N.M.); (R.B.)
- Dipartimento di Scienze Clinico-Chirurgiche, Diagnostiche e Pediatriche–Università di Pavia, 27100 Pavia, Italy
| | - Raffaele Bruno
- U.O.C. Malattie Infettive I Fondazione IRCCS Policlinico San Matteo–Università di Pavia, 27100 Pavia, Italy; (E.A.); (M.C.); (L.N.M.); (R.B.)
- Dipartimento di Scienze Clinico-Chirurgiche, Diagnostiche e Pediatriche–Università di Pavia, 27100 Pavia, Italy
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13
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Medas R, Liberal R, Macedo G. Discontinuation of antiviral therapy in chronic hepatitis B patients. World J Clin Cases 2021; 9:6979-6986. [PMID: 34540953 PMCID: PMC8409197 DOI: 10.12998/wjcc.v9.i24.6979] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/29/2021] [Accepted: 07/02/2021] [Indexed: 02/06/2023] Open
Abstract
Nucleos(t)ide analogs (NUC) are the first-line therapy for patients with chronic hepatitis B (CHB) recommended by most current guidelines. NUC therapy decreases progression of liver disease, reduces the risk of liver-related complications, and improves the quality of life of patients with CHB. Although indefinite or long-term NUC therapy is usually recommended, this strategy raises several concerns, such as side-effects, adherence, costs, and patient willingness to stop therapy. Recent data showed the feasibility, efficacy, and safety of stopping antiviral therapy in carefully selected CHB patients, leading to its incorporation in international guidelines. Patients who discontinue NUC have a higher likelihood of hepatitis B surface antigen (HBsAg) loss compared to patients who continue on therapy. Recommendations pertaining endpoints allowing safety discontinuation of NUC therapy differ among international guidelines. For hepatitis B e antigen (HBeAg)-positive patients, durable HBeAg seroconversion is considered an acceptable treatment endpoint. For HBeAg-negative patients, some guidelines propose undetectability hepatitis B virus DNA for at least 2 or 3 years, while others consider HBsAg loss as the only acceptable endpoint. CHB patients who stop therapy should remain under strict clinical and laboratorial follow-up protocols to detect and manage relapses in a timely manner. No reliable predictor of relapse has been consistently identified to date, although quantitative HBsAg has been increasingly studied as a reliable biomarker to predict safe NUC discontinuation.
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Affiliation(s)
- Renato Medas
- Department of Gastroenterology and Hepatology, Centro Hospitalar Universitário de São João, Porto 4200-319, Portugal
| | - Rodrigo Liberal
- Department of Gastroenterology and Hepatology, Centro Hospitalar Universitário de São João, Porto 4200-319, Portugal
| | - Guilherme Macedo
- Department of Gastroenterology and Hepatology, Centro Hospitalar Universitário de São João, Porto 4200-319, Portugal
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14
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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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15
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Su T, Kao J. Withdrawal of Nucleos(t)ide Analogues in Hepatitis B e Antigen-Negative Patients: An Asian Perspective. Clin Liver Dis (Hoboken) 2021; 16:244-248. [PMID: 33489096 PMCID: PMC7805293 DOI: 10.1002/cld.950] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 01/22/2020] [Accepted: 03/06/2020] [Indexed: 02/04/2023] Open
Affiliation(s)
- Tung‐Hung Su
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan,Department of Internal MedicineNational Taiwan University College of MedicineTaipeiTaiwan,Hepatitis Research CenterNational Taiwan University HospitalTaipeiTaiwan
| | - Jia‐Horng Kao
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan,Department of Internal MedicineNational Taiwan University College of MedicineTaipeiTaiwan,Hepatitis Research CenterNational Taiwan University HospitalTaipeiTaiwan,Graduate Institute of Clinical MedicineNational Taiwan University College of MedicineTaipeiTaiwan,Department of Medical ResearchNational Taiwan University HospitalTaipeiTaiwan
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16
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Kaewdech A, Tangkijvanich P, Sripongpun P, Witeerungrot T, Jandee S, Tanaka Y, Piratvisuth T. Hepatitis B surface antigen, core-related antigen and HBV RNA: Predicting clinical relapse after NA therapy discontinuation. Liver Int 2020; 40:2961-2971. [PMID: 32668074 DOI: 10.1111/liv.14606] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 06/10/2020] [Accepted: 07/09/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND & AIMS The safe discontinuation of nucleos(t)ide analogue therapy remains challenging in chronic hepatitis B. We investigated the potential role of quantitative hepatitis B surface antigen, hepatitis B core-related antigen and hepatitis B virus RNA at the end of treatment in predicting off-therapy relapse. METHODS Patients who fulfilled the stopping criteria of the Asian Pacific Association for the Study of the Liver guideline were enrolled. Virological relapse was defined as hepatitis B virus DNA level greater than 2000 IU/mL, and clinical relapse was defined as virological relapse plus alanine aminotransferase level of more than twice the upper limit of normal. RESULTS Ninety-two patients participated. The combination of end-of-treatment hepatitis B core-related antigen and hepatitis B virus RNA levels was most predictive of clinical relapse. Multivariate analysis revealed that end-of-treatment hepatitis B core-related antigen and hepatitis B virus RNA were independently associated with clinical relapse. During follow-up, no patients with undetectable hepatitis B core-related antigen (<3.0 log10 U/mL) and hepatitis B virusRNA (<2.0 log10 copies/mL) at end of treatment developed clinical relapse, in comparison with 22.9% and 62.5% patients with detectable levels of one or both biomarkers respectively. End-of-treatment quantitative hepatitis B surface antigen was linked to a likelihood of hepatitis B surface antigen clearance. CONCLUSIONS The combined hepatitis B core-related antigen and hepatitis B virus RNA assays at end of treatment were highly predictive of subsequent clinical relapse. These novel biomarkers could potentially be used to identify patients who could safely discontinue nucleos(t)ide analogue therapy.
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Affiliation(s)
- Apichat Kaewdech
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pimsiri Sripongpun
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Teepawit Witeerungrot
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Songkhla, Thailand
| | - Sawangpong Jandee
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Yasuhito Tanaka
- Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Teerha Piratvisuth
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Songkhla, Thailand
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17
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Papatheodoridi M, Papatheodoridis G. Emerging Diagnostic Tools to Decide When to Discontinue Nucleos(t)ide Analogues in Chronic Hepatitis B. Cells 2020; 9:cells9020493. [PMID: 32093411 PMCID: PMC7072769 DOI: 10.3390/cells9020493] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 02/09/2020] [Accepted: 02/15/2020] [Indexed: 12/27/2022] Open
Abstract
The aim of this review is to outline emerging biomarkers that can serve as diagnostic tools to identify non-cirrhotic chronic hepatitis B (CHB) patients who could safely discontinue nucleos(t)ide analogues (NAs) before HBsAg loss. Regarding possible predictors of post-NAs outcomes, a number of studies have evaluated numerous factors, which can be categorised in markers of hepatitis B virus (HBV) activity, markers of host immune response and markers of other patient characteristics. In clinical practice, the most important question for patients who discontinue NAs is to differentiate those who will benefit by achieving HBsAg loss or at least by remaining in remission and those who will relapse requiring retreatment. Most of the discontinuation studies so far came from Asian and only few from European populations and examined the rates and predictors of post-NA virological and/or combined relapses or HBsAg loss. To date, there is still controversy about predictors of post-NA relapses, while only HBsAg serum levels at NA discontinuation seem to be the most robust predictive marker of the probability of subsequent off-treatment HBsAg seroclearance. Newer viral markers such as HBV RNA and hepatitis B core-related antigen seem promising, but further research is required.
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Affiliation(s)
- Margarita Papatheodoridi
- Institute of Liver and Digestive Health, Royal Free Hospital, University College of London, London NW3 2QG, UK;
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, 11527 Athens, Greece
| | - George Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, 11527 Athens, Greece
- Correspondence: ; Tel.: +30-2132061115
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18
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Papatheodoridi M, Hadziyannis E, Berby F, Zachou K, Testoni B, Rigopoulou E, Gatselis NK, Lyberopoulou A, Vlachogiannakos I, Manolakopoulos S, Dalekos GN, Zoulim F, Papatheodoridis GV. Predictors of hepatitis B surface antigen loss, relapse and retreatment after discontinuation of effective oral antiviral therapy in noncirrhotic HBeAg-negative chronic hepatitis B. J Viral Hepat 2020; 27:118-126. [PMID: 31562748 DOI: 10.1111/jvh.13211] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 06/11/2019] [Accepted: 08/26/2019] [Indexed: 12/12/2022]
Abstract
Reliable predictors of outcomes after treatment discontinuation in HBeAg-negative chronic hepatitis B (CHB) patients have not been established. We investigated the role of hepatitis B surface antigen (HBsAg), interferon-inducible protein-10 (IP10) and hepatitis B core-related antigen (HBcrAg) serum levels as predictors of HBsAg loss, relapse and retreatment in noncirrhotic HBeAg-negative CHB patients who discontinued long-term antiviral therapy. All HBsAg-positive (n = 57) patients of the prospective DARING-B study were included and followed monthly for 3 months, every 2/3 months until month-12 and every 3/6 months thereafter. HBsAg, IP10 and HBcrAg levels were measured by enzyme immunoassays, and SCALE-B score was calculated. Twelve patients achieved HBsAg loss before retreatment with 18-month cumulative incidence of 25%. Independent predictors of HBsAg loss were baseline HBsAg and month-1 IP10 levels. Of 10 patients with baseline HBsAg ≤100 IU/mL, 70% cleared HBsAg and 10% required retreatment. Of 23 patients with baseline HBsAg >1000 IU/mL, 4% cleared HBsAg and 43% required retreatment. Of 24 patients with intermediate baseline HBsAg (100-1000 IU/mL), 17% cleared HBsAg and 21% required retreatment; in this subgroup, month-1 IP10 was significantly associated with HBsAg loss, which occurred in 30% and 7% of cases with IP10 >150 and ≤150 pg/mL, respectively. Baseline HBcrAg was undetectable in all patients who cleared HBsAg and was associated with retreatment. SCALE-B was associated with HBsAg loss but not with relapse or retreatment. In conclusion, HBsAg, IP10 and HBcrAg serum levels can be useful for the decisions and management of treatment discontinuation in noncirrhotic Caucasian patients with HBeAg-negative CHB.
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Affiliation(s)
- Margarita Papatheodoridi
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
| | - Emilia Hadziyannis
- 2nd Department of Internal Medicine, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Hippokratio", Athens, Greece
| | - Françoise Berby
- INSERM U1052 - Cancer Research Center of Lyon (CRCL), Lyon, France
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Barbara Testoni
- INSERM U1052 - Cancer Research Center of Lyon (CRCL), Lyon, France
| | - Eirini Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Nikolaos K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Ioannis Vlachogiannakos
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
| | - Spilios Manolakopoulos
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
- 2nd Department of Internal Medicine, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Hippokratio", Athens, Greece
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, Thessaly University Medical School, Larissa, Greece
| | - Fabien Zoulim
- INSERM U1052 - Cancer Research Center of Lyon (CRCL), Lyon, France
| | - George V Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
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19
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Gao X, Duan X, Cai H, Hu Y, Liu M, Kang K, Zhou M, Fu D, Yi W. Pregnancy Outcome of Women with Chronic Hepatitis B who Discontinued Antiviral Treatment before or in the Early Pregnancy. Int J Med Sci 2020; 17:170-175. [PMID: 32038100 PMCID: PMC6990883 DOI: 10.7150/ijms.38410] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Accepted: 12/12/2019] [Indexed: 01/15/2023] Open
Abstract
Background: The aim of this study was to describe biochemical, virological features and Mother-to child-transmission (MTCT) rate in chronic hepatitis B (CHB) women who stopped antiviral therapy before or in the early pregnancy. Methods: This was a single-center, retrospective study. Forty-three CHB women who stopped treatment before or in the early pregnancy and 103 CHB women with tenofovir disoproxil fumarate (TDF) treatment throughout pregnancy were enrolled. The virological and biochemical flares during pregnancy and postpartum period were studied. MTCT rates were also compared. Results: During pregnancy, ALT flares (43.9% vs 1.0%) and viral rebound (31.7% vs 0) were more common in women who stopped treatment (P<0.001). Postpartum ALT flares were less frequent in women with treatment than those stopped treatment (0 vs 6/35, P = 0.001). The birth defect rate in the mothers who stopped treatment did not statistically differ from that of mothers treated throughout pregnancy (4.9 % vs 3.9 %, P = 1.000). There were no significant differences of gestational complications between the two groups, except intrahepatic cholestasis of pregnancy (12.2% vs 0, P = 0.002). The rate of MTCT in mothers who discontinued treatment was higher (2.4% vs 0, P = 0.285), although there was no statistically significant. Conclusion: ALT flares were common in mothers who discontinued antiviral therapy. Thus, these pregnant women should be monitored closely. Cessation of treatment was not recommended although no hepatic failure was observed. Larger studies are needed to evaluate the safety of discontinuation before pregnancy.
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Affiliation(s)
- Xuesong Gao
- Department of General Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xuefei Duan
- Department of General Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Haodong Cai
- Hepatology clinic, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuhong Hu
- Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Min Liu
- Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Kai Kang
- Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Mingfang Zhou
- Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Dong Fu
- Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wei Yi
- Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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