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Li S, Shi L, Huang C, Li M, Meng T, Wang H, Zhao X, Xu X, You H, Jia J, Kong Y. Impact of hepatitis B surface antigen quantification on achieving a functional cure in patients with chronic hepatitis B: A systematic review and meta-analysis. Ann Hepatol 2025:101921. [PMID: 40316220 DOI: 10.1016/j.aohep.2025.101921] [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: 12/02/2024] [Revised: 03/17/2025] [Accepted: 03/25/2025] [Indexed: 05/04/2025]
Abstract
INTRODUCTION AND OBJECTIVES Baseline hepatitis B surface antigen (HBsAg) levels are associated with the likelihood of achieving HBsAg loss which defines the functional cure. However, optimal HBsAg cut-offs for predicting HBsAg loss have not been systematically investigated." Therefore, in this systematic review and meta-analysis, we evaluated the impact of baseline levels of HBsAg on achieving a functional cure in patients with chronic hepatitis B (CHB). MATERIALS AND METHODS We searched PubMed, Embase, and Cochrane Library up to December 31, 2023, to identify studies comparing combination therapy with nucleos(t)ide analogues (NAs) and conventional/pegylated interferon (IFN) versus monotherapy. We pooled the proportion of HBsAg loss among studies stratified by different 75th percentile of baseline HBsAg levels and other clinical characteristics. RESULTS We included 24 studies with 3446 participants. At the end of treatment, studies recruiting patients with 75th percentile of baseline HBsAg below 500 and 1000 IU/mL had the highest proportions of HBsAg loss in the combination group, reaching 14 % (95 % CI: 9-21 %) and 17 % (95 % CI: 10-24 %), respectively. One-year IFN-NAs combination treatment achieved a higher proportion of HBsAg loss (9 %, 95 % CI: 6-12 %) than six-month IFN-NAs treatment (1 %, 95 % CI: 0-2 %). Patients with normal alanine transaminase (ALT) had higher HBsAg loss (11 %, 95 % CI: 6-17 %) than those with elevated ALT (4 %, 95 % CI: 2-7 %). Meta-regression indicated a positive association between male percentage in studies and HBsAg loss. CONCLUSIONS The optimal baseline HBsAg thresholds would be 500-1000 IU/mL, which represents high-response subpopulation for achieving functional cure with currently available therapy.
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Affiliation(s)
- Shun Li
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Lichen Shi
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; Department of Clinical Epidemiology and Clinical Trial, Capital Medical University, China.
| | - Cheng Huang
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; Department of Clinical Epidemiology and Clinical Trial, Capital Medical University, China.
| | - Min Li
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Tongtong Meng
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Hao Wang
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Xinyu Zhao
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Xiaoqian Xu
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Hong You
- National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Jidong Jia
- Department of Clinical Epidemiology and Clinical Trial, Capital Medical University, China; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Yuanyuan Kong
- Clinical Epidemiology and EBM Unit, Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
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Wu J, Xie S, Ma Y, He X, Dong X, Shi Q, Wang Q, Li M, Yao N, Yao L. Entecavir for children and adults with chronic hepatitis B. Cochrane Database Syst Rev 2025; 4:CD015536. [PMID: 40260837 PMCID: PMC12012880 DOI: 10.1002/14651858.cd015536.pub2] [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] [Indexed: 04/24/2025]
Abstract
RATIONALE Chronic hepatitis B is a major worldwide public health concern. Entecavir, one nucleos(t)ide analogue antiviral therapy option, is recommended as the first-line drug for chronic hepatitis B in many clinical guidelines. However, none of the guideline recommendations are based on the findings of a systematic review with meta-analysis, where entecavir versus no treatment or placebo are compared directly. OBJECTIVES To evaluate the benefits and harms of entecavir versus no treatment or placebo in children and adults with chronic hepatitis B, who are either hepatitis B e-antigen (HBeAg)-positive or HBeAg-negative. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE Ovid, Embase Ovid, three other databases, online trial registries, and reference lists, and contacted authors. The latest search was on 19 July 2024. ELIGIBILITY CRITERIA We included randomised clinical trials comparing entecavir versus no treatment or placebo in children or adults, or both, with chronic hepatitis B, and irrespective of treatment history with other antiviral drugs and other viral co-infections. We allowed co-interventions when administered equally to all intervention groups. OUTCOMES The outcomes reported in this abstract and in the summary of findings table are all-cause mortality, health-related quality of life, and proportion of people with serious adverse events at the longest follow-up. RISK OF BIAS We used the Cochrane RoB 2 tool to assess risk of bias in the included trials. SYNTHESIS METHODS We used a random-effects model to meta-analyse outcome results, where possible, and presented the results as a risk ratio (RR) with 95% confidence interval (CI). Where there was considerable heterogeneity, we performed a narrative analysis. We used a fixed-effect model for sensitivity analysis. We used GRADE to evaluate the certainty of evidence. INCLUDED STUDIES We included 22 randomised clinical trials (published from 2005 to 2022) with 2940 participants diagnosed with chronic hepatitis B. All trials had a parallel-group design. The experimental intervention was oral entecavir, with a follow-up duration of 5 weeks to 228 weeks. The comparator in 12 trials was no treatment, and in 10 trials was placebo. Fourteen trials equally administered co-interventions to the trial participants in the entecavir and no treatment and placebo groups. One trial included participants between 14 years and 55 years of age, one trial included only children, 19 trials included only adults, and one trial did not provide the age of participants. SYNTHESIS OF RESULTS Twenty trials contributed data to the quantitative analysis. Ten trials (1379 participants) reported all-cause mortality with a mean follow-up duration of 48.9 weeks (range 5 to 100 weeks). The result was not estimable because no deaths occurred in any of the entecavir and no treatment or placebo groups. None of the trials provided data on health-related quality of life. We are very uncertain about the effect of entecavir versus no treatment or placebo on the proportion of people with serious adverse events (RR 0.66, 95% CI 0.33 to 1.32; absolute risk difference 22 fewer per 1000 (from 44 fewer to 21 more); 15 trials, 1676 participants; very low-certainty evidence). The mean follow-up duration was 58.4 weeks (range 5 weeks to 228 weeks). We downgraded the certainty of evidence for these outcomes to very low, mainly because the overall risk of bias in most trials was with some concerns or high, and serious imprecision (no events or few events). AUTHORS' CONCLUSIONS Given the issues of risk of bias and insufficient power of the included trials and the very low certainty of the available evidence, we could not determine the effect of entecavir versus no treatment or placebo on critical outcomes such as all-cause mortality and serious adverse events. There is a lack of data on health-related quality of life. Given the first-line recommendation and wide usage of entecavir in people with chronic hepatitis B, further evidence on clinically important outcomes, analysed in this review, is needed. FUNDING This Cochrane review had no dedicated funding. REGISTRATION Registration: Entecavir for children and adults with chronic hepatitis B, CD015536 via DOI 10.1002/14651858.CD015536.
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Affiliation(s)
- Jing Wu
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Shitong Xie
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
| | - Yanfang Ma
- Chinese EQUATOR Centre, Hong Kong Baptist University, Hong Kong, China
| | - Xiaoning He
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Xinyue Dong
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Qianling Shi
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Evidence-based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Qi Wang
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
| | - Meixuan Li
- Evidence-based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Naijuan Yao
- The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Liang Yao
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
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Kim KS, Iwamoto M, Kitagawa K, Park H, Hayashi S, Tsukuda S, Matsui T, Atsukawa M, Matsuura K, Chuaypen N, Tangkijvanich P, Allweiss L, Nishiyama T, Nakamura N, Fujita Y, Kawakami E, Nakaoka S, Muramatsu M, Aihara K, Wakita T, Perelson AS, Dandri M, Watashi K, Iwami S, Tanaka Y. Prediction of cccDNA dynamics in hepatitis B patients by a combination of serum surrogate markers. PLoS Comput Biol 2025; 21:e1012615. [PMID: 39787253 PMCID: PMC11753647 DOI: 10.1371/journal.pcbi.1012615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 01/22/2025] [Accepted: 11/04/2024] [Indexed: 01/12/2025] Open
Abstract
Quantification of intrahepatic covalently closed circular DNA (cccDNA) is a key for evaluating an elimination of hepatitis B virus (HBV) in infected patients. However, quantifying cccDNA requires invasive methods such as a liver biopsy, which makes it impractical to access the dynamics of cccDNA in patients. Although HBV RNA and HBV core-related antigens (HBcrAg) have been proposed as surrogate markers for evaluating cccDNA activity, they do not necessarily estimate the amount of cccDNA. Here, we employed a recently developed multiscale mathematical model describing intra- and intercellular viral propagation and applied it in HBV-infected patients under treatment. We developed a model that can predict intracellular HBV dynamics by use of extracellular viral markers, including HBsAg, HBV DNA, and HBcrAg in peripheral blood. Importantly, the model prediction of the amount of cccDNA in patients over time was confirmed to be well correlated with the data for quantified cccDNA by paired liver biopsy. Thus, our method combining classic and emerging surrogate markers enables us to predict the decay dynamics of cccDNA in patients undergoing treatment.
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Affiliation(s)
- Kwang Su Kim
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
- Department of Scientific Computing, Pukyong National University, Busan, South Korea
| | - Masashi Iwamoto
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Kosaku Kitagawa
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
| | - Hyeongki Park
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
| | - Sanae Hayashi
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Senko Tsukuda
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Takeshi Matsui
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Masanori Atsukawa
- Department of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Kentaro Matsuura
- Department of Gastroenterology and Metabolism, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan
| | - Natthaya Chuaypen
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Lena Allweiss
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems partner sites, Germany
| | - Takara Nishiyama
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
| | - Naotoshi Nakamura
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
| | - Yasuhisa Fujita
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
| | - Eiryo Kawakami
- Artificial Intelligence Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
- Medical Sciences Innovation Hub Program; RIKEN, Yokohama, Kanagawa, Japan
| | - Shinji Nakaoka
- Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan
| | - Masamichi Muramatsu
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Kazuyuki Aihara
- International Research Center for Neurointelligence, The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Tokyo, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Alan S. Perelson
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
| | - Maura Dandri
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Koichi Watashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
- Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, Japan
- Department of Applied Biological Sciences, Faculty of Science and Technology, Tokyo University of Sciences, Chiba, Japan
| | - Shingo Iwami
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
- International Research Center for Neurointelligence, The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Tokyo, Japan
- Institute of Mathematics for Industry, Kyushu University,; Fukuoka, Japan
- Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan
- NEXT-Ganken Program, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
- Interdisciplinary Theoretical and Mathematical Sciences (iTHEMS), RIKEN, Wako, Japan
- Science Groove Inc., Fukuoka, Japan
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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Zhang Y, Lin X, Wu H, Chen J, Zheng Q. Systematic review with network meta-analysis: sustained hepatitis B surface antigen clearance after pegylated interferon cessation. Eur J Gastroenterol Hepatol 2024; 36:1159-1170. [PMID: 39083054 DOI: 10.1097/meg.0000000000002823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
The efficacy of different pegylated interferon (PEG-IFN) treatment strategies for achieving sustained hepatitis B surface antigen (HBsAg) clearance in chronic hepatitis B (CHB) remains controversial. This study assesses the efficacy of different PEG-IFN treatment regimens and factors influencing sustained HBsAg clearance after PEG-IFN discontinuation. PubMed , Embase , Web of Science , and the Cochrane Library databases were searched from inception to June 2023, regarding PEG-IFN therapy in CHB. Methodological quality was assessed using the Cochrane risk of bias tool. We explored sources of heterogeneity through univariate meta-regression. Frequentist network meta-analyses were used to compare the efficacy of different PEG-IFN treatment strategies. We analyzed 53 studies (including 9338 CHB patients). After PEG-IFN withdrawal, the annual rates of HBsAg clearance and seroconversion were 6.9% [95% confidence interval (CI), 5.10-9.31] and 4.7% (95% CI, 2.94-7.42). The pooled 1-, 3-, and 5-year sustained HBsAg clearance rates were 7.4%, 9.9%, and 13.0%, and the sustained HBsAg seroconversion rates were 6.6%, 4.7%, and 7.8%, respectively. HBsAg quantification, hepatitis B e antigen status, and PEG-IFN treatment protocols were major sources of heterogeneity. Baseline HBsAg quantification was significantly lower in patients with sustained HBsAg clearance versus those without ( P < 0.046). PEG-IFN combined with tenofovir has the highest probability of achieving HBsAg seroconversion (surface under the cumulative ranking of 81.9%). Sustained HBsAg clearance increased approximately linearly from years 1 to 5 after PEG-IFN discontinuation. Low baseline HBsAg quantification has a significant impact on sustained HBsAg clearance. PEG-IFN combined with tenofovir may be optimal in achieving sustained HBsAg seroconversion.
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Affiliation(s)
- Ying Zhang
- Department of Hepatology, Hepatology Research Institute, the First Affiliated Hospital
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital
| | - Xiaoyu Lin
- Department of Hepatology, Hepatology Research Institute, the First Affiliated Hospital
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital
| | - Huizhen Wu
- Department of Medical Administration, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jing Chen
- Department of Hepatology, Hepatology Research Institute, the First Affiliated Hospital
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital
| | - Qi Zheng
- Department of Hepatology, Hepatology Research Institute, the First Affiliated Hospital
- Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital
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Wei N, Zheng B, Cai H, Li N, Yang J, Liu M. Systematic review and meta-analysis: de novo combination of nucleos(t)ide analogs and pegylated interferon alpha versus pegylated interferon alpha monotherapy for the functional cure of chronic hepatitis B. Front Pharmacol 2024; 15:1403805. [PMID: 39035984 PMCID: PMC11259969 DOI: 10.3389/fphar.2024.1403805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 06/10/2024] [Indexed: 07/23/2024] Open
Abstract
Introduction: Chronic hepatitis B (CHB) is a worldwide infectious disease caused by hepatitis B virus (HBV). Optimizing antiviral treatment strategies could improve the functional cure (FC) rate of patients with CHB. This study aims to systematically review the FC rate of the de novo combination of nucleos(t)ide analogs (NAs) and pegylated interferon α (PEG-IFNα) versus that of PEG-IFNα monotherapy for CHB. Methods: Databases were searched until 31 December 2023. Selected studies included randomized controlled trials on the de novo combination of NAs and PEG-IFNα versus PEG-IFNα monotherapy for 48 weeks in patients with CHB to achieve FC, which was defined as hepatitis B surface antigen (HBsAg) loss and/or HBsAg seroconversion. Meta-analysis was conducted in accordance with the efficacy at the end of treatment and different time points during follow-up. Results: A total of 10 studies, encompassing 2,339 patients in total, were included. Subgroup analysis was conducted in accordance with whether first-line NAs were used. It found no statistically significant difference between HBsAg loss and HBsAg seroconversion at the end of treatment. Serum HBV DNA <500 copies/mL significantly differed between the two groups at the end of treatment and did not significantly differ during follow-up. Meanwhile, HBsAg loss and HBsAg seroconversion showed statistically significant differences at 24 weeks of follow-up. By contrast, no statistically significant difference was found in HBsAg loss at 48 weeks of follow-up. Discussion: Without distinguishing the eligible preponderant population, the efficacy of the de novo combination of NAs and PEG-IFNα in treating patients with CHB was not superior to that of PEG-IFNα monotherapy. Systematic Review Registration: PROSPERO, identifier CRD42022325239.
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Affiliation(s)
| | | | | | | | | | - Maobai Liu
- Department of Pharmacy, Fujian Medical Union Hospital, Fuzhou, China
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Abstract
The last few years have seen a resurgence of activity in the hepatitis B drug pipeline, with many compounds in various stages of development. This review aims to provide a comprehensive overview of the latest advances in therapeutics for chronic hepatitis B (CHB). We will discuss the broad spectrum of direct-acting antivirals in clinical development, including capsids inhibitors, siRNA, HBsAg and polymerase inhibitors. In addition, host-targeted therapies (HTT) will be extensively reviewed, focusing on the latest progress in immunotherapeutics such as toll-like receptors and RIG-1 agonists, therapeutic vaccines and immune checkpoints modulators. A growing number of HTT in pre-clinical development directly target the key to HBV persistence, namely the covalently closed circular DNA (cccDNA) and hold great promise for HBV cure. This exciting area of HBV research will be highlighted, and molecules such as cyclophilins inhibitors, APOBEC3 deaminases and epigenetic modifiers will be discussed.
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Affiliation(s)
- Sandra Phillips
- Institute of Hepatology Foundation for Liver Research London UK, School of Immunology and Microbial Sciences King's College London, UK
| | - Ravi Jagatia
- Institute of Hepatology Foundation for Liver Research London UK, School of Immunology and Microbial Sciences King's College London, UK
| | - Shilpa Chokshi
- Institute of Hepatology Foundation for Liver Research London UK, School of Immunology and Microbial Sciences King's College London, UK
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A Prospective Five-Year Follow-up After peg-Interferon Plus Nucleotide Analogue Treatment or no Treatment in HBeAg Negative Chronic Hepatitis B Patients. J Clin Exp Hepatol 2022; 12:735-744. [PMID: 35677522 PMCID: PMC9168707 DOI: 10.1016/j.jceh.2021.12.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 12/16/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Currently available treatment options for chronic hepatitis B (CHB) are not recommended for HBeAg-negative patients with a low viral load. These patients may however benefit from treatment by achieving a functional cure, defined by HBsAg-loss and undetectable HBV DNA. This study evaluated the long-term effect of combination treatment with peg-interferon-alpha-2a (peg-IFN) and adefovir or tenofovir compared to no treatment in these patients. METHODS HBeAg-negative CHB patients with HBV-DNA levels < 20,000 IU/mL (n = 151) were previously randomised 1:1:1 for peg-IFN 180 μg/week plus either adefovir 10 mg/day or tenofovir 245 mg/day, or no treatment and treated for 48 weeks in an open-label study. In this prospective long-term follow-up study, patients were monitored yearly up to five years after end of treatment (week 308). The primary outcome was sustained HBsAg-loss and secondary outcome the dynamics of HBsAg and HBV-DNA levels over time. RESULTS Of the 131 followed patients, the HBsAg-status was known for 118 patients after five-year follow-up. HBsAg-loss occurred similarly (P = 0.703) in all arms: 8/43 (18.6%) peg-IFN + adefovir, 4/34 (11.7%) peg-IFN + tenofovir, and 6/41 (14.6%) among the untreated patients. The time to HBsAg-loss did not differ between groups (P = 0.641). Low baseline HBsAg levels and genotype A were independently associated with HBsAg-loss irrespective of allocation. HBsAg and HBV-DNA levels declined similarly during follow-up in all patient groups. CONCLUSIONS This prospective randomised controlled study showed that HBsAg-loss overtime was not influenced by treatment with a combination of nucleotide analogue and Peg-IFN. Low baseline HBsAg levels can predict HBsAg-loss irrespective of treatment allocation.
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Key Words
- ADV, Adefovir dipivoxil
- ALT, Alanine aminotransferase
- CHB, Chronic hepatitis B
- EOT, End of treatment
- GZ, Grey zone
- HBeAg, Hepatitis B e antigen
- HBsAg, Hepatitis B surface antigen
- HCC, Hepatocellular Carcinoma
- HNCH, HBeAg-negative chronic infection
- NA, Nucleot(s)ide analogue
- ROC, Receiver operating characteristic
- TAF, Tenofovir alafenamide fumarateor
- TDF, Tenofovir disoproxil fumarate
- ULN, Upper limit of normal
- UMC, University Medical Centers
- combination therapy
- functional cure
- hepatitis B virus
- inactive carrier
- low viral load
- peg-IFN, Pegylated-interferon
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Charatcharoenwitthaya P, Kaewdech A, Piratvisuth T. Controversies in Treating Chronic HBV: The Role of PEG-interferon-alfa. Clin Liver Dis 2021; 25:741-762. [PMID: 34593151 DOI: 10.1016/j.cld.2021.06.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Pegylated interferon-alpha therapy is one of the first-line chronic hepatitis B treatment. Finite treatment duration, absence of drug resistance, delayed response, and higher hepatitis B surface antigen loss than nucleos(t)ides analog therapy are the advantages of pegylated interferon-alpha treatment. Common side effects and subcutaneous injections requirement limit its use. Identifying patients likely to respond to pegylated interferon-alpha and optimizing treatment is reasonable. Motivating patients to complete the 48-week treatment is necessary. Treatment is stopped or switched to other treatment strategies in patients with stopping rule criteria. Combination therapy with nucleos(t)ides analog may improve response, but remains controversial.
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Affiliation(s)
- Phunchai Charatcharoenwitthaya
- Gastroenterology Division, Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Wang-Lang Road, Bangkok 10700, Thailand
| | - Apichat Kaewdech
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand
| | - Teerha Piratvisuth
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand; NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand.
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Yoshida K, Enomoto M, Tamori A, Nishiguchi S, Kawada N. Combination of Entecavir or Tenofovir with Pegylated Interferon-α for Long-Term Reduction in Hepatitis B Surface Antigen Levels: Simultaneous, Sequential, or Add-on Combination Therapy. Int J Mol Sci 2021; 22:1456. [PMID: 33535672 PMCID: PMC7867160 DOI: 10.3390/ijms22031456] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/21/2021] [Accepted: 01/27/2021] [Indexed: 12/16/2022] Open
Abstract
Seroclearance of hepatitis B surface antigen (HBsAg) ("functional cure") is the optimal endpoint of antiviral therapy for chronic hepatitis B virus (HBV) infection. Currently available anti-HBV therapy includes nucleoside/nucleotide analogs (NAs) and peginterferon-α (Peg-IFNα). Combination of NAs and Peg-IFNα, each with different mechanisms of action, is an attractive approach for treating chronic HBV infection. In earlier studies, compared with monotherapy using IFNα, combination therapy showed greater on-treatment HBV DNA suppression but no difference in the sustained response. However, responses to the combination of non-pegylated IFNα with lamivudine or adefovir were not assessed based on HBsAg quantification but were defined by normal alanine aminotransferase levels, testing negative for hepatitis B e-antigen, and low HBV DNA load over a short term. Here, we reviewed previous reports regarding the effects of combination therapy of entecavir or tenofovir with Peg-IFNα, focusing on long-term reduction in HBsAg levels. Regimens of combination therapy were classified into "simultaneous" combination ("de novo" strategy); "sequential" combination, which involved starting with one therapy followed by the other ("switch-to" strategy); "add-on" combination, which involved adding Peg-IFNα to an ongoing NAs. Some studies have shown promising results, but there is no robust evidence that combination therapy is superior to monotherapy. Large studies are needed to assess the safety and efficacy of combination therapies to increase the rates of HBsAg seroclearance over the long term.
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Affiliation(s)
- Kanako Yoshida
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan; (K.Y.); (A.T.); (N.K.)
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan; (K.Y.); (A.T.); (N.K.)
| | - Akihiro Tamori
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan; (K.Y.); (A.T.); (N.K.)
| | - Shuhei Nishiguchi
- Division of Medical Science of Regional Cooperation for Liver Diseases, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan;
- Department of Internal Medicine, Kano General Hospital, Osaka 531-0041, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan; (K.Y.); (A.T.); (N.K.)
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10
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Wigfield P, Sbarigia U, Hashim M, Vincken T, Heeg B. Are Published Health Economic Models for Chronic Hepatitis B Appropriately Capturing the Benefits of HBsAg Loss? A Systematic Literature Review. PHARMACOECONOMICS - OPEN 2020; 4:403-418. [PMID: 31428938 PMCID: PMC7426349 DOI: 10.1007/s41669-019-00175-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
OBJECTIVES Sustained hepatitis B surface antigen (HBsAg) loss or 'functional cure' (FC) is considered an optimal treatment endpoint by international clinical guidelines for chronic hepatitis B (CHB), yet rarely is this achieved with current standard of care (SoC). This leads to an under-reporting of FC in clinical trials, observational studies and health economic (HE) models. This paper systematically identifies and assesses how FC is incorporated in published HE models of CHB. METHODS A systematic literature review was conducted in PubMed and Embase (conducted February 2019) to review how HBsAg loss is captured in HE models. The following items were extracted: rate of (and transition probabilities to) HBsAg loss, HBsAg loss health state costs, and HBsAg loss health state utilities. RESULTS Sixty-five economics evaluations were identified, and < 50% of these (27/65) incorporated HBsAg loss in their models. Only 15/27 stated HBsAg loss health state costs, 15/27 stated HBsAg loss health state utilities, and 11/27 mentioned treatment-specific transition probabilities to HBsAg loss. The majority of sources these inputs were derived from are not transparent. CONCLUSIONS The benefits of FC in current HE models are not well captured, as FC is often not reported or not directly related to modelled treatments. This has the potential for novel agents with higher efficacy compared with SoC to be overlooked and undervalued if their worth is not appropriately communicated. In order to ensure optimal access for patients to new and effective therapies, it is important that the benefits of FC are better assessed and captured within HE models.
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Affiliation(s)
- Peter Wigfield
- Ingress-health Nederland, Hofplein 20, 3032 AC Rotterdam, The Netherlands
| | - Urbano Sbarigia
- Janssen Pharmaceutica, Turnhoutseweg 30, 2340 Beerse, Belgium
| | - Mahmoud Hashim
- Ingress-health Nederland, Hofplein 20, 3032 AC Rotterdam, The Netherlands
| | - Talitha Vincken
- Ingress-health Nederland, Hofplein 20, 3032 AC Rotterdam, The Netherlands
| | - Bart Heeg
- Ingress-health Nederland, Hofplein 20, 3032 AC Rotterdam, The Netherlands
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11
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Fonseca MA, Ling JZJ, Al-Siyabi O, Co-Tanko V, Chan E, Lim SG. The efficacy of hepatitis B treatments in achieving HBsAg seroclearance: A systematic review and meta-analysis. J Viral Hepat 2020; 27:650-662. [PMID: 32170983 DOI: 10.1111/jvh.13283] [Citation(s) in RCA: 15] [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: 08/27/2019] [Revised: 11/20/2019] [Accepted: 01/13/2020] [Indexed: 02/06/2023]
Abstract
Current therapies for chronic hepatitis B (CHB) include nucleos(t)ide analogues (NAs) and interferon (IFN), but their relative efficacy as monotherapy or in combination has not been examined systematically for HBsAg loss (functional cure). Hence, we systematically reviewed the evidence for HBsAg loss in CHB patients treated with IFN, NA or the combination. We searched PubMed, EMBASE and abstracts from EASL, Asia Pacific Association for study of the Liver and American Association for the Study of Liver Disease for randomized controlled trials of CHB patients, comparing NA, IFN or the combination. The Cochrane Risk of Bias tool v2.0 and GRADE method were used. Analyses were stratified by NA genetic barrier, cirrhosis, type of combination therapy, HBeAg, treatment naivety, IFN dosage/duration and outcome duration. Sensitivity analysis was performed for selected strata, and HBsAg loss was measured at the end-of-study (EOS), end-of-treatment (EOT) or end-of-follow-up (EOF). Effects were reported as risk differences (RD) with 95% confidence intervals (CI) using a random-effects model. Forty-five studies were included, all with low risk of bias. For HBsAg loss at EOS, when comparing combination vs IFN, RD = 1%, 95%CI-1%, 2%; combination vs NA, RD = 5%, 95%CI 3%,7%; IFN vs NA, RD = 3%, 95%CI 2%,5%. Subgroup analysis showed a significant effect of standard IFN dose vs nonstandard; IFN duration ≥48 weeks vs <48 weeks, and loss of efficacy >2 years of follow-up. Similar findings were seen in HBsAg seroconversion, but only three studies reported HBsAg seroreversion. In conclusion, IFN monotherapy/combination had a small but significant increase in HBsAg loss over NA, associated with standard dose of IFN and ≥48 weeks of therapy, although this effect faded over time.
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Affiliation(s)
- Mariana Alves Fonseca
- Hospital DivinaProvidência, Porto Alegre, Brazil
- Hospital Moinhos de Vento, Porto Alegre, Brazil
| | - Joanna Zhi Jie Ling
- Royal Melbourne Institute of Technology, Melbourne, Vic., Australia
- Singapore Clinical Research Institute, Singapore City, Singapore
| | - Omar Al-Siyabi
- Division of Gastroenterology and Hepatology, Department of Medicine, Royal Hospital, Oman Muscat, Oman
| | - Vanessa Co-Tanko
- Division of Gastroenterology and Hepatology, Department of Medicine, UP-Philippine General Hospital, Manila, Philippines
| | - Edwin Chan
- Singapore Clinical Research Institute, Singapore City, Singapore
- Duke-NUS Medical School, Singapore City, Singapore
| | - Seng Gee Lim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore City, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore
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12
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Ma A, Motyka B, Gutfreund K, Shi YE, George R. A dendritic cell receptor-targeted chimeric immunotherapeutic protein (C-HBV) for the treatment of chronic hepatitis B. Hum Vaccin Immunother 2019; 16:756-778. [PMID: 31687879 PMCID: PMC7227630 DOI: 10.1080/21645515.2019.1689080] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
In chronic Hepatitis B Virus (HBV) infections HBV-specific T cells are functionally impaired. Immunotherapy may restore HBV-specific T cell responses essential for sustained disease remission off-treatment and induction of a functional cure. Chimigen® Molecules are fusion proteins of antigen(s) with the Fc fragment of a xenotypic antibody designed to target specific receptors on dendritic cells (DCs). Here we describe the production and pre-clinical evaluation of Chimigen® HBV (C-HBV), containing HBV PreS1 and PreS2 peptide fragments, HBV core and murine Fc, produced in insect cells. C-HBV binding to immature DCs and internalization by endocytosis was FcγRII (CD32) and mannose receptor (CD206) dependent and led to increased MHC I and MHC II surface expression. Upon exposure of human T cells isolated from HBV un-infected healthy and chronically HBV-infected donors to C-HBV-pulsed mature DCs ex vivo, C-HBV induced vigorous T cell proliferation and enhanced expression of IFN-γ, TNF-α, perforin and granzyme B in both CD4+ and CD8+ T cell subsets. Re-stimulation of C-HBV-activated T cells from chronically infected donors with HBV PreS1/PreS2 and core overlapping peptides induced IFN-γ production in both CD4+ and CD8+ populations. C-HBV-activation of peripheral blood mononuclear cells (PBMCs) from chronically HBV-infected patients stimulated granzyme B production by CD4+CD25- T responder (Tresp) cells, accompanied by an increase in Annexin V staining on CD4+CD25+ T regulatory (Treg) cell phenotype, consistent with apoptosis. The observed HBV-specific cellular responses induced by C-HBV ex vivo suggest that C-HBV is a promising immunotherapeutic candidate for the treatment of chronic HBV infections.
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Affiliation(s)
- Allan Ma
- Akshaya Bio Inc., Edmonton, Canada
| | - Bruce Motyka
- Department of Pediatrics, University of Alberta, Edmonton, Canada
| | - Klaus Gutfreund
- Department of Medicine, University of Alberta, Edmonton, Canada
| | - Yuenian Eric Shi
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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13
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Limothai U, Chuaypen N, Poovorawan K, Chotiyaputta W, Tanwandee T, Poovorawan Y, Tangkijvanich P. Baseline and kinetics of serum hepatitis B virus RNA predict response to pegylated interferon-based therapy in patients with hepatitis B e antigen-negative chronic hepatitis B. J Viral Hepat 2019; 26:1481-1488. [PMID: 31446638 DOI: 10.1111/jvh.13195] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 07/24/2019] [Accepted: 07/30/2019] [Indexed: 12/18/2022]
Abstract
Serum hepatitis B virus (HBV) RNA has emerged as a novel biomarker of treatment response. This study aimed to investigate the role of this marker in predicting long-term outcome of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) receiving pegylated interferon (PEG-IFN)-based therapy. Serial serum samples from 91 patients with HBeAg-negative CHB previously treated with PEG-IFN alone or combined with entecavir in a randomized trial were retrospectively analysed. HBV RNA quantification was examined by droplet digital PCR. At the end of 3 years post-treatment follow-up, maintained virological response (MVR, HBV DNA < 2000 IU/mL), and hepatitis B surface antigen (HBsAg) clearance were achieved in 37.4% (34/91) and 7.7% (7/91), respectively. Baseline serum HBV RNA concentrations correlated with HBV DNA and covalently closed circular DNA but did not correlate with HBsAg levels. Multiple regression analysis showed that pre-treatment HBV RNA and HBsAg were independently associated with MVR and HBsAg clearance. Baseline HBV RNA (cut-off 2.0 log10 copies/mL) had a positive predictive value (PPV) and a negative predictive value in predicting MVR of 80.8% and 80.0%, respectively. At the same cut-off value, PPV and NPV for predicting HBsAg clearance were 30.8% and 95.4%, respectively. At week 12 during therapy, HBV RNA level ≥ 2 log10 copies/mL displayed high NPVs of achieving MVR and HBsAg clearance (95% and 100%, respectively). In conclusion, the measurement of HBV RNA prior to PEG-IFN-based therapy could identify patients with high probability of MVR. In addition, HBV RNA kinetics may serve as a promising "stopping rule" in patients infected with HBV genotypes B or C.
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Affiliation(s)
- Umaporn Limothai
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Natthaya Chuaypen
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Kittiyod Poovorawan
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Watcharasak Chotiyaputta
- Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Tawesak Tanwandee
- Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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14
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Brouwer WP, Chan HLY, Lampertico P, Hou J, Tangkijvanich P, Reesink HW, Zhang W, Mangia A, Tanwandee T, Montalto G, Simon K, Ormeci N, Chen L, Tabak F, Gunsar F, Flisiak R, Ferenci P, Akdogan M, Akyuz F, Hirankarn N, Jansen L, Wong VWS, Soffredini R, Liang X, Chen S, Groothuismink ZMA, Santoro R, Jaroszewicz J, Ozaras R, Kozbial K, Brahmania M, Xie Q, Chotiyaputta W, Xun Q, Pazgan-Simon M, Oztas E, Verhey E, Montanari NR, Sun J, Hansen BE, Boonstra A, Janssen HLA. Genome-wide Association Study Identifies Genetic Variants Associated With Early and Sustained Response to (Pegylated) Interferon in Chronic Hepatitis B Patients: The GIANT-B Study. Clin Infect Dis 2019; 69:1969-1979. [PMID: 30715261 PMCID: PMC6853659 DOI: 10.1093/cid/ciz084] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 03/11/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND (Pegylated) Interferon ([Peg]IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. Host genetic determinants of response are therefore in demand. METHODS In this genome-wide association study (GWAS), CHB patients, treated with (Peg)IFN for at least 12 weeks ± nucleos(t)ide analogues within randomized trials or as standard of care, were recruited at 21 centers from Europe, Asia, and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined hepatitis B e antigen (HBeAg) loss with hepatitis B virus (HBV) DNA <2000 IU/mL, or an HBV DNA <2000 IU/mL for HBeAg-negative patients. RESULTS Of 1144 patients, 1058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% hepatitis B surface antigen (HBsAg) loss. GWAS analysis stratified by HBeAg status, adjusted for age, sex, and the 4 ancestry components identified PRELID2 rs371991 (B= -0.74, standard error [SE] = 0.16, P = 3.44 ×10-6) for HBeAg-positive patients. Importantly, PRELID2 was cross-validated for long-term response in HBeAg-negative patients. G3BP2 rs3821977 (B = 1.13, SE = 0.24, P = 2.46 × 10-6) was associated with response in HBeAg-negative patients. G3BP2 has a role in the interferon pathway and was further examined in peripheral blood mononuclear cells of healthy controls stimulated with IFNα and TLR8. After stimulation, less production of IP-10 and interleukin (IL)-10 proteins and more production of IL-8 were observed with the G3BP2 G-allele. CONCLUSIONS Although no genome-wide significant hits were found, the current GWAS identified genetic variants associated with (Peg)IFN response in CHB. The current findings could pave the way for gene polymorphism-guided clinical counseling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies. CLINICAL TRIALS REGISTATION NCT01401400.
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Affiliation(s)
- Willem P Brouwer
- Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, The Netherlands
| | - Henry L Y Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Italy
| | - Pietro Lampertico
- Centro di riferimento per la diagnosi e lo studio delle malattie del fegato e delle vie biliari “Angela Maria ed Antonio Migliavacca” Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica Cà Granda Ospedale Maggiore Policlinico, University of Milan, Italy
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Hepatology Unit and Dept of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | | | | | - Wenhong Zhang
- Clinical Center Hepatitis, Institute of Biomedical Science, Huashan hospital “Fu Dan University,” Shanghai, China
| | - Alessandra Mangia
- Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica Casa Sollievo della Sofferenza, Foggia, Italy
| | - Tawesak Tanwandee
- Division of Gastroenterology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Giuseppe Montalto
- Biomedical Department of Internal Medicine and Specialties, University of Palermo, Italy
| | - Kris Simon
- Wroclaw University of Medicine Department of Infectious Diseases and Hepatology, Poland
| | | | - Liang Chen
- Shanghai Public Health Center “Fu Dan University,” China
| | - Fehmi Tabak
- Cerrahpasa Medical Faculty, Department of Infectious Diseases, Istanbul
| | | | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Poland
| | | | | | - Filiz Akyuz
- Istanbul Üniversitesi Istanbul Tip Fakültesi Hastanesi, Istanbul, Turkey
| | | | - Louis Jansen
- Academic Medical Centre, Amsterdam, The Netherlands
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Italy
| | - Roberta Soffredini
- Centro di riferimento per la diagnosi e lo studio delle malattie del fegato e delle vie biliari “Angela Maria ed Antonio Migliavacca” Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica Cà Granda Ospedale Maggiore Policlinico, University of Milan, Italy
| | - Xieer Liang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Hepatology Unit and Dept of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shalom Chen
- Clinical Center Hepatitis, Institute of Biomedical Science, Huashan hospital “Fu Dan University,” Shanghai, China
| | | | - Rosanna Santoro
- Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica Casa Sollievo della Sofferenza, Foggia, Italy
| | - Jerzy Jaroszewicz
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Poland
- Department of Infectious Diseases and Hepatology, Medical University of Silesia, Katowice, Poland
| | - Resat Ozaras
- Cerrahpasa Medical Faculty, Department of Infectious Diseases, Istanbul
| | | | - Mayur Brahmania
- Liver Clinic, Toronto General Hospital, University Health Network, Toronto, Canada
| | - Qing Xie
- Shanghai Ruijin Hospital, Jiao Tong University School of Medicine, Shanghai, China
| | - Watcharasak Chotiyaputta
- Division of Gastroenterology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Qi Xun
- Shanghai Public Health Center “Fu Dan University,” China
| | - Monika Pazgan-Simon
- Wroclaw University of Medicine Department of Infectious Diseases and Hepatology, Poland
| | | | - Elke Verhey
- Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, The Netherlands
| | - Noé R Montanari
- Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, The Netherlands
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Hepatology Unit and Dept of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bettina E Hansen
- Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, The Netherlands
| | - Andre Boonstra
- Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, The Netherlands
| | - Harry L A Janssen
- Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, The Netherlands
- Liver Clinic, Toronto General Hospital, University Health Network, Toronto, Canada
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15
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Abstract
Introduction: Universal infant hepatitis B virus (HBV) vaccination program has reduced HBV infection dramatically in vaccinated young generations. Management of chronically infected children is still challenging concerning high viral load with mostly mild diseases, yet with a nonnegligible proportion of advanced diseases, and long-term effect of antivirals. However, with more potent antivirals approved for pediatric patients, to start antivirals earlier in eligible patients may benefit their outcomes. This review aimed to update the current management of chronic hepatitis B in children.Areas covered: This review covered the natural history of chronic HBV infection, management of chronic hepatitis B in children from the past to the present, current consensus on the treatment of chronic hepatitis B in children, controversies in cessation of oral antivirals, and management of special populations such as pregnancy and co-infections.Expert opinions: Without contraindication, peginterferon is recommended for immune-active children ≥ 3 years old. For those intolerant, decompensating or preferring oral therapy, first-line Nucleos(t)ide analogs (NUC), Entecavir or Tenofovir, may be applied. For immune-tolerant or inactive carriers, close monitoring is crucial. When to stop NUCs and novel therapies for HBV cure await further research.
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Affiliation(s)
- Ming-Wei Lai
- Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan.,Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Linkou, Taiwan.,Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
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16
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Ning Q, Wu D, Wang GQ, Ren H, Gao ZL, Hu P, Han MF, Wang Y, Zhang WH, Lu FM, Wang FS. Roadmap to functional cure of chronic hepatitis B: An expert consensus. J Viral Hepat 2019; 26:1146-1155. [PMID: 31087479 DOI: 10.1111/jvh.13126] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 04/25/2019] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) infection continues to be a major public health issue worldwide. HBsAg loss is associated with functional remission and improved long-term outcome, and is considered to be a 'functional cure' (also referred to as clinical or immunologic cure) for chronic hepatitis B. This ideal goal of therapy can be achieved using optimized combination regimens with direct-acting antivirals [eg nucleos(t)ide analogues (NAs)] and immunomodulators [eg pegylated interferon alpha2a (Peg-IFN)] in selected patients with chronic hepatitis B. Among different combination therapies currently available, those with NA lead-in followed by Peg-IFN in virally suppressed patients has been demonstrated to be effective. This review provides an updated overview of the evidence supporting the use of combination therapies and summarizes expert consensus on the roadmap to attain functional cure for chronic hepatitis B patients.
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Affiliation(s)
- Qin Ning
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Di Wu
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gui-Qiang Wang
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing, China
| | - Hong Ren
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhi-Liang Gao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Peng Hu
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mei-Fang Han
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Wang
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing, China
| | - Wen-Hong Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Feng-Min Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Fu-Sheng Wang
- Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of the General Hospital of PLA, Beijing, China
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17
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Wong WWL, Pechivanoglou P, Wong J, Bielecki JM, Haines A, Erman A, Saeed Y, Phoon A, Tadrous M, Younis M, Rayad NZ, Rac V, Janssen HLA, Krahn MD. Antiviral treatment for treatment-naïve chronic hepatitis B: systematic review and network meta-analysis of randomized controlled trials. Syst Rev 2019; 8:207. [PMID: 31426837 PMCID: PMC6699129 DOI: 10.1186/s13643-019-1126-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 08/04/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Chronic hepatitis B (CHB) infection poses a significant burden to public health worldwide. Most cases are clinically silent until late in the disease course. The main goal of current therapy is to improve survival and quality of life by preventing disease progression to cirrhosis and liver failure, and consequently hepatocellular carcinoma development. The objective of this review is to provide a contemporary and comprehensive evaluation of the effectiveness of treatment options. METHODS We performed a systematic review of peer-reviewed literature for randomized controlled trials involving treatment-naïve CHB adult population who received antiviral therapy. The endpoints were virologic response (VR), normalization of alanine aminotransferase (ALT norm), HBeAg loss, HBeAg seroconversion, and HBsAg loss for the HBeAg-positive population; and VR and ALT norm for the HBeAg-negative population. Network meta-analysis (NMA) was performed to synthesize evidence on the efficacy of treatment. RESULTS Forty-two publications were selected. Twenty-three evaluated HBeAg-positive population, 13 evaluated HBeAg-negative population, and six evaluated both. We applied NMA to the efficacy outcomes of the two populations separately. Treatment strategies were ranked by the probability of achieving outcomes, and pairwise comparisons calculated from NMA were reported in odds ratios (OR). For HBeAg-positive population, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) were the best for VR; OR vs adefovir = 14.29, 95% CI 7.69-25 and 12.5, 95% CI 4.35-33.33 respectively. TAF was the best for achieving ALT norm (OR vs placebo = 12.5, 95% CI 4.55-33.33), HBeAg loss, and seroconversion (OR vs entecavir/TDF combination = 3.03, 95% CI 1.04-8.84 and 3.33, 95% CI 1.16-10 respectively). In the HBeAg-negative population, TDF and TAF were the best for VR (OR vs adefovir = 9.79, 95% CI 2.38-42.7 and 11.71, 95% CI 1.03-150.48 respectively). Telbivudine and TAF were the best for ALT norm. Certain nucleos(t)ide combinations also had high probability of achieving positive outcomes. CONCLUSIONS Our results are consonant with current clinical guidelines and other evidence reviews. For both HBeAg-positive and HBeAg-negative populations, TDF and TAF are the most effective agents for virologic suppression, and TAF is effective across all outcomes.
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Affiliation(s)
- William W L Wong
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada. .,University of Waterloo, School of Pharmacy, Waterloo, ON, Canada. .,University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, ON, Canada.
| | - Petros Pechivanoglou
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada.,The Hospital for Sick Children, Toronto, ON, Canada
| | - Josephine Wong
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada
| | - Joanna M Bielecki
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada
| | - Alex Haines
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada
| | - Aysegul Erman
- University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, ON, Canada
| | - Yasmin Saeed
- University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, ON, Canada
| | - Arcturus Phoon
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada
| | - Mina Tadrous
- University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, ON, Canada.,The Ontario Drug Policy Research Network, St. Michael's Hospital, Toronto, ON, Canada
| | - Mona Younis
- University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, ON, Canada
| | - Noha Z Rayad
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada.,BioPharma Services Inc, Toronto, ON, Canada
| | - Valeria Rac
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada.,Ted Rogers Centre for Heart Research at Peter Munk Cardiac Centre, Toronto General Hospital Research Institute (TGHRI), University Health Network (UHN), Toronto, Canada.,Institute of Health Policy, Management and Evaluation (IHPME), Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.,Diabetes Action Canada, CIHR SPOR Network, Toronto, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON, Canada
| | - Murray D Krahn
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada.,University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, ON, Canada
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18
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Zhang Z, Wang C, Liu Z, Zou G, Li J, Lu M. Host Genetic Determinants of Hepatitis B Virus Infection. Front Genet 2019; 10:696. [PMID: 31475028 PMCID: PMC6702792 DOI: 10.3389/fgene.2019.00696] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 07/03/2019] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is still a major health problem worldwide. Recently, a great number of genetic studies based on single nucleotide polymorphisms (SNPs) and genome-wide association studies have been performed to search for host determinants of the development of chronic HBV infection, clinical outcomes, therapeutic efficacy, and responses to hepatitis B vaccines, with a focus on human leukocyte antigens (HLA), cytokine genes, and toll-like receptors. In addition to SNPs, gene insertions/deletions and copy number variants are associated with infection. However, conflicting results have been obtained. In the present review, we summarize the current state of research on host genetic factors and chronic HBV infection, its clinical type, therapies, and hepatitis B vaccine responses and classify published results according to their reliability. The potential roles of host genetic determinants of chronic HBV infection identified in these studies and their clinical significance are discussed. In particular, HLAs were relevant for HBV infection and pathogenesis. Finally, we highlight the need for additional studies with large sample sizes, well-matched study designs, appropriate statistical methods, and validation in multiple populations to improve the treatment of HBV infection.
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Affiliation(s)
- Zhenhua Zhang
- Department of Infectious Diseases, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
- College of Pharmacy, Anhui Medical University, Hefei, China
| | - Changtai Wang
- Department of Infectious Diseases, the Affiliated Anqing Hospital of Anhui Medical University, Anqing, China
| | - Zhongping Liu
- Department of Infectious Diseases, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Guizhou Zou
- Department of Infectious Diseases, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jun Li
- College of Pharmacy, Anhui Medical University, Hefei, China
| | - Mengji Lu
- Institute of Virology, University Hospital of Duisburg-Essen, Essen, Germany
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19
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Qiu K, Liu B, Li SY, Li H, Chen ZW, Luo AR, Peng ML, Ren H, Hu P. Systematic review with meta-analysis: combination treatment of regimens based on pegylated interferon for chronic hepatitis B focusing on hepatitis B surface antigen clearance. Aliment Pharmacol Ther 2018; 47:1340-1348. [PMID: 29577360 DOI: 10.1111/apt.14629] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 10/29/2017] [Accepted: 03/04/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND The seroclearance of hepatitis B surface antigen (HBsAg) in patients with chronic hepatitis B (CHB) is considered to be associated with favourable clinical outcomes. AIMS This meta-analysis was performed to establish the proportion of HBsAg loss rates among CHB patients who received combination treatment based on pegylated interferon (PegIFN). Four combination strategies have been studied with the aim of improving HBsAg loss: "de novo," "NA-experienced," "switch-to" and "add-on." This meta-analysis was performed to determine which, if any, of these combination strategies was more effective. METHODS Medline, Web of Science and Embase databases were searched from inception to December 2017. The proportion of patients who achieved HBsAg loss after combination therapy was pooled using a random-effects model. RESULTS Twenty-four studies fulfilled the meta-analysis criteria. The overall pooled proportion suggested that the rate of HBsAg loss could be increased to 9% (95% CI: 7%-12%) based on the combination treatment in CHB patients. Compared with "de novo" strategy (8%, 95% CI: 6%-10%), the "nucleos(t)ide analogues-experienced" (11%, 95% CI: 8%-15%) was found to be more likely (P = 0.036) to achieve a response. Compared with the "add-on" strategy (8%, 95% CI: 5%-13%), the "switch-to" (14%, 95% CI: 9%-20%) was found to be more likely (P = 0.012) to achieve HBsAg loss. CONCLUSION The "nucleos(t)ide analogues-experienced" strategy was more effective than the "De novo" strategy in achieving HBsAg loss for CHB patients. Combination treatment using regimens based on Peg-IFN may be useful to help nucleos(t)ide analogues-treated patients, who have experienced at least 48 weeks of nucleot(s)ide analogue, achieve HBsAg seroclearance.
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Affiliation(s)
- K Qiu
- The Key Laboratory of Molcular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - B Liu
- The Key Laboratory of Molcular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - S-Y Li
- The Key Laboratory of Molcular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - H Li
- The Key Laboratory of Molcular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Z-W Chen
- The Key Laboratory of Molcular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - A-R Luo
- The Key Laboratory of Molcular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - M-L Peng
- The Key Laboratory of Molcular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - H Ren
- The Key Laboratory of Molcular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - P Hu
- The Key Laboratory of Molcular Biology for Infectious Diseases, Department of Infectious Diseases, Institute for Viral Hepatitis, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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20
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Mendes LC, Stucchi RS, Vigani AG. Diagnosis and staging of fibrosis in patients with chronic hepatitis C: comparison and critical overview of current strategies. Hepat Med 2018; 10:13-22. [PMID: 29662329 PMCID: PMC5892613 DOI: 10.2147/hmer.s125234] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
In the past years, what has always been considered undisputed true in liver fibrosis staging has been challenged. Diagnostic performance of histological evaluation has proven to be significantly influenced by sample- and observer-related variabilities. Differentiation between lower levels of fibrosis remains difficult for many, if not all, test modalities, including liver biopsy but, perhaps, such a distinction is not indispensable in light of current therapeutic approaches. Biomarkers and elastography offer, nonetheless, high predictive values for advanced fibrosis and cirrhosis and correlate well with liver-related outcomes. Necroinflammation, steatosis, and hemodynamic changes may significantly interfere with elastography-based techniques, and longitudinal follow-up strategies must be tailored in light of these findings. Knowledge of different test modalities and diagnostic performance indicators can allow for better clinical decision-making and resource allocation.
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Affiliation(s)
- Leandro César Mendes
- Department of Infectious Diseases, State University of Campinas, Campinas, SP, Brazil
| | - Raquel Sb Stucchi
- Department of Infectious Diseases, State University of Campinas, Campinas, SP, Brazil
| | - Aline G Vigani
- Department of Infectious Diseases, State University of Campinas, Campinas, SP, Brazil
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21
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Chuaypen N, Posuwan N, Chittmittraprap S, Hirankarn N, Treeprasertsuk S, Tanaka Y, Shinkai N, Poovorawan Y, Tangkijvanich P. Predictive role of serum HBsAg and HBcrAg kinetics in patients with HBeAg-negative chronic hepatitis B receiving pegylated interferon-based therapy. Clin Microbiol Infect 2018; 24:306.e7-306.e13. [PMID: 28750917 DOI: 10.1016/j.cmi.2017.07.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 07/12/2017] [Accepted: 07/16/2017] [Indexed: 02/06/2023]
Abstract
OBJECTIVES To investigate the role of serum hepatitis B core-related antigen (HBcrAg) kinetics in predicting long-term outcome of pegylated interferon (PEG-IFN)-based therapy in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). METHODS A total of 121 Thai patients with HBeAg-negative CHB recruited from a previous randomized trial of 48-week PEG-IFN alone or combined with entecavir were enrolled. Hepatitis B surface antigen (HBsAg) and HBcrAg levels were serially examined. Paired biopsy samples taken at baseline and after treatment were assessed for intrahepatic covalently closed circular DNA (cccDNA). RESULTS Persistent virologic remission (PVR, defined by persistent hepatitis B virus (HBV) DNA <2000 IU/mL) and HBsAg clearance at 3 years after treatment were 29% (35/121) and 9% (11/121) respectively. Baseline HBcrAg correlated with HBV DNA and cccDNA but not with HBsAg. Baseline HBsAg, as well as HBsAg and HBcrAg, declines were associated with PVR, while HBsAg decline was predictive of HBsAg clearance. High baseline antigen levels (HBsAg ≥3.4 log10 IU/mL plus HBcrAg ≥3.7 log10 U/mL) yielded high negative predictive values of PVR (45/50, 90%) and HBsAg clearance (50/50, 100%). At week 12, declines of HBsAg, HBcrAg and both antigens combined of <0.5 log10 yielded negative predictive values for PVR of 90% (71/79), 82% (61/74) and 96% (48/50) respectively. CONCLUSIONS Quantitative HBcrAg was significantly associated with cccDNA in HBeAg-negative CHB. This novel antigen, together with HBsAg, could identify patients with low probability of PVR and HBsAg clearance in long-term follow-up.
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Affiliation(s)
- N Chuaypen
- Research Unit of Hepatitis and Liver Cancers, Thailand
| | - N Posuwan
- Center of Excellence in Clinical Virology, Thailand
| | | | - N Hirankarn
- Immunology Unit, Department of Microbiology, Thailand
| | - S Treeprasertsuk
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Y Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - N Shinkai
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Y Poovorawan
- Center of Excellence in Clinical Virology, Thailand
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22
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Arends JE, Lieveld FI, Ahmad S, Ustianowski A. New Viral and Immunological Targets for Hepatitis B Treatment and Cure: A Review. Infect Dis Ther 2017; 6:461-476. [PMID: 29071665 PMCID: PMC5700893 DOI: 10.1007/s40121-017-0173-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Indexed: 12/16/2022] Open
Abstract
Although current therapies can be successful at suppressing hepatitis B viral load, long-term viral cure is not within reach. Subsequent strategies combining pegylated interferon alfa with nucleoside/nucleotide analogues have not resulted in any major paradigm shift. An improved understanding of the hepatitis B virus (HBV) lifec ycle and virus-induced immune dysregulation has, however, revealed many potential therapeutic targets, and there are hopes that treatment of hepatitis B could soon be revolutionized. This review summarizes the current developments in HBV therapeutics-both virus directed and host directed.
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Affiliation(s)
- Joop E Arends
- Department of Internal Medicine, Section Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
- Utrecht University, Utrecht, The Netherlands.
| | - Faydra I Lieveld
- Department of Internal Medicine, Section Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands
- Utrecht University, Utrecht, The Netherlands
| | - Shazaad Ahmad
- Regional Infectious Diseases Unit, North Manchester General Hospital, Manchester, UK
| | - Andrew Ustianowski
- Regional Infectious Diseases Unit, North Manchester General Hospital, Manchester, UK
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23
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Wu D, Ning Q. Toward a Cure for Hepatitis B Virus Infection: Combination Therapy Involving Viral Suppression and Immune Modulation and Long-term Outcome. J Infect Dis 2017; 216:S771-S777. [PMID: 29156046 DOI: 10.1093/infdis/jix355] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains a major global health burden. Currently, the approved therapeutic regimens include nucleos(t)ide analogues (NAs) and either interferon or pegylated interferon. NA therapy is generally safe and well tolerated, but the rate of posttreatment virologic relapse is high, making NA treatment a lifetime commitment. The benefits of pegylated interferon treatment include a finite duration, more-durable response and absence of viral resistance. However, sustained response to interferon alone is achieved only in a minority of patients, and side effects are common, which limit its clinical use. Given that HBV covalently closed circular DNA and the integrated HBV genome persist stably in the nuclei of infected hepatocytes, elimination (complete cure) of HBV is rarely achieved. After completion of treatment, sustained HBV surface antigen loss, with or without seroconversion to HBV surface antibody positivity (ie, functional cure), is therefore recommended as the ideal end point for anti-HBV treatment, despite the lack of complete eradication of HBV. Theoretically, combination of antiviral agents with differential mechanisms of actions on HBV, including viral suppression combined with immune modulation (as occurs during treatment with NA plus pegylated interferon), is an encouraging strategy to treat chronic hepatitis B. Recent studies have confirmed certain virological and serological advantages of simultaneous administration of NA and pegylated interferon (de novo combination therapy) or addition of pegylated interferon to ongoing NA therapy (sequential combination therapy) over monotherapy. Few data exist, however, on the long-term outcomes of patients receiving combination therapy. This review summarizes current combination therapy developed to cure chronic HBV infection.
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Affiliation(s)
- Di Wu
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qin Ning
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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24
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Persistent Loss of Hepatitis B Virus Markers in Serum without Cellular Immunity by Combination of Peginterferon and Entecavir Therapy in Humanized Mice. Antimicrob Agents Chemother 2017; 61:AAC.00725-17. [PMID: 28696237 DOI: 10.1128/aac.00725-17] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 06/23/2017] [Indexed: 12/23/2022] Open
Abstract
Nucleot(s)ide analogues and peginterferon (PEG-IFN) treatment are the only approved therapies for chronic hepatitis B virus (HBV) infection. However, complete eradication of the virus, as indicated by persistent loss of hepatitis B surface antigen (HBsAg), is rare among treated patients. This is due to long-term persistence of the HBV genome in infected hepatocytes in the form of covalently closed circular DNA (cccDNA). In this study, we investigated whether administration of a large dose of a nucleoside analogue in combination with PEG-IFN can achieve long-term loss of HBsAg in human hepatocyte chimeric mice. Mice were treated with a high dose of entecavir and/or PEG-IFN for 6 weeks. High-dose combination therapy with both drugs resulted in persistently negative HBV DNA in serum. Although small amounts of HBV DNA and cccDNA (0.1 and 0.01 copy/cell, respectively) remained in the mouse livers, some of the mice remained persistently negative for serum HBV DNA at 13 weeks after cessation of the therapy. Serum HBsAg and hepatitis B core-related antigen (HBcrAg) continued to decrease and eventually became negative at 12 weeks after cessation of the therapy. Analysis of the HBV genome in treated mice showed accumulation of G-to-A hypermutation and CpG III island methylation. Persistent loss of serum HBV DNA and loss of HBV markers by high-dose entecavir and PEG-IFN combination treatment in chimeric mice suggests that control of HBV can be achieved even in the absence of a cellular immune response.
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25
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Li H, Wang H, Peng C, Zheng X, Liu J, Weng ZH, Yang DL. Predictors for efficacy of combination therapy with a nucleos(t)ide analogue and interferon for chronic hepatitis B. ACTA ACUST UNITED AC 2017; 37:547-555. [PMID: 28786051 DOI: 10.1007/s11596-017-1771-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 06/06/2017] [Indexed: 12/25/2022]
Abstract
This study aims to explore the efficacy of interferon-α (IFN-α) combined with either entecavir (ETV) or adefovir (ADV) therapy versus IFN-α mono-therapy for chronic hepatitis B (CHB) patients, and to identify the factors associated with treatment outcomes. Totally, 159 CHB patients receiving interferon-based treatment for 48 weeks were enrolled in this retrospective study, including IFN-α mono-therapy group (group A, n=44), IFN-α plus ADV group (group B, n=53) and IFN-α plus ETV group (group C, n=62). The primary measures of efficacy assessments were the changes in HBsAg. Cox regression analysis was used to identify the predictors of treatment outcomes. The predictive values of the factors were assessed by ROC analysis. For patients with baseline hepatitis B surface antigen (HBsAg) level <1000 IU/mL, the reductions in mean HBsAg levels at week 48 were greater in group C than that in group A (P<0.05). Higher rate of HBeAg seroconversion was achieved in the combined therapy group than in IFN-α mono-therapy group at week 48 (P<0.05). Two factors were independently associated with HBeAg seroconversion: baseline HBeAg level <2.215 log10 index/mL and ΔHBeAg (decline in HBeAg from baseline) >0.175 log10 at week 12. In conclusion, interferon-α plus ETV therapy can accelerate HBsAg decline as compared with interferon-α mono-therapy in CHB patients with lower baseline HBsAg levels, and the combination therapy was superior to IFN-α mono-therapy in increasing the rate of HBeAg seroconversion. Baseline HBeAg and ΔHBeAg at week 12 can independently predict HBeAg seroconversion in patients subject to interferon-based therapy for 48 weeks.
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Affiliation(s)
- Hong Li
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hua Wang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Cheng Peng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xin Zheng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhi-Hong Weng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Dong-Liang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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26
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Kayaaslan B, Guner R. Adverse effects of oral antiviral therapy in chronic hepatitis B. World J Hepatol 2017; 9:227-241. [PMID: 28261380 PMCID: PMC5316843 DOI: 10.4254/wjh.v9.i5.227] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 11/29/2016] [Accepted: 12/07/2016] [Indexed: 02/06/2023] Open
Abstract
Oral nucleoside/nucleotide analogues (NAs) are currently the backbone of chronic hepatitis B (CHB) infection treatment. They are generally well-tolerated by patients and safe to use. To date, a significant number of patients have been treated with NAs. Safety data has accumulated over the years. The aim of this article is to review and update the adverse effects of oral NAs. NAs can cause class adverse effects (i.e., myopathy, neuropathy, lactic acidosis) and dissimilar adverse effects. All NAs carry a "Black Box" warning because of the potential risk for mitochondrial dysfunction. However, these adverse effects are rarely reported. The majority of cases are associated with lamivudine and telbivudine. Adefovir can lead to dose- and time-dependent nephrotoxicity, even at low doses. Tenofovir has significant renal and bone toxicity in patients with human immunodeficiency virus (HIV) infection. However, bone and renal toxicity in patients with CHB are not as prominent as in HIV infection. Entecavir and lamivudine are not generally associated with renal adverse events. Entecavir has been claimed to increase the risk of lactic acidosis in decompensated liver disease and high Model for End-Stage Liver Disease scores. However, current studies reported that entecavir could be safely used in decompensated cirrhosis. An increase in fetal adverse events has not been reported with lamivudine, telbivudine and tenofovir use in pregnant women, while there is no adequate data regarding entecavir and adefovir. Further long-term experience is required to highlight the adverse effects of NAs, especially in special patient populations, including pregnant women, elderly and patients with renal impairment.
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Affiliation(s)
- Bircan Kayaaslan
- Bircan Kayaaslan, Rahmet Guner, Department of Infectious Disease and Clinical Microbiology, Yildirim Beyazit University Faculty of Medicine, Ataturk Education and Research Hospital, 06800 Ankara, Turkey
| | - Rahmet Guner
- Bircan Kayaaslan, Rahmet Guner, Department of Infectious Disease and Clinical Microbiology, Yildirim Beyazit University Faculty of Medicine, Ataturk Education and Research Hospital, 06800 Ankara, Turkey
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Gu SW, Wu DP, Li RQ. Combination or sequential therapy with entecavir and interferon in chronic hepatitis B patients: Current status, problems and prospects. Shijie Huaren Xiaohua Zazhi 2016; 24:2799-2810. [DOI: 10.11569/wcjd.v24.i18.2799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Sixteen years have passed since the initial antiviral treatment of chronic hepatitis B (CHB). Goal of the antiviral treatment is not only to suppress viral replication, but to achieve sustained response after a limited period of treatment and then discontinuation of drugs. Nucleos(t)ide analogues (NAs) and interferons are two types of therapeutic agents with different antiviral mechanisms for treatment of CHB. Monotherapy with NAs or interferons can only achieve ideal goal in a part of CHB patients, and combination and/or sequential therapy with both is an important attempt for CHB treatment in recent years. For patients previously treated with NAs, interferons can be used to replace NAs or in combination with them for a limited period. If interferons do not show good efficacy, then NAs, alone or in combination with interferons, can be used. For patients with high viral load, initial combination therapy may show better efficacy. According to the baseline and response guidelines, the treatment plan should be optimized frequently, and the treatment compliance emphasized with maintenance, medication and examination, along with the administration of chronic diseases, in order to ensure that HBV DNA level is lower than baseline level. For those who have had a continuous drop of HBsAg and HBeAg levels, prolonged treatment or combination of the treatment with dendritic cell (DC) therapy and immunotherapy may achieve more persistent immune control.
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Wang L, Zou ZQ, Wang K. Clinical Relevance of HLA Gene Variants in HBV Infection. J Immunol Res 2016; 2016:9069375. [PMID: 27243039 PMCID: PMC4875979 DOI: 10.1155/2016/9069375] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 04/14/2016] [Indexed: 01/01/2023] Open
Abstract
Host gene variants may influence the natural history of hepatitis B virus (HBV) infection. The human leukocyte antigen (HLA) system, the major histocompatibility complex (MHC) in humans, is one of the most important host factors that are correlated with the clinical course of HBV infection. Genome-wide association studies (GWASs) have shown that single nucleotide polymorphisms (SNPs) near certain HLA gene loci are strongly associated with not only persistent HBV infection but also spontaneous HBV clearance and seroconversion, disease progression, and the development of liver cirrhosis and HBV-related hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB). These variations also influence the efficacy of interferon (IFN) and nucleot(s)ide analogue (NA) treatment and response to HBV vaccines. Meanwhile, discrepant conclusions were reached with different patient cohorts. It is therefore essential to identify the associations of specific HLA allele variants with disease progression and viral clearance in chronic HBV infection among different ethnic populations. A better understanding of HLA polymorphism relevance in HBV infection outcome would enable us to elucidate the roles of HLA SNPs in the pathogenesis and clearance of HBV in different areas and ethnic groups, to improve strategies for the prevention and treatment of chronic HBV infection.
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Affiliation(s)
- Li Wang
- Infectious Disease Hospital of Yantai, 62 Huanshan Road, Zhifu District, Yantai, Shandong 264001, China
| | - Zhi-Qiang Zou
- Infectious Disease Hospital of Yantai, 62 Huanshan Road, Zhifu District, Yantai, Shandong 264001, China
| | - Kai Wang
- Hepatology Department, Qilu Hospital of Shandong University, 44 Wenhua West Road, Lixia District, Jinan, Shandong 250012, China
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Boglione L, Cariti G, Di Perri G, D'Avolio A. Sequential therapy with entecavir and peginterferon alpha in chronic hepatitis B: for many but not for all? J Viral Hepat 2016; 23:402-3. [PMID: 26840371 DOI: 10.1111/jvh.12502] [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] [Indexed: 12/09/2022]
Affiliation(s)
- L Boglione
- Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy.
| | - G Cariti
- Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - G Di Perri
- Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
| | - A D'Avolio
- Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy
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