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Liang H, Zheng X, Mao Q, Yang J, Ruan Q, Wu C, Liu Y, Chen S, Zhang L, Zhang M, Zhuang H, Lin L, Chen S. Comparative efficacy and safety of pegylated interferon-alpha monotherapy vs combination therapies with entecavir or tenofovir in chronic hepatitis B patients. Microbiol Spectr 2025; 13:e0269424. [PMID: 40172187 PMCID: PMC12054097 DOI: 10.1128/spectrum.02694-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 02/03/2025] [Indexed: 04/04/2025] Open
Abstract
Current treatments for chronic hepatitis B (CHB) virus involve nucleos(t)ide analogs and pegylated interferon-alpha (PEG-IFNα). This study compares the efficacy and safety of PEG-IFNα monotherapy with its combinations with entecavir (ETV) and tenofovir disoproxil fumarate (TDF) in managing CHB. We included 147 treatment-naïve patients divided into three groups: Group A (PEG-IFNα-2b with ETV), Group B (PEG-IFNα-2b with TDF), and Group C (PEG-IFNα-2b monotherapy). Evaluations occurred every 12 weeks up to 48 weeks. The Kaplan-Meier method showed no significant differences in cumulative HBsAg loss, but HBV DNA clearance rates were higher in the TDF group than in the ETV group (P = 0.01). Higher incidences of elevated alanine aminotransferase (ALT), aspartate aminotransferase, and thrombocytopenia were observed in the TDF group compared to other groups. After propensity score matching, the TDF group had a higher undetectable HBV DNA rate than the IFN group, but no significant differences in HBsAg clearance rates. Both TDF and ETV groups achieved more significant HBsAg reductions from baseline to week 48 than the IFN group (P < 0.05). ETV showed a lower HBeAg clearance rate (30.00% vs 87.50%, P < 0.05) but higher ALT normalization (76.92% vs 45.45%, P < 0.05). In the TDF group, patients with lower baseline HBsAg levels, high ALT levels, and lower aspartate aminotransferase-to-platelet ratio index (APRI) scores were more likely to achieve HBsAg loss. These findings suggest that TDF and ETV are effective for viral suppression, with TDF showing superior HBV DNA clearance but more adverse events. IMPORTANCE This study investigates how different treatments for chronic hepatitis B (CHB), a widespread liver infection, compare in effectiveness and safety. By evaluating the use of pegylated interferon-alpha alone and in combination with two other drugs, entecavir and tenofovir disoproxil fumarate (TDF), researchers found that TDF offers better viral suppression but also comes with more side effects. For patients receiving TDF combined with PEG-IFN therapy, low HBsAg levels, elevated alanine aminotransferase levels, and lower APRI scores were associated with a higher likelihood of achieving HBsAg loss. Consistent with previous findings, this study confirms the benefits of nucleos(t)ide analog plus PEG-IFN therapy for CHB treatment and further explores which patients are more likely to benefit from combination therapy. Furthermore, this study underscores the importance of further monitoring adverse events in patients receiving combination therapy.
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Affiliation(s)
- Huiqing Liang
- Hepatology Unit, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, Fujian, China
| | - Xiaoting Zheng
- Hepatology Unit, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, Fujian, China
| | - Qianguo Mao
- Hepatology Unit, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, Fujian, China
| | - Jiaen Yang
- Hepatology Unit, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, Fujian, China
| | - Qingfa Ruan
- Hepatology Unit, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, Fujian, China
| | - Chuncheng Wu
- Hepatology Unit, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, Fujian, China
| | - Yaoyu Liu
- Hepatology Unit, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, Fujian, China
| | - Siyan Chen
- School of Clinical Medicine, Fujian University of Traditional Chinese Medicine, Fujian, China
| | - Luyun Zhang
- School of Clinical Medicine, Fujian University of Traditional Chinese Medicine, Fujian, China
| | - Manying Zhang
- Hepatology Unit, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, Fujian, China
| | - Hongli Zhuang
- Department of Traditional Chinese Medicine, First Affiliated Hospital of Xiamen University, Xiamen, Fujian Province, China
| | - Li Lin
- Hepatology Unit, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, Fujian, China
| | - Shaodong Chen
- School of Medicine, Xiamen University, Xiamen, Fujian Province, China
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Wu D, Kao JH, Piratvisuth T, Wang X, Kennedy PT, Otsuka M, Ahn SH, Tanaka Y, Wang G, Yuan Z, Li W, Lim YS, Niu J, Lu F, Zhang W, Gao Z, Kaewdech A, Han M, Yan W, Ren H, Hu P, Shu S, Kwo PY, Wang FS, Yuen MF, Ning Q. Update on the treatment navigation for functional cure of chronic hepatitis B: Expert consensus 2.0. Clin Mol Hepatol 2025; 31:S134-S164. [PMID: 39838828 PMCID: PMC11925436 DOI: 10.3350/cmh.2024.0780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 01/18/2025] [Accepted: 01/21/2025] [Indexed: 01/23/2025] Open
Abstract
As new evidence emerges, treatment strategies toward the functional cure of chronic hepatitis B are evolving. In 2019, a panel of national hepatologists published a Consensus Statement on the functional cure of chronic hepatitis B. Currently, an international group of hepatologists has been assembled to evaluate research since the publication of the original consensus, and to collaboratively develop the updated statements. The 2.0 Consensus was aimed to update the original consensus with the latest available studies, and provide a comprehensive overview of the current relevant scientific literatures regarding functional cure of hepatitis B, with a particular focus on issues that are not yet fully clarified. These cover the definition of functional cure of hepatitis B, its mechanisms and barriers, the effective strategies and treatment roadmap to achieve this endpoint, in particular new surrogate biomarkers used to measure efficacy or to predict response, and the appropriate approach to pursuing a functional cure in special populations, the development of emerging antivirals and immunomodulators with potential for curing hepatitis B. The statements are primarily intended to offer international guidance for clinicians in their practice to enhance the functional cure rate of chronic hepatitis B.
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Affiliation(s)
- Di Wu
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand
| | - Xiaojing Wang
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Patrick T.F. Kennedy
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Motoyuki Otsuka
- Department of Gastroenterology and Hepatology, Academic Fields of Medicine, Dentistry, and Pharmaceutical Science, Okayama University, Okayama, Japan
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Guiqiang Wang
- Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, Beijing, China
| | - Zhenghong Yuan
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Wenhui Li
- National Institute of Biological Sciences, Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Junqi Niu
- Department of Hepatology, First Hospital of Jilin University, Jilin University, Jilin, China
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Wenhong Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhiliang Gao
- Department of Infectious Diseases, Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Apichat Kaewdech
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Meifang Han
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Weiming Yan
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Ren
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Peng Hu
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Sainan Shu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Paul Yien Kwo
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford University School of Medicine, Stanford, CA, USA
| | - Fu-sheng Wang
- Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine & State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
| | - Qin Ning
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
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Jiang C, Zhang ZH, Li JX. Current status of drug therapy for chronic hepatitis B. World J Gastroenterol 2025; 31:99443. [PMID: 39811512 PMCID: PMC11684199 DOI: 10.3748/wjg.v31.i2.99443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 11/04/2024] [Accepted: 11/25/2024] [Indexed: 12/18/2024] Open
Abstract
In this editorial, we comment on the article by Meng et al. Chronic hepatitis B (CHB) is a significant global health problem, particularly in developing countries. Hepatitis B virus (HBV) infection is one of the most important risk factors for cirrhosis and hepatocellular carcinoma. Prevention and treatment of HBV are key measures to reduce complications. At present, drug therapy can effectively control virus replication and slow disease progression, but completely eliminating the virus remains a challenge. Anti-HBV treatment is a long-term process, and there are many kinds of antiviral drugs with different mechanisms of action, it is essential to evaluate the safety and efficacy of these drugs to reduce side effects and improve patients' compliance. We will summarize the current status of CHB drug treatment, hoping to provide a reference for the selection of clinical antiviral drugs.
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Affiliation(s)
- Chuang Jiang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Zhi-Hong Zhang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jia-Xin Li
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of General Surgery, Dafang County People's Hospital, Bijie 551600, Guizhou Province, China
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Xu S, Ye XT, Zhang D, Dong P, Wu YH, Pan CW. Predicting clinical outcomes in chronic hepatitis B patients receiving nucleoside analogues and pegylated interferon alpha: a hematochemical and clinical analysis. BMC Infect Dis 2024; 24:1149. [PMID: 39396949 PMCID: PMC11472561 DOI: 10.1186/s12879-024-10057-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 10/03/2024] [Indexed: 10/15/2024] Open
Abstract
BACKGROUND The best antiviral treatment for chronic hepatitis B (CHB) poses a complex challenge. The treatment effect of the combination of nucleoside analogues (NAs) and pegylated interferon alpha (PegIFN) was still in debate. METHODS We studied patients treated with NAs and PegIFN-2b at our institution from November 2019 to January 2022. Logistic regression identified independent factors influencing clinical cure. The predictive accuracy of the formula was assessed using the Receiver operating characteristic (ROC) curve at different time points (before therapy, 12 weeks, and 24 weeks into treatment). RESULTS A total of 120 patients were enrolled in the final analysis. Among the cohort of patients under study, 71 (59.1%) patients had clinical cure while 49 (40.9%) patients did not. Hepatitis B surface antigen (HBsAg) at baseline and age were the powerful variables predicting the clearance of HBsAg. The area under the ROC (AUC) was 0.907 for pre-treatment predictive model, 0.958 for 12-week predictive model and 0.747 for 24-week predictive model. CONCLUSION This study provided predictive formulas for clinical cure, offering valuable insights for CHB treatment. PegIFN and NAs exhibited efficacy. Future research that explores additional factors, such as HBV genotype, in a larger cohort study is needed.
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Affiliation(s)
- Shuang Xu
- Department of infectious Diseases, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiao-Ting Ye
- Department of infectious Diseases, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Dong Zhang
- Department of infectious Diseases, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Pu Dong
- Department of infectious Diseases, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yang-He Wu
- Department of infectious Diseases, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chen-Wei Pan
- Department of infectious Diseases, The Second Affiliated Hospital and Yuying Children's Hospital, of Wenzhou Medical University, Wenzhou, China.
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Zhang PX, Tang QQ, Zhu J, Deng WY, Zhang ZH. Predictive models for functional cure in patients with CHB receiving PEG-IFN therapy based on HBsAg quantification through meta-analysis. Hepatol Int 2024; 18:1110-1121. [PMID: 38913149 DOI: 10.1007/s12072-024-10666-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 02/25/2024] [Indexed: 06/25/2024]
Abstract
BACKGROUND AND AIMS The efficacy of achieving HBsAg clearance through pegylated interferon (PEG-IFNα) therapy in patients with chronic hepatitis B (CHB) remains uncertain, especially regarding the probability of achieving functional cure among patients with varying baseline HBsAg levels. We aimed to investigate the predictive value of HBsAg quantification for HBsAg seroclearance in CHB patients undergoing PEG-IFNα treatment. METHODS A systematic search was conducted in PubMed, Embase, and the Cochrane Library up to January 11, 2022. Subgroup analyses were performed for HBeAg-positive and HBeAg-negative patients, PEG-IFNα monotherapy and PEG-IFNα combination therapy, treatment-naive and treatment-experienced patients, and patients with or without liver cirrhosis. RESULTS This predictive model incorporated 102 studies. The overall HBsAg clearance rates at the end of treatment (EOT) and the end of follow-up (EOF) were 10.6% (95% CI 7.8-13.7%) and 11.1% (95% CI 8.4-14.1%), respectively. Baseline HBsAg quantification was the most significant factor. According to the model, it is projected that when baseline HBsAg levels are 100, 500, 1500, and 10,000 IU/ml, the HBsAg clearance rates at EOF could reach 53.9% (95% CI 40.4-66.8%), 32.1% (95% CI 24.8-38.7%), 14.2% (95% CI 9.8-18.8%), and 7.9% (95% CI 4.2-11.8%), respectively. Additionally, treatment-experienced patients with HBeAg-negative status, and without liver cirrhosis exhibited higher HBsAg clearance rates after PEG-IFNα treatment. CONCLUSION A successful predictive model has been established to predict the achievement of functional cure in CHB patients receiving PEG-IFNα therapy.
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Affiliation(s)
- Pei-Xin Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, China
| | - Qian-Qian Tang
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, China
| | - Jie Zhu
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, China
| | - Wan-Yu Deng
- College of Life Science, Shangrao Normal University, Shangrao, China
| | - Zhen-Hua Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, China.
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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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Li YP, Liu CR, He L, Dang SS. Hepatitis B cure: Current situation and prospects. World J Hepatol 2024; 16:900-911. [PMID: 38948438 PMCID: PMC11212658 DOI: 10.4254/wjh.v16.i6.900] [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] [Received: 03/24/2024] [Revised: 05/05/2024] [Accepted: 06/03/2024] [Indexed: 06/20/2024] Open
Abstract
Achievement of a 'clinical cure' in chronic hepatitis B (CHB) implies sustained virological suppression and immunological control over the infection, which is the ideal treatment goal according to domestic and international CHB management guidelines. Clinical practice has shown encouraging results for specific patient cohorts using tailored treatment regimens. These regimens incorporate either nucleos(t)ide analogs, immunomodulatory agents such as pegylated interferon α, or a strategic combination of both, sequentially or concurrently administered. Despite these advancements in the clinical handling of hepatitis B, achieving a clinical cure remains elusive for a considerable subset of patients due to the number of challenges that preclude the realization of optimal treatment outcomes. These include, but are not limited to, the emergence of antiviral resistance, incomplete immune recovery, and the persistence of covalently closed circular DNA. Moreover, the variance in response to interferon therapy and the lack of definitive biomarkers for treatment cessation also contribute to the complexity of achieving a clinical cure. This article briefly overviews the current research progress and existing issues in pursuing a clinical cure for hepatitis B.
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Affiliation(s)
- Ya-Ping Li
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Chen-Rui Liu
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Ling He
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Shuang-Suo Dang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
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Jiang S, Guo S, Huang Y, Yin Y, Feng J, Zhou H, Guo Q, Wang W, Xin H, Xie Q. Predictors of HBsAg seroclearance in patients with chronic HBV infection treated with pegylated interferon-α: a systematic review and meta-analysis. Hepatol Int 2024; 18:892-903. [PMID: 38461186 PMCID: PMC11126512 DOI: 10.1007/s12072-024-10648-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 01/22/2024] [Indexed: 03/11/2024]
Abstract
BACKGROUND AND AIMS The identification of reliable predictors for hepatitis B surface antigen (HBsAg) seroclearance remains controversial. We aimed to summarize potential predictors for HBsAg seroclearance by pegylated interferon-α (PegIFNα) in patients with chronic HBV infection. METHODS A systematic search of the Cochrane Library, Embase, PubMed, and Web of Science databases was conducted from their inception to 28 September 2022. Meta-analyses were performed following the PRISMA statement. Predictors of HBsAg seroclearance were evaluated based on baseline characteristics and on-treatment indicators. RESULTS This meta-analysis encompasses 27 studies, including a total of 7913 patients. The findings reveal several factors independently associated with HBsAg seroclearance induced by PegIFNα-based regimens. These factors include age (OR = 0.961), gender (male vs. female, OR = 0.537), genotype (A vs. B/D; OR = 7.472, OR = 10.738), treatment strategy (combination vs. monotherapy, OR = 2.126), baseline HBV DNA (OR = 0.414), baseline HBsAg (OR = 0.373), HBsAg levels at week 12 and 24 (OR = 0.384, OR = 0.294), HBsAg decline from baseline to week 12 and 24 (OR = 6.689, OR = 6.513), HBsAg decline from baseline ≥ 1 log10 IU/ml and ≥ 0.5 log10 IU/ml at week 12 (OR = 18.277; OR = 4.530), and ALT elevation at week 12 (OR = 3.622). Notably, subgroup analysis suggests no statistical association between HBsAg levels at week 12 and HBsAg seroclearance for treatment duration exceeding 48 weeks. The remaining results were consistent with the overall analysis. CONCLUSIONS This is the first meta-analysis to identify predictors of HBsAg seroclearance with PegIFNα-based regimens, including baseline and on-treatment factors, which is valuable in developing a better integrated predictive model for HBsAg seroclearance to guide individualized treatment and achieve the highest cost-effectiveness of PegIFNα.
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Affiliation(s)
- Shaowen Jiang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Simin Guo
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Huang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yalin Yin
- School of Life Sciences, Xiamen University, Xiamen, China
| | - Jingwen Feng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Huijuan Zhou
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing Guo
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weijing Wang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Department of Infectious Diseases, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Haiguang Xin
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Zhang TP, Terrault NA. Peginterferon as Part of a Functional Cure Strategy for Hepatitis B: Is the Juice Worth the Squeeze? J Clin Exp Hepatol 2024; 14:101300. [PMID: 38107185 PMCID: PMC10724687 DOI: 10.1016/j.jceh.2023.10.092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 10/26/2023] [Indexed: 12/19/2023] Open
Affiliation(s)
- Tiange P Zhang
- Division of Gastroenterology and Liver Diseases, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - Norah A Terrault
- Division of Gastroenterology and Liver Diseases, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
- Institute for Addiction Science, University of Southern California, Los Angeles, CA, USA
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Kasianchuk N, Dobrowolska K, Harkava S, Bretcan A, Zarębska-Michaluk D, Jaroszewicz J, Flisiak R, Rzymski P. Gene-Editing and RNA Interference in Treating Hepatitis B: A Review. Viruses 2023; 15:2395. [PMID: 38140636 PMCID: PMC10747710 DOI: 10.3390/v15122395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 12/04/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
The hepatitis B virus (HBV) continues to cause substantial health and economic burdens, and its target of elimination may not be reached in 2030 without further efforts in diagnostics, non-pharmaceutical prevention measures, vaccination, and treatment. Current therapeutic options in chronic HBV, based on interferons and/or nucleos(t)ide analogs, suppress the virus replication but do not eliminate the pathogen and suffer from several constraints. This paper reviews the progress on biotechnological approaches in functional and definitive HBV treatments, including gene-editing tools, i.e., zinc-finger proteins, transcription activator-like effector nucleases, and CRISPR/Cas9, as well as therapeutics based on RNA interference. The advantages and challenges of these approaches are also discussed. Although the safety and efficacy of gene-editing tools in HBV therapies are yet to be demonstrated, they show promise for the revitalization of a much-needed advance in the field and offer viral eradication. Particular hopes are related to CRISPR/Cas9; however, therapeutics employing this system are yet to enter the clinical testing phases. In contrast, a number of candidates based on RNA interference, intending to confer a functional cure, have already been introduced to human studies. However, larger and longer trials are required to assess their efficacy and safety. Considering that prevention is always superior to treatment, it is essential to pursue global efforts in HBV vaccination.
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Affiliation(s)
- Nadiia Kasianchuk
- Faculty of Biology, Adam Mickiewicz University in Poznań, 61-614 Poznań, Poland
| | | | - Sofiia Harkava
- Junior Academy of Sciences of Ukraine, Regional Branch in Dnipro, 49000 Dnipro, Ukraine;
| | - Andreea Bretcan
- National College “Ienăchiță Văcărescu”, 130016 Târgoviște, Romania;
| | - Dorota Zarębska-Michaluk
- Department of Infectious Diseases and Allergology, Jan Kochanowski University, 25-317 Kielce, Poland;
| | - Jerzy Jaroszewicz
- Department of Infectious Diseases and Hepatology, Medical University of Silesia in Katowice, 41-902 Bytom, Poland;
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, 15-540 Białystok, Poland;
| | - Piotr Rzymski
- Department of Environmental Medicine, Poznan University of Medical Sciences, 60-806 Poznań, Poland
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11
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Congly SE, Syed A, Haylock-Jacobs S, Israelson H, Pinto J, Williams S, Lee SS, Coffin CS. A real-world retrospective single-centre study of the cost-effectiveness and long-term outcomes of pegylated interferon for chronic hepatitis B. CANADIAN LIVER JOURNAL 2023; 6:305-313. [PMID: 38020196 PMCID: PMC10652987 DOI: 10.3138/canlivj-2022-0043] [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: 11/09/2022] [Accepted: 11/20/2022] [Indexed: 12/01/2023]
Abstract
Background Pegylated interferon (Peg-IFN) is recommended as first-line therapy for chronic hepatitis B (CHB) but has significant side effects and is rarely used compared to oral nucleos(t)ide analogues (NA). There are limited recent clinical efficacy or economic analysis data comparing approved CHB therapy in North America. Methods This retrospective study examined clinical outcomes, off-treatment durability, and cost-effectiveness of Peg-IFN versus NA for CHB. Demographic (age, sex, ethnicity), clinical data (i.e., liver tests, hepatitis B virus DNA, serology, transient elastography) and documented side effects were collected by retrospective chart review of patients followed in the University of Calgary Liver Unit who received Peg-IFN therapy from January 2007 to December 2020. The cost-effectiveness of Peg-IFN versus NA therapy was modelled over a 10-year time horizon. Results Sixty-eight CHB patients were treated with Peg-IFN (median age 45.65, 74% male, 84% Asian); 50/68 (74%) completed 48 weeks of treatment with a median follow-up of 6.54 years (interquartile range 5.07). At the last known follow-up, 23/68 (34%) have not required NA treatment and one had HBsAg loss; 27 have been started on NA. Predictors of obtaining a sustained virological response included being hepatitis B e antigen-negative at treatment end and a quantitative hepatitis B surface antigen <1000 IU/mL. Economic modelling showed that finite Peg-IFN was not cost-effective versus NA at a 10-year time horizon. Conclusions PEG-IFN remains a potential treatment for CHB although there is a significant intolerance/failure rate. Using PEG-IFN based on patient preference is reasonable and optimal patient selection may improve treatment cost-effectiveness.
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Affiliation(s)
- Stephen E Congly
- Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- O’Brien Institute of Public Health, University of Calgary, Calgary, Alberta, Canada
| | - Ahsan Syed
- Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Sarah Haylock-Jacobs
- Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Heidi Israelson
- Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Jacqueline Pinto
- Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Sarah Williams
- Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Samuel S Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Carla S Coffin
- Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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12
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Combination treatment of pegylated interferon and tenofovir versus tenofovir for people with chronic hepatitis B. Cochrane Database Syst Rev 2023; 2023:CD015730. [PMCID: PMC10401907 DOI: 10.1002/14651858.cd015730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2024]
Abstract
This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the benefits and harms of pegylated interferon combined with tenofovir versus tenofovir monotherapy in adults with chronic hepatitis B.
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13
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Yaici L, Gatouillat G, Andreoletti L, N'Guyen Y, Hentzien M, Gordien E, Bani-Sadr F. Chronic hepatitis delta cirrhosis cured by adapting PEG-IFNα-2a + tenofovir disoproxil fumarate treatment duration until HBsAg loss. Clin Res Hepatol Gastroenterol 2023; 47:102148. [PMID: 37244588 DOI: 10.1016/j.clinre.2023.102148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 05/25/2023] [Accepted: 05/25/2023] [Indexed: 05/29/2023]
Abstract
As the loss of HBsAg during treatment of chronic hepatitis delta (CHD) is mandatory for definitive clearance and durable response, the optimal target of therapy should be complete response (CR), defined as loss of HDV RNA and HBsAg, plus development of anti-HBs. The optimal treatment duration of CHD is not well established. We present 2 cases of patients with CHD cirrhosis who were treated with prolonged Peg-IFNα-2a + tenofovir disoproxil fumarate until HBsAg loss, and who achieved CR after 46 and 55 months of treatment respectively. A personalized approach and prolonged treatment duration determined by HBsAg loss may increase the likelihood of CR in CHD.
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Affiliation(s)
- L Yaici
- Department of Internal Medicine, Infectious Diseases, and Clinical Immunology, University Hospital of Reims, Avenue du Général Koenig, Reims 51092, France
| | - G Gatouillat
- Department of Immunology, University Hospital of Reims, France
| | - L Andreoletti
- Department of Virology, University Hospital of Reims, Reims, France; EA-4684 CardioVir, Faculté de Médecine de Reims, Reims, France
| | - Y N'Guyen
- Department of Internal Medicine, Infectious Diseases, and Clinical Immunology, University Hospital of Reims, Avenue du Général Koenig, Reims 51092, France
| | - M Hentzien
- Department of Internal Medicine, Infectious Diseases, and Clinical Immunology, University Hospital of Reims, Avenue du Général Koenig, Reims 51092, France
| | - E Gordien
- Department of Virology, APHP, Bobigny, France
| | - F Bani-Sadr
- Department of Internal Medicine, Infectious Diseases, and Clinical Immunology, University Hospital of Reims, Avenue du Général Koenig, Reims 51092, France.
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14
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Thompson AJ, Jackson K, Bonanzinga S, Hall SA, Hume S, Burns GS, Sundararajan V, Ratnam D, Levy MT, Lubel J, Nicoll AJ, Strasser SI, Sievert W, Desmond PV, Ngu MC, Sinclair M, Meredith C, Matthews G, Revill PA, Littlejohn M, Bowden DS, Canchola JA, Torres J, Siew P, Lau J, La Brot B, Kuchta A, Visvanathan K. Baseline serum HBV RNA is associated with the risk of hepatitis flare after stopping nucleoside analog therapy in HBeAg-negative participants. Hepatol Commun 2023; 7:e0188. [PMID: 37459199 PMCID: PMC10351945 DOI: 10.1097/hc9.0000000000000188] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 04/11/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND AND AIMS HBV RNA in peripheral blood reflects HBV cccDNA transcriptional activity and may predict clinical outcomes. The prospective Melbourne HBV-STOP trial studied nucleot(s)ide analog discontinuation in HBeAg-negative non-cirrhotic participants with long-term virological suppression. Ninety-six weeks after stopping treatment, the proportion of participants with virological relapse (HBV DNA > 2000 IU/mL), biochemical relapse (ALT > 2 × ULN and HBV DNA > 2000 IU/mL), or hepatitis flare (ALT > 5 × ULN and HBV DNA > 2000 IU/mL) was 89%, 58%, and 38%, respectively. We evaluated the ability of serum HBV RNA levels to predict these outcomes. APPROACH RESULTS HBV RNA levels were measured using the Roche cobas 6800/8800 HBV RNA Investigational Assay. Sixty-five participants had baseline and longitudinal off-treatment specimens available for RNA testing. HBV RNA was detectable at baseline in 25% of participants and was associated with a higher risk of biochemical relapse (81% vs. 51%, p value 0.04) and hepatitis flare (63% vs. 31%, p value 0.04). Participants who had undetectable serum HBV RNA as well as HBsAg ≤ 100 IU/mL at baseline were less likely to experience virological relapse (4 of 9, 44%) than participants with detectable HBV RNA and HBsAg level > 100 IU/mL (15/15, 100%; p value 0.0009). Off-treatment levels of HBV RNA were correlated with HBV DNA and were associated with the risk of hepatitis flare. CONCLUSIONS Serum HBV RNA may be a useful biomarker for guiding clinical decision-making before stopping nucleot(s)ide analog therapy. Baseline HBV RNA and HBsAg levels are associated with the risk of clinical relapse, hepatitis flare, and disease remission off-treatment.
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Affiliation(s)
- Alexander J. Thompson
- Department of Gastroenterology, St Vincent’s Hospital Melbourne, Melbourne, Victoria, Australia
- Immunology Research Centre, Department of Medicine (St Vincent’s Hospital), The University of Melbourne, Melbourne, Victoria, Australia
| | - Kathy Jackson
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Sara Bonanzinga
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Sam A.L. Hall
- Department of Gastroenterology, St Vincent’s Hospital Melbourne, Melbourne, Victoria, Australia
- Immunology Research Centre, Department of Medicine (St Vincent’s Hospital), The University of Melbourne, Melbourne, Victoria, Australia
| | - Simon Hume
- Department of Gastroenterology, St Vincent’s Hospital Melbourne, Melbourne, Victoria, Australia
- Immunology Research Centre, Department of Medicine (St Vincent’s Hospital), The University of Melbourne, Melbourne, Victoria, Australia
| | - Gareth S. Burns
- Department of Gastroenterology, St Vincent’s Hospital Melbourne, Melbourne, Victoria, Australia
- Immunology Research Centre, Department of Medicine (St Vincent’s Hospital), The University of Melbourne, Melbourne, Victoria, Australia
| | - Vijaya Sundararajan
- Immunology Research Centre, Department of Medicine (St Vincent’s Hospital), The University of Melbourne, Melbourne, Victoria, Australia
- Department of Public Health, La Trobe University, Melbourne, Victoria, Australia
| | - Dilip Ratnam
- Gastroenterology & Hepatology Unit, Monash Health, Melbourne, Victoria, Australia
- Monash University, Melbourne, Victoria, Australia
| | - Miriam T. Levy
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, Australia
| | - John Lubel
- Department of Gastroenterology, Alfred Health, Melbourne, Victoria, Australia
- Central Clinical School, Monash University, The Alfred Centre, Melbourne, Victoria, Australia
| | - Amanda J. Nicoll
- Gastroenterology Department of Eastern Health, Melbourne, Victoria, Australia
| | - Simone I. Strasser
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia
- University of Sydney, Sydney, Australia
| | - William Sievert
- Gastroenterology & Hepatology Unit, Monash Health, Melbourne, Victoria, Australia
- Monash University, Melbourne, Victoria, Australia
| | - Paul V. Desmond
- Department of Gastroenterology, St Vincent’s Hospital Melbourne, Melbourne, Victoria, Australia
| | - Meng C. Ngu
- Department of Gastroenterology, Concord Repatriation General Hospital, Sydney, Australia
| | - Marie Sinclair
- Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Victoria, Australia
| | | | - Gail Matthews
- Department of Infectious Disease, St Vincent’s Hospital Sydney, Sydney, Australia
| | - Peter A. Revill
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Margaret Littlejohn
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - D. Scott Bowden
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | | | - Jason Torres
- Roche Molecular Systems, Inc., Pleasanton, California, USA
| | - Philip Siew
- Roche Diagnostics, Pty Ltd, North Ryde, Australia
| | - Jasmin Lau
- Roche Molecular Systems, Inc., Pleasanton, California, USA
| | | | - Alison Kuchta
- Roche Molecular Systems, Inc., Pleasanton, California, USA
| | - Kumar Visvanathan
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
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15
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Akbar SMF, Al Mahtab M, Yoshida O, Aguilar J, Gerardo GN, Hiasa Y. Development of Therapy Based on the Exploration of Biological Events Underlying the Pathogenetic Mechanisms of Chronic Hepatitis B Infection. Biomedicines 2023; 11:1944. [PMID: 37509583 PMCID: PMC10376977 DOI: 10.3390/biomedicines11071944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/06/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
According to the World Health Organization (WHO), an estimated 296 million people are chronically infected with hepatitis B virus (HBV). Approximately 15-25% of these people develop complications such as advanced chronic liver diseases (ACLDs). Mortality due to HBV-related complications accounted for an estimated 882,000 deaths in 2019. Potent preventive vaccines have already restricted new HBV infections, and several drugs are available to treat chronic HBV infections. However, the positive impacts of these drugs have been recorded in only a few patients with chronic HBV infection. These drugs do not show long-term efficacy and cannot halt the progression to complications. Thus, more effective and evidence-based therapeutic strategies need to be urgently developed for patients with chronic HBV infection. CHB is a pathological entity induced by HBV that progresses due to impaired host immunity. This indicates the inherent limitations of antiviral-drug-based monotherapy for treating patients with chronic HBV infection. Additionally, commercially available antiviral drugs are not available to patients in developing and resource-constrained countries, posing a challenge to achieving the following WHO goal: "Elimination of Hepatitis by 2030". As such, this review aimed to provide insights regarding evidence-based and effective management strategies for chronic HBV infection.
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Affiliation(s)
- Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon 791-0295, Japan
- Miyakawa Memorial Research Foundation, Tokyo 107-0062, Japan
| | - Mamun Al Mahtab
- Interventional Hepatology Division, Bangabandhu Sheikh Mujib Medical University, Dhaka 1000, Bangladesh
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon 791-0295, Japan
| | - Julio Aguilar
- Center for Genetic Engineering and Biotechnology, Havana 10400, Cuba
| | | | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon 791-0295, Japan
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16
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He J, Guo Y, Zhang Y, Han J, Chen J, Jia Y, Ma Z, Wu J, Zhang S, Li F, Mao R, Zhang J. Comparison of Pegylated Interferon Alfa Therapy in Combination with Tenofovir Alafenamide Fumarate or Tenofovir Disoproxil Fumarate for Treatment of Chronic Hepatitis B Patients. Infect Drug Resist 2023; 16:3929-3941. [PMID: 37361938 PMCID: PMC10290461 DOI: 10.2147/idr.s411183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 06/02/2023] [Indexed: 06/28/2023] Open
Abstract
Purpose The study aims to evaluate the effectiveness of a tenofovir alafenamide fumarate (TAF) and pegylated interferon alfa (PegIFN-α) regimen compared to a tenofovir disoproxil fumarate (TDF) and PegIFN-α therapy in patients with chronic hepatitis B (CHB). Patients and Methods Patients who were treated with PegIFN-α in combination with TAF or TDF were retrospectively enrolled. The primary outcome measured was the HBsAg loss rate. The rates of virological response, serological response for HBeAg, and normalization of alanine aminotransferase (ALT) were also calculated. The cumulative incidences of response rates were compared between the two groups using Kaplan-Meier analysis. Results A total of 114 patients were retrospectively enrolled in the study, with 33 receiving TAF plus PegIFN-α treatment and 81 receiving TDF plus PegIFN-α treatment. The HBsAg loss rate for the TAF plus PegIFN-α group was 15.2% at 24 weeks and 21.2% at 48 weeks, while the TDF plus PegIFN-α group had rates of 7.4% at 24 weeks and 12.3% at 48 weeks (P=0.204 at 24 weeks, P=0.228 at 48 weeks). In subgroup analysis of HBeAg positive patients, the TAF group had a higher HBsAg loss rate of 25% at week 48, compared to 3.8% in the TDF group (P=0.033). According to Kaplan-Meier analysis, the TAF plus PegIFN-α group achieved virological response more quickly than the TDF plus PegIFN-α group (p=0.013). There was no statistical difference in HBeAg serological rate or ALT normalization rate. Conclusion There was no significant difference in the HBsAg loss between the two groups. However, subgroup analysis revealed that TAF plus PegIFN-α treatment had a higher HBsAg loss rate than TDF plus PegIFN-α treatment in HBeAg-positive patients. Additionally, TAF plus PegIFN-α treatment demonstrated better virological suppression for CHB patients. Therefore, TAF plus PegIFN-α treatment regimen is recommended for CHB patients who aim to achieve functional cure.
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Affiliation(s)
- Jingjing He
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Yifei Guo
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Yao Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Jiajia Han
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Jingwen Chen
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Yidi Jia
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Zhenxuan Ma
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Jingwen Wu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Shenyan Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Fahong Li
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Richeng Mao
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
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17
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Xie Y, Zhu H, Guo Y, Ma Z, Qi X, Yang F, Mao R, Zhang J. Reduction of Hepatitis B Surface Antigen May Be More Significant in PEGylated Interferon-Alpha Therapy Combined with Nucleotide Analogues than Combined with Nucleoside Analogues in Chronic Hepatitis B Patients: A Propensity Score Matching Study. Can J Gastroenterol Hepatol 2022; 2022:4325352. [PMID: 36531834 PMCID: PMC9750779 DOI: 10.1155/2022/4325352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 11/09/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
Background Nucleotide analogues (NTs) monotherapy may have a more significant effect on reducing hepatitis B surface antigen (HBsAg) than nucleoside analogues (NSs) due to their immunomodulatory function. However, this superiority remains unknown when combined with PEGylated interferon α (PegIFNα). Therefore, this study aimed to explore whether NTs have more significant antiviral effects than NSs in combination therapy with PegIFNα. Methods Chronic hepatitis B (CHB) patients treated with PegIFNα plus nucleos(t)ide analogues (NAs) were retrospectively recruited. Efficacy and the predictors of hepatitis B surface antigen (HBsAg) reduction >1 log10 IU/mL after 48 weeks were analyzed. Results A total of 95 patients were included and divided into the PegIFNα + NTs group and the PegIFNα + NSs group. Propensity score matching (PSM) was performed. The PegIFNα + NTs group had a greater reduction of HBsAg (-3.52 vs. -2.33 log10 IU/mL, P=0.032) and a higher proportion of patients with HBsAg reduction >1 log10 IU/mL (100.0% vs. 72.2%, P=0.003) even after PSM. However, HBsAg and hepatitis B e-antigen (HBeAg) loss rates, HBeAg seroconversion rates, degree of HBeAg and hepatitis B virus (HBV) DNA decline, HBV DNA undetectable rates, and alanine aminotransferase (ALT) normalization rates showed no significant differences. Subgroup analyses showed the difference in the reduction of HBsAg was particularly evident in HBeAg-positive and the "add-on" subgroups. PegIFNα plus NTs (OR = 36.667, 95% CI = 3.837-350.384) was an independent predictor for HBsAg reduction >1 log10 IU/mL after 48 weeks. Conclusion This study suggests that PegIFNα plus NTs may lead to more HBsAg reduction, especially in HBeAg-positive and "add-on" patients.
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Affiliation(s)
- Yiran Xie
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Haoxiang Zhu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yifei Guo
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhenxuan Ma
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Xun Qi
- Shanghai Public Health Center of Fudan University, Shanghai, China
| | - Feifei Yang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Richeng Mao
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- Department of Infectious Diseases, Jing'An Branch of Huashan Hospital, Fudan University, Shanghai, China
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18
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Butt SRR, Satnarine T, Ratna P, Sarker A, Ramesh AS, Munoz C, Jamil D, Tran HHV, Mansoor M, Khan S. A Systematic Review on Current Trends in the Treatment of Chronic Hepatitis B to Predict Disease Remission and Relapse. Cureus 2022; 14:e32247. [PMID: 36620830 PMCID: PMC9814228 DOI: 10.7759/cureus.32247] [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: 07/10/2022] [Accepted: 12/06/2022] [Indexed: 12/12/2022] Open
Abstract
Despite decreasing the prevalence of chronic hepatitis B (CHB), it is still a major health care challenge. Current antiviral regimens aim to suppress hepatitis B virus (HBV) deoxyribonucleic acid (DNA) activity to prevent the risk of hepatic decompensation, liver cirrhosis, and hepatocellular carcinoma (HCC). Currently, pegylated interferon (Peg-IFN) and nucleos(t)ide analogs (NA) are the first-line choices of drugs. Peg-IFN is now discontinued due to its mode of application and side effects. NA is used once daily to suppress HBV DNA activity but has little effect on covalently closed circular DNA (cccDNA), so continuous long-term therapy is required to suppress HBV DNA. Due to this effect, disease remission, relapse, and even clinical flare are common phenomena after the end of treatment (EOT). This review aimed to analyze the current regimens for treating chronic hepatitis B. Their mode of action, duration of treatment, and events after stopping therapy. The review was performed using the preferred reporting items for systematic reviews and meta-analysis (PRISMA) 2020 guidelines. A search was undertaken in PubMed, PubMed Central, Google Scholar, and ScienceDirect. Screening of articles was carried out to find relevant and appropriate articles. Articles were then quality-checked before inclusion. Our analysis showed that long-term finite therapy with nucleoside analogs could improve clinical outcomes and suppress viral DNA activity. However, a functional cure, loss of hepatitis B surface antigen (HBsAg), is rarely achieved. The decision to end treatment depends on quantitative HBsAg level (qHBsAg), alanine aminotransferase (ALT), HBV DNA (deoxyribonucleic acid), hepatitis B e antigen (HBeAg), and fibrosis assessment. It is concluded that patients with HBeAg negative without cirrhosis can be easily withdrawn from treatment if they have long-term viral remission and a high HBsAg loss rate. However, patients with positive HBeAg should continue treatment because there is a high chance of disease relapse and even acute flare. To predict whether patients will benefit from EOT, some immunomodulatory markers are studied, including interleukin (IL-20, IL-8), fas ligand (FASGL), and IFN gamma. Although these factors are reliable, none pose an independent effect on disease remission. Combination therapy (IFN alpha + oral nucleoside analogs) is promising but has clinical shortcomings.
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Affiliation(s)
- Samia Rauf R Butt
- General Practice, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Travis Satnarine
- Pediatrics, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Pranuthi Ratna
- General Practice, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Aditi Sarker
- General Practice, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Adarsh Srinivas Ramesh
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Carlos Munoz
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Dawood Jamil
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Hadrian Hoang-Vu Tran
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Mafaz Mansoor
- General Practice, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Safeera Khan
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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19
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Bazinet M, Anderson M, Pântea V, Placinta G, Moscalu I, Cebotarescu V, Cojuhari L, Jimbei P, Iarovoi L, Smesnoi V, Musteata T, Jucov A, Dittmer U, Gersch J, Holzmayer V, Kuhns M, Cloherty G, Vaillant A. HBsAg isoform dynamics during NAP-based therapy of HBeAg-negative chronic HBV and HBV/HDV infection. Hepatol Commun 2022; 6:1870-1880. [PMID: 35368148 PMCID: PMC9315123 DOI: 10.1002/hep4.1951] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/15/2022] [Accepted: 03/03/2022] [Indexed: 12/11/2022] Open
Abstract
Nucleic acid polymers block the assembly of hepatitis B virus (HBV) subviral particles, effectively preventing hepatitis B surface antigen (HBsAg) replenishment in the circulation. Nucleic acid polymer (NAP)-based combination therapy of HBV infection or HBV/hepatitis D virus (HDV) co-infection is accompanied by HBsAg clearance and seroconversion, HDV-RNA clearance in co-infection, and persistent functional cure of HBV (HBsAg < 0.05 IU/ml, HBV-DNA target not dected, normal alanine aminotransferase) and persistent clearance of HDV RNA. An analysis of HBsAg isoform changes during quantitative HBsAg declines (qHBsAg), and subsequent treatment-free follow-up in the REP 301/REP 301-LTF (HBV/HDV) and REP 401 (HBV) studies was conducted. HBsAg isoforms were analyzed from frozen serum samples using Abbott Research Use Only assays for HBsAg isoforms (large [L], medium [M], and total [T]). The relative change over time in small HBsAg relative to the other isoforms was inferred by the change in the ratio over time of T-HBsAg to M-HBsAg. HBsAg isoform declines followed qHBsAg declines in all participants. No HBsAg isoforms were detectable in any participants with functional cure. HBsAg declines > 2 log10 IU/ml from baseline were correlated with selective clearance of S-HBsAg in 39 of 42 participants. Selective S-HBsAg decline was absent in 9 of 10 participants with HBsAg decline < 2 log10 IU/ml from baseline. Mild qHBsAg rebound during follow-up <10 IU/ml consisted mostly of S-HBsAg and M-HBsAg and not accompanied by significant covalently closed circular DNA activity. Conclusion: The faster observed declines in S-HBsAg indicate the selective clearance of subviral particles from the circulation, consistent with previous mechanistic studies on NAPs. Trace HBsAg rebound in the absence of HBV DNA may reflect HBsAg derived from integrated HBV DNA and not rebound of viral infection.
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Affiliation(s)
| | | | - Victor Pântea
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | - Gheorghe Placinta
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | - Iurie Moscalu
- ARENSIA Exploratory MedicineRepublican Clinical HospitalChișinăuRepublic of Moldova
| | - Valentin Cebotarescu
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | - Lilia Cojuhari
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | - Pavlina Jimbei
- Toma Ciorbǎ Infectious Clinical HospitalChișinăuRepublic of Moldova
| | - Liviu Iarovoi
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | | | - Tatina Musteata
- Toma Ciorbǎ Infectious Clinical HospitalChișinăuRepublic of Moldova
| | - Alina Jucov
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova.,ARENSIA Exploratory MedicineRepublican Clinical HospitalChișinăuRepublic of Moldova
| | - Ulf Dittmer
- Institute for VirologyUniversity of Duisburg-EssenEssenGermany
| | | | | | - Mary Kuhns
- Abbott DiagnosticsAbbott ParkIllinoisUSA
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20
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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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21
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Novel Pegylated Interferon for the Treatment of Chronic Viral Hepatitis. Viruses 2022; 14:v14061128. [PMID: 35746606 PMCID: PMC9230558 DOI: 10.3390/v14061128] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/12/2022] [Accepted: 05/20/2022] [Indexed: 11/17/2022] Open
Abstract
Ropeginterferon alfa-2b is a novel mono-pegylated and extra-long-acting interferon, being developed for the treatment of myeloproliferative neoplasm (MPN) and chronic viral hepatitis. It has a favorable pharmacokinetic profile and less frequent dosing schedule, i.e., once every two to four weeks, compared to conventional pegylated interferon products, which have multiple isomers and are administered weekly. It was approved for the long-term treatment of polycythemia vera, an MPN, and has been included in the NCCN clinical practice guidelines for this indication. Ropeginterferon alfa-2b has demonstrated efficacy and showed a favorable safety profile for the treatment of chronic viral hepatitis in several clinical studies. In this article, we review its pharmacokinetics and available clinical data and suggest that ropeginterferon alfa-2b administered once every two weeks can serve as a new treatment option for patients with chronic viral hepatitis, including chronic hepatitis B, C, and D.
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22
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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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23
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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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24
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Lee WM, King WC, Janssen HL, Ghany MG, Fontana RJ, Fried M, Sterling RK, Feld JJ, Wang J, Mogul DB, Cooper SL, Di Bisceglie AM, Hepatitis B Research Network (HBRN). Hepatitis B e antigen loss in adults and children with chronic hepatitis B living in North America: A prospective cohort study. J Viral Hepat 2021; 28:1526-1538. [PMID: 34355475 PMCID: PMC8622507 DOI: 10.1111/jvh.13591] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 07/23/2021] [Indexed: 01/15/2023]
Abstract
Hepatitis B e antigen (HBeAg) is a soluble viral protein in plasma of patients with hepatitis B virus infection. HBeAg loss is an important first stage of viral antigen clearance. We determined the rate and predictors of HBeAg loss in a North American cohort with chronic hepatitis B viral infection (CHB). Among children and adults with CHB and without HIV, HCV or HDV co-infection enrolled in the Hepatitis B Research Network prospective cohort studies, 819 were HBeAg positive at their first assessment (treatment naïve or >24 weeks since treatment). Of these, 577 (200 children, 377 adults) were followed every 24-48 weeks. HBeAg loss was defined as first HBeAg-negative value; sustained HBeAg loss was defined as ≥2 consecutive HBeAg-negative values ≥24 weeks apart. During a median follow-up of 1.8 years, 164 participants experienced HBeAg loss, a rate of 11.4 (95% CI, 9.8-13.3) per 100 person-years. After adjustment for confounders, HBeAg loss rate was significantly higher in males than females, in older than younger individuals, in Whites or Blacks than Asians, in those with genotype A2 or B versus C, and in those with basal core promoter/pre-core mutations versus wild type. Additionally, during follow-up, an ALT flare and a lower quantitative HBsAg, quantitative HBeAg or HBV DNA level predicted higher rates of HBeAg loss. The majority (88%) with HBeAg loss had sustained HBeAg loss. In conclusion, a number of specific demographic, clinical and viral characteristics impacted rate of HBeAg loss and may prove useful in design and interpretation of future therapeutic studies.
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Affiliation(s)
| | - Wendy C. King
- Graduate School of Public Health University of Pittsburgh, Pittsburgh, PA
| | - Harry L.A. Janssen
- Toronto Centre for Liver Disease, University of Toronto, Toronto, Canada
| | | | | | | | - Richard K. Sterling
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, VA
| | - Jordan J. Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto
| | - Junyao Wang
- Graduate School of Public Health University of Pittsburgh, Pittsburgh, PA
| | | | - Stewart L. Cooper
- California Pacific Medical Center & Research Institute, San Francisco, CA
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25
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Vaillant A. HBsAg, Subviral Particles, and Their Clearance in Establishing a Functional Cure of Chronic Hepatitis B Virus Infection. ACS Infect Dis 2021; 7:1351-1368. [PMID: 33302622 DOI: 10.1021/acsinfecdis.0c00638] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In diverse viral infections, the production of excess viral particles containing only viral glycoproteins (subviral particles or SVP) is commonly observed and is a commonly evolved mechanism for immune evasion. In hepatitis B virus (HBV) infection, spherical particles contain the hepatitis B surface antigen, outnumber infectious virus 10 000-100 000 to 1, and have diverse inhibitory effects on the innate and adaptive immune response, playing a major role in the chronic nature of HBV infection. The current goal of therapies in development for HBV infection is a clinical outcome called functional cure, which signals a persistent and effective immune control of the infection. Although removal of spherical SVP (and the HBsAg they carry) is an important milestone in achieving functional cure, this outcome is rarely achieved with current therapies due to distinct mechanisms for assembly, secretion, and persistence of SVP, which are poorly targeted by direct acting antivirals or immunotherapies. In this Review, the current understanding of the distinct mechanisms involved in the production and persistence of spherical SVP in chronic HBV infection and their immunoinhibitory activity will be reviewed as well as current therapies in development with the goal of clearing spherical SVP and achieving functional cure.
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Affiliation(s)
- Andrew Vaillant
- Replicor Inc., 6100 Royalmount Avenue, Montreal, Quebec H8Y 3E6, Canada
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26
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Song A, Lin X, Chen X. Functional cure for chronic hepatitis B: accessibility, durability, and prognosis. Virol J 2021; 18:114. [PMID: 34082765 PMCID: PMC8176700 DOI: 10.1186/s12985-021-01589-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 05/28/2021] [Indexed: 01/27/2023] Open
Abstract
Hepatitis B surface antigen (HBsAg) clearance is regarded as the ideal endpoint for antiviral treatment in terms of drug withdrawal safety and improvements in prognosis. However, the overall rate of HBsAg clearance is low and differs based on treatment method and course. The recent application of combined and extended treatment strategies have improved the HBsAg clearance rate, and several patients achieved HBsAg clearance in clinical treatment. In addition, the durability of and clinical outcomes after HBsAg clearance have become the focus of both researchers and clinicians. This article reviews HBsAg clearance in terms of accessibility, durability, improvements in prognosis and relevant advances.
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Affiliation(s)
- Aixin Song
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xiao Lin
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xinyue Chen
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing, China.
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27
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Bazinet M, Pântea V, Placinta G, Moscalu I, Cebotarescu V, Cojuhari L, Jimbei P, Iarovoi L, Smesnoi V, Musteata T, Jucov A, Dittmer U, Krawczyk A, Vaillant A. Benefit of transaminase elevations in establishing functional cure of HBV infection during nap-based combination therapy. J Viral Hepat 2021; 28:817-825. [PMID: 33556206 DOI: 10.1111/jvh.13483] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 01/18/2021] [Indexed: 12/12/2022]
Abstract
Treatment of HBV infection with nucleic acid polymers and pegIFN is accompanied by transaminase elevations in 95% of participants. HBV viral rebound, partial cure (HBV DNA < 2000 IU/mL, normal ALT) or functional cure (HBV DNA target not detected, HBsAg <LLOQ, normal ALT) occurred in 27%, 38% and 35% of participants. Correlations between ALT, AST and GGT elevations, virologic baseline, response during therapy and HBV therapeutic outcome were investigated. A retrospective analysis of all 40 participants in the REP 401 study (NCT02565719) included maxima and area under the curve for ALT, AST and GGT, baseline virology, HBsAg and anti-HBs response and HBV therapeutic outcomes. ALT, AST and GGT elevations were asymptomatic, independent of baseline virologic status and anti-HBs response but correlated with HBsAg reduction ≥3 log10 from baseline. Functional cure was associated with significantly lower HBsAg during the nadir of ALT flares versus viral rebound or partial cure. ALT elevations >3X ULN while HBsAg was <1 IU/mL occurred in 3/11 (27%), 11/15 (74%) and 14/14 (100%) of participants experiencing viral rebound, partial or functional cure. ALT elevation >3X ULN during HBsAg <1 IU/mL and <10 IU/mL were the best predictors of partial and functional cure. In conclusion, elevations in ALT, AST or GGT while HBsAg <10 IU/ml during therapy with REP 2139 + pegIFN are associated with partial and functional cure. More potent HBsAg reduction during flare nadir is associated with the establishment of functional cure, suggesting a critical role for HBsAg-specific immunity to achieve this outcome. These on-therapy milestones may have similar positive prognostic value with other combination therapies.
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Affiliation(s)
| | - Victor Pântea
- Department of Infectious Diseases, Nicolae Testemiţanu State University of Medicine and Pharmacy, Chișinău, Republic of Moldova
| | - Gheorghe Placinta
- Department of Infectious Diseases, Nicolae Testemiţanu State University of Medicine and Pharmacy, Chișinău, Republic of Moldova
| | - Iurie Moscalu
- ARENSIA Exploratory Medicine, Republican Clinical Hospital Chișinău, Moldova
| | - Valentin Cebotarescu
- Department of Infectious Diseases, Nicolae Testemiţanu State University of Medicine and Pharmacy, Chișinău, Republic of Moldova
| | - Lilia Cojuhari
- Department of Infectious Diseases, Nicolae Testemiţanu State University of Medicine and Pharmacy, Chișinău, Republic of Moldova
| | - Pavlina Jimbei
- Toma Ciorbă Infectious Clinical Hospital, Chișinău, Republic of Moldova
| | - Liviu Iarovoi
- Department of Infectious Diseases, Nicolae Testemiţanu State University of Medicine and Pharmacy, Chișinău, Republic of Moldova
| | - Valentina Smesnoi
- Toma Ciorbă Infectious Clinical Hospital, Chișinău, Republic of Moldova
| | - Tatiana Musteata
- Toma Ciorbă Infectious Clinical Hospital, Chișinău, Republic of Moldova
| | - Alina Jucov
- Department of Infectious Diseases, Nicolae Testemiţanu State University of Medicine and Pharmacy, Chișinău, Republic of Moldova.,ARENSIA Exploratory Medicine, Republican Clinical Hospital Chișinău, Moldova
| | - Ulf Dittmer
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Adalbert Krawczyk
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.,Department of Infectious Diseases, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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28
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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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Hu C, Song Y, Tang C, Li M, Liu J, Liu J, Liao M, Zhou F, Zhang YY, Zhou Y. Effect of Pegylated Interferon Plus Tenofovir Combination on Higher Hepatitis B Surface Antigen Loss in Treatment-naive Patients With Hepatitis B e Antigen -positive Chronic Hepatitis B: A Real-world Experience. Clin Ther 2021; 43:572-581.e3. [PMID: 33516527 DOI: 10.1016/j.clinthera.2020.12.022] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/25/2020] [Accepted: 12/30/2020] [Indexed: 12/26/2022]
Abstract
PURPOSE The loss of serum hepatitis B surface antigen (HBsAg) in patients with chronic hepatitis B (CHB) is considered an ideal clinical outcome but rarely achieved with current standard of care. We evaluated the effectiveness in inducing HBsAg seroclearance in a real-world clinical cohort of Chinese patients with CHB treated with a combination of pegylated interferon (Peg-IFN) with tenofovir disoproxil fumarate (TDF) or monotherapy with each agent. METHODS A total of 330 patients with CHB were assigned to receive Peg-IFN plus TDF for 48 weeks (Peg-IFN plus TDF group), Peg-IFN alone for 48 weeks (Peg-IFN group), or TDF alone for 144 weeks (TDF group). The primary end point was the percentages of patients who achieved HBsAg seroclearance at week 72. Differences from the baseline characteristics and treatment data were compared using the χ2 test for categorical variables or 1-way ANOVA for continuous variables. A Kaplan-Meier test was performed to compare the HBsAg loss among the 3 groups. Discrimination of responders versus nonresponders was quantified using AUC curves. Optimal cut-offs were selected based on Youden's J statistic defined as J = sensitivity + specificity-1. FINDINGS At week 72, the Kaplan-Meier cumulative HBsAg loss was 11.5% in the Peg-IFN plus TDF group, 5.7% in the Peg-IFN group, and 0% in the TDF group. The percentage of patients with HBsAg loss was comparable in the Peg-IFN plus TDF and Peg-IFN groups (P = 0.143), but both were significantly higher than that in the TDF group (P = 0.000 and P = 0.010). In addition, a significantly higher percentage of patients in the combination group and Peg-IFN group had serum HBsAg of <100 IU/mL compared with the TDF group (32.7% vs 23.6% vs 9.2%; P < 0.001) but no significant differences in the percentages of patients with HBsAg <1000 IU/mL, the undetectable serum HBV DNA and hepatitis B e antigen seroconversion. Our model predicted serum HBsAg loss at week 72 (AUC = 0.846) if the HBsAg level was reduced by > 1.5 log10 IU/mL from baseline at treatment week 24, an optimal timepoint for prediction of HBsAg loss in this cohort. IMPLICATIONS A 48-week course of Peg-IFN and TDF combination therapy led to profound reduction in serum HBsAg level, resulting in a significantly higher rate of HBsAg loss compared with TDF monotherapy. Patients with steep HBsAg decline >1.5 log10 IU/mL at week 24 well signaled a higher probability of achieving HBsAg loss at week 72.
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Affiliation(s)
- Chengguang Hu
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yangda Song
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Cuirong Tang
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Meng Li
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Junwei Liu
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jia Liu
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Minjun Liao
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fuyuan Zhou
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | | | - Yuanping Zhou
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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Mak LY, Yuen MF. Novel Therapy for Functional Cure of Chronic Hepatitis B Virus Infection. HEPATITIS B VIRUS AND LIVER DISEASE 2021:455-473. [DOI: 10.1007/978-981-16-3615-8_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Jeng WJ, Lok ASF. Is Cure of Hepatitis B Infection a Mission Possible? HEPATITIS B VIRUS AND LIVER DISEASE 2021:475-495. [DOI: 10.1007/978-981-16-3615-8_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Matsumoto A, Nishiguchi S, Enomoto H, Tanaka Y, Shinkai N, Okuse C, Kang JH, Matsui T, Miyase S, Yatsuhashi H, Nagaoka S, Kanda T, Enomoto M, Yamada R, Hiramatsu N, Saito S, Takaguchi K, Ito K, Masaki T, Morihara D, Tsuge M, Chayama K, Ikeda F, Kagawa T, Kondo Y, Murata K, Tanaka E. Pilot study of tenofovir disoproxil fumarate and pegylated interferon-alpha 2a add-on therapy in Japanese patients with chronic hepatitis B. J Gastroenterol 2020; 55:977-989. [PMID: 32666202 DOI: 10.1007/s00535-020-01707-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 06/25/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND A prospective pilot study of tenofovir disoproxil fumarate (TDF) and pegylated interferon alpha 2a (P-IFN) add-on therapy was conducted to evaluate its efficacy in reducing viral antigen levels in Japanese patients with chronic hepatitis B (UMIN 000020179). METHODS Patients with chronic hepatitis B receiving maintenance TDF therapy and exhibiting hepatitis B surface antigen (HBsAg) level > 800 IU/ml were divided into two arms. P-IFN was added for 48 weeks in the add-on arm (n = 32), while TDF monotherapy was maintained in the control arm (n = 51). Both groups were followed for 96 weeks after baseline measurements. RESULTS Almost all patients in the control arm displayed a slow and constant reduction in HBsAg during follow-up. In contrast, roughly half of the add-on arm exhibited a sharp decline in HBsAg during P-IFN administration, which disappeared after halting P-IFN. At 96 weeks after baseline, 41% (13/32) of patients in the add-on arm had shown a rapid decrease in HBsAg, versus 2% (1/51) in the control arm (p < 0.001). Add-on therapy and increased cytotoxic T-cell response were significant factors associated with a rapid decrease in HBsAg according to multivariate analysis. In addition, higher HB core-related antigen (HBcrAg) level at baseline (p = 0.001) and add-on therapy (p = 0.036) were significant factors associated with a rapid reduction in HBcrAg. CONCLUSIONS TDF and P-IFN add-on therapy in Japanese patients with chronic hepatitis B facilitated rapid decreases in HBsAg and HBcrAg. Further studies are needed to improve early HBsAg clearance rate.
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Affiliation(s)
- Akihiro Matsumoto
- Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hirayuki Enomoto
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Noboru Shinkai
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Chiaki Okuse
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kawasaki Municipal Tama Hospital, Kawasaki, Japan
| | - Jong-Hon Kang
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Takeshi Matsui
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Shiho Miyase
- Department of Gastroenterology and Hepatology, Kumamoto Shinto General Hospital, Kumamoto, Japan
| | - Hiroshi Yatsuhashi
- The Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Japan
| | - Shinya Nagaoka
- The Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Japan
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Masaru Enomoto
- Department of Hepatology, Osaka City University Medical School, Osaka, Japan
| | - Ryoko Yamada
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Naoki Hiramatsu
- Department of Gastroenterology, Osaka Rosai Hospital, Sakai, Japan
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Kiyoaki Ito
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan
| | - Daisuke Morihara
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Fusao Ikeda
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Tatehiro Kagawa
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Yasuteru Kondo
- Department of Hepatology, Sendai Kousei Hospital, Sendai, Japan
| | - Kazumoto Murata
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Japan
| | - Eiji Tanaka
- Department for the Promotion of Regional Medicine, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto, 390-8621, Japan.
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Hepatitis B Surface Antigen Levels Are Related to Spontaneous Hepatitis B Surface Antigen Seroconversion in Inactive Hepatitis B Carriers. J Clin Gastroenterol 2020; 54:573-576. [PMID: 32049690 DOI: 10.1097/mcg.0000000000001324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND The cure for hepatitis B is defined as the hepatitis B surface antigen (HBsAg) seroclearance and/or seroconversion. Predictors of spontaneous seroconversion are not well described. The objective of this study is to identify predictors of spontaneous HBsAg seroconversion from community practice. METHODS We performed a matched analysis of patients who HBsAg seroconverted (cases) and patients who did not HBsAg seroconvert (control) in a 1:5 ratio according to date of clinic visit between 2014 and 2019 in a large community practice situated in Los Angeles area. Baseline laboratory and clinical data were collected. Univariate analysis and 2-sided t tests were performed, χ test for proportions, and logistic regression. RESULTS We identified 14 cases and 70 controls. The mean (±SD) ages of the cases and controls were 53.6 (±12.2) and 49.5 (±13.1), respectively (P=0.45). Most patients were women, and all patients were of Asian descent. There were statistically significant mean (±SD) baseline differences between cases and controls in HBsAg titers (459.8±311.0 and 782.0±393.3 IU/mL, P=0.01) and alanine aminotransferase (ALT) values (17.6±4.4 and 25.1±16.7 IU/mL, P<0.01), respectively. Baseline hepatitis B virus DNA and other pertinent laboratory values did not differ between cases and controls. Eleven of 14 cases (79%) and 11 of 70 controls (16%) baseline HBsAg titers were <1000 IU/mL (P<0.01). The results of a logistic regression demonstrated that HBsAg titers and ALT values were predictor variables for HBsAg seroconversion (P=0.01 and <0.01, respectively). CONCLUSIONS Spontaneous HBsAg seroclearance and seroconversion is an uncommon event in patients with chronic hepatitis B. The most important predictors of seroconversion are HBsAg titers<1000 IU/mL and low baseline ALT values.
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Abstract
Chronic hepatitis B (CHB) is a widespread global infection and a leading cause of hepatocellular carcinoma and liver failure. Current approaches to treat CHB involve the suppression of viral replication with either interferon or nucleos(t)ide analog therapy, but neither of these approaches can reliably induce viral eradication, immunologic control or long-lived viral suppression in the absence of continued therapy. In this update, we explore the major obstacles of CHB cure and review new therapeutic strategies and drug candidates.
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Affiliation(s)
- Lydia Tang
- Division of Clinical Care & Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Program in Oncology, University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
| | - Shyam Kottilil
- Division of Clinical Care & Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Program in Oncology, University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
| | - Eleanor Wilson
- Division of Clinical Care & Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Program in Oncology, University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
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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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Tao Y, Wu D, Zhou L, Chen E, Liu C, Tang X, Jiang W, Han N, Li H, Tang H. Present and Future Therapies for Chronic Hepatitis B. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1179:137-186. [PMID: 31741336 DOI: 10.1007/978-981-13-9151-4_6] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis B (CHB) remains the leading cause of liver-related morbidity and mortality across the world. If left untreated, approximately one-third of these patients will progress to severe end-stage liver diseases including liver failure, cirrhosis, and hepatocellular carcinoma (HCC). High level of serum HBV DNA is strongly associated with the development of liver failure, cirrhosis, and HCC. Therefore, antiviral therapy is crucial for the clinical management of CHB. Current antiviral drugs including nucleoside/nucleotide analogues (NAs) and interferon-α (IFN-α) can suppress HBV replication and reduce the progression of liver disease, thus improving the long-term outcomes of CHB patients. This chapter will discuss the standard and optimization antiviral therapies in treatment-naïve and treatment-experienced patients, as well as in the special populations. The up-to-date advances in the development of new anti-HBV agents will be also discussed. With the combination of the current antiviral drugs and the newly developed antiviral agents targeting the different steps of the viral life cycle or the newly developed agents modulating the host immune responses, the ultimate eradication of HBV will be achieved in the future.
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Affiliation(s)
- Yachao Tao
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Dongbo Wu
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lingyun Zhou
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Enqiang Chen
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Changhai Liu
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaoqiong Tang
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Wei Jiang
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ning Han
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hong Li
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Hong Tang
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Lok AS, Zoulim F, Dusheiko G, Chan HLY, Buti M, Ghany MG, Gaggar A, Yang JC, Wu G, Flaherty JF, Subramanian GM, Locarnini S, Marcellin P. Durability of Hepatitis B Surface Antigen Loss With Nucleotide Analogue and Peginterferon Therapy in Patients With Chronic Hepatitis B. Hepatol Commun 2019; 4:8-20. [PMID: 31909352 PMCID: PMC6939500 DOI: 10.1002/hep4.1436] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 09/07/2019] [Indexed: 12/11/2022] Open
Abstract
In patients with chronic hepatitis B (CHB), loss of hepatitis B surface antigen (HBsAg) is considered a functional cure. However, HBsAg loss is uncommon with existing therapies, and predictive factors associated with HBsAg seroreversion are unknown. Using pooled data from three phase 3 clinical trials of patients with CHB treated with nucleos(t)ide analogue (NUC) monotherapy or peginterferon (Peg‐IFN) ± NUC combination therapy, we conducted a retrospective analysis to characterize patients who achieved sustained HBsAg loss, the predictors of HBsAg seroreversion, and the impact of hepatitis B surface antibody (anti‐HBs) seroconversion on durability of HBsAg loss. In these three international trials, 1,381 adults with CHB received either NUC monotherapy for up to 10 years or Peg‐IFN‐containing regimens for up to 1 year. A total of 55 patients had confirmed HBsAg loss, defined as two or more consecutive negative‐qualitative HBsAg results, with a minimum of one repeat result after the end of treatment. Throughout a median of 96 (quartile [Q]1, Q3, 46, 135) weeks follow‐up after HBsAg loss, HBsAg loss was durable in 82% (n = 45) of patients, with 10 patients experiencing HBsAg seroreversion. Anti‐HBs seroconversion was observed during follow‐up in 78% of patients who lost HBsAg and in 60% of those who subsequently seroreverted. In analyzing predictors of HBsAg seroreversion, study treatment was significant, yet anti‐HBs seroconversion and treatment duration after initial HBsAg loss were not. Risk of HBsAg seroreversion was observed to be lower if HBsAg loss was sustained through the off‐treatment week 24 visit (8/10 seroreversions occurred by posttreatment week 24). Conclusion: HBsAg loss after NUC or Peg‐IFN‐containing regimens was durable in 82% of patients with CHB. Anti‐HBs seroconversion and treatment duration after initial HBsAg loss were not significantly associated with durability of HBsAg loss.
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Affiliation(s)
| | - Fabien Zoulim
- Hospices Civils de Lyon and INSERM Unit 1052 Lyon France
| | - Geoffrey Dusheiko
- Kings College Hospital University College London Medical School London United Kingdom
| | | | | | | | | | | | - George Wu
- Gilead Sciences, Inc. Foster City CA
| | | | | | - Stephen Locarnini
- Victorian Infectious Diseases Reference Laboratory Melbourne Australia
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Clinical utility of HBV surface antigen quantification in HBV e antigen-negative chronic HBV infection. Nat Rev Gastroenterol Hepatol 2019; 16:631-641. [PMID: 31477873 DOI: 10.1038/s41575-019-0197-8] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/25/2019] [Indexed: 12/17/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is a serious problem owing to its worldwide distribution and potential adverse sequelae that include cirrhosis and/or hepatocellular carcinoma. Current antiviral therapies have much improved outcomes, but few patients achieve the ultimate goal of hepatitis B surface antigen (HBsAg) loss (functional cure). As hepatitis B e antigen (HBeAg)-negative chronic HBV infection is the final phase prior to HBsAg loss, the management of patients in this phase together with quantification of HBsAg has attracted increasing clinical and research interest. This Review integrates the findings from research in HBsAg kinetics and discusses how they might inform our understanding and management of HBeAg-negative chronic HBV infection. Studies have shown that HBsAg levels are highly predictive of the presence of inactive HBV infection and that serial changes in HBsAg levels might predict HBsAg loss within 1-3 years. Data also suggest that quantitative HBsAg monitoring is important during hepatitis flare and antiviral therapy, especially in the timing of the decision to stop therapy and to start off-therapy retreatment. These findings have shed new light on the natural course of HBV infection and might lead to optimization of the management of HBeAg-negative chronic HBV infection and contribute to the paradigm shift from indefinite to finite therapy for patients with HBV infection.
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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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Yeh ML, Huang JF, Dai CY, Yu ML, Chuang WL. Pharmacokinetics and pharmacodynamics of pegylated interferon for the treatment of hepatitis B. Expert Opin Drug Metab Toxicol 2019; 15:779-785. [PMID: 31593639 DOI: 10.1080/17425255.2019.1678584] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 10/07/2019] [Indexed: 02/06/2023]
Abstract
Introduction: Interferon (IFN) had both antiviral and immunomodulatory effects, and was one of the approved treatments for hepatitis B virus (HBV). Herein, we reviewed the pharmacokinetics and pharmacodynamics of pegylated IFN-α (PegIFN-α) for the treatment of HBV. Areas covered: The steady-state serum levels of PegIFN-α were reached within 5 to 8 weeks, and the week 48 mean trough concentrations were approximately 2-fold higher than week 1. There was also no difference of the pharmacokinetics in male or female, healthy volunteers or patients with hepatitis B or C infection. PegIFN-α did not affect the metabolism of the cytochrome P450 (CYP) isozymes, except inhibition of CYP1A2. There was also no pharmacokinetic interaction between PegIFN-α and HBV nucleot(s)ide analogues (NUCs). Forty-eight weeks of PegIFN-α achieved 32% of HBeAg seroconversion, 32-43% of HBV DNA suppression, 41-59% of ALT normalization, and 3% of HBsAg seroconversion rate with a post-treatment durable response up to 80% in the initial responders. Expert opinion: On-treatment HBsAg titer guided the treatment of HBV with PegIFN-α. The recommendation of PegIFN-α and NUC combination or switch remained controversial. New immunotherapeutic agents are now in development. Although, PegIFN-α should continue to play a role in the treatment of HBV.
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Affiliation(s)
- Ming-Lun Yeh
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital , Kaohsiung , Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan
| | - Jee-Fu Huang
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital , Kaohsiung , Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan
- Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University , Kaohsiung , Taiwan
| | - Chia-Yen Dai
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital , Kaohsiung , Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan
- Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University , Kaohsiung , Taiwan
| | - Ming-Lung Yu
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital , Kaohsiung , Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan
- Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University , Kaohsiung , Taiwan
- Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B) and Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University , Hsin-Chu , Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University , Kaohsiung , Taiwan
| | - Wan-Long Chuang
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital , Kaohsiung , Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan
- Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University , Kaohsiung , Taiwan
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Zhang Y, Li W, Liu Z, Ye J, Zou G, Zhang Z, Li J. Combination therapy based on pegylated interferon alfa improves the therapeutic response of patients with chronic hepatitis B who exhibit high levels of hepatitis B e-antigen at 24 weeks: A retrospective observational study. Medicine (Baltimore) 2019; 98:e17022. [PMID: 31490387 PMCID: PMC6738969 DOI: 10.1097/md.0000000000017022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 07/31/2019] [Accepted: 08/11/2019] [Indexed: 12/14/2022] Open
Abstract
Pegylated interferon alpha (PEG-IFN-α) is a first-line treatment for patients with chronic hepatitis B (CHB), but its efficacy varies from individual to individual. Early discrimination between responder and non-responder patients is important for optimal clinical management. In addition, low therapeutic efficacy is still a major issue; thus, treatment timing should be optimized.We reviewed our experience with hepatitis B e-antigen (HBeAg)-positive patients treated with PEG-IFN-α, alone or in combination with nucleoside analogues (NAs), from 2009 through 2014. Collected data included both general characteristics of 113 patients and laboratory data at baseline and at treatment weeks 12, 24, 52, and 76. The endpoint was HBeAg seroconversion at week 76.A total of 113 patients with changed to or start of NAs therapy were included in this study. At the end of treatment, 44 (38.9%) patients exhibited HBeAg seroconversion. Patients with HBeAg seroconversion had lower baseline HBeAg (475.5 vs 751.7; P = .007). The incidence of HBeAg seroconversion was significantly higher among patients with HBeAg ≤ 500 signal-to-cutoff ratio (S/CO) (OR = 2.60, 95% CI: 1.16-5.83, P = .02) at baseline, HBeAg S/CO ≤ 20 (OR = 3.37, 95% CI: 1.47-7.73, P = .003), or a higher than 10-fold HBeAg drop (OR = 3.55, 95% CI: 1.50-8.37, P = .003) at week 12 or HBeAg ≤ 15 S/CO (OR = 10.35, 95% CI: 4.09-26.20, P < .001) at week 24. Subgroup analyses demonstrated that in patients with HBeAg >20 S/CO at 24 weeks, the addition of NAs treatment may increase HBeAg seroconversion (23.3% vs 0%, P = .03).HBeAg levels had an impact on the rate of serological conversion in CHB patients receiving PEG-IFN-based treatment. Combination therapy with NAs should be considered in CHB patients maintaining a high HBeAg level after 24 weeks of PEG-IFN monotherapy.
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Affiliation(s)
- Yafei Zhang
- Department of Infectious Diseases, The First Affiliated Hospital, Anhui Medical University
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei
| | - Wei Li
- Department of Liver Diseases, Fuyang Second People's Hospital, Fuyang, China
| | - Zhongping Liu
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei
| | - Jun Ye
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei
| | - Guizhou Zou
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei
| | - Zhenhua Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei
| | - Jiabin Li
- Department of Infectious Diseases, The First Affiliated Hospital, Anhui Medical University
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Abstract
Chronic hepatitis B remains a significant cause of morbidity and mortality worldwide. Most hepatitis B virus (HBV)-infected individuals are neither diagnosed nor treated. In those treated, nucleos(t)ide polymerase inhibitors persistently suppress viremia to the limits of quantitation; however, few achieve a "functional cure," defined as sustained off-treatment loss of detectable serum HBV DNA with or without loss of hepatitis B surface antigen. The low cure rate has been attributed to an inability to eliminate the viral reservoir of covalently closed circular DNA from hepatocytes. This review focuses on the diverse therapeutic approaches currently under development that may contribute to the goal of HBV cure.
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Ren H, Huang Y. Effects of pegylated interferon-α based therapies on functional cure and the risk of hepatocellular carcinoma development in patients with chronic hepatitis B. J Viral Hepat 2019; 26 Suppl 1:5-31. [PMID: 31380584 DOI: 10.1111/jvh.13150] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 05/15/2009] [Indexed: 12/23/2022]
Abstract
Chronic hepatitis B virus (HBV) infection continues to pose a serious global health threat and a significant socio-economic burden in many areas of the world. Almost all current clinical practice guidelines on the management of chronic hepatitis B (CHB) infection recommend that eligible patients pursue the optimal treatment endpoint, which is defined as HBsAg loss with or without anti-HBs seroconversion. This review describes the effects of various regimens containing pegylated interferon (peg-IFN)-alpha on functional cure and the outcome of hepatocellular carcinoma (HCC) in patients with CHB. Peg-IFN-α monotherapy is a treatment option recommended by local and international clinical practice guidelines to help more CHB patients achieve a sustained off-treatment virological response, which is particularly appropriate for relatively young patients who demand a finite treatment approach. Peg-IFN-α add-on or sequential therapy in patients who have achieved a suppressed viral load after nucleos(t)ide analog (NA) therapy may offer further benefits on HBeAg seroconversion and HBsAg decline, although the effects of de novo combination therapy with peg-IFN-α and NAs on long-term outcomes remain unclear. Evaluation of baseline and on-treatment predictors is useful for selecting the patients who are likely to achieve additional benefits. Furthermore, some recent studies have shown that peg-IFN-α-based therapy results in better prevention of HBV-related hepatocellular carcinoma (HCC), especially in high-risk patients.
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Affiliation(s)
- Hong Ren
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yan Huang
- Department of Medical Science, Shanghai Roche Pharmaceuticals Ltd., Shanghai, China
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Zhang L, Zhang FK. Recent advances in assessment and treatment of chronic hepatitis B. Shijie Huaren Xiaohua Zazhi 2019; 27:209-219. [DOI: 10.11569/wcjd.v27.i4.209] [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] [Indexed: 02/06/2023] Open
Abstract
This paper reviews the recent advances in the assessment and treatment of chronic hepatitis B with regard to predicting inflammation and fibrosis with non-invasive biomarkers and transient elastography, clinical benefits of long-term nucleos(t)ide analog (NA) antiviral therapy, serological benefits (HBeAg and HBsAg loss) of concurrent or sequential NAs and pegylated interferon, as well as risk factors for the development of hepatocellular carcinoma.
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Affiliation(s)
- Li Zhang
- Department of Gastroenterology, Beijing Shijingshan Hospital, Beijing 100043, China
| | - Fu-Kui Zhang
- Department of Gastroenterology, Beijing Shijingshan Hospital, Beijing 100043, China
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