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Jian W, Yin Y, Xue J, Chen R, Feng J, Zeng J, He R, Zhou T. Hepatitis surface B antigen clearance induced by long-term tenofovir disoproxil fumarate monotherapy in chronic hepatitis B treatment: a meta-analysis and longitudinal modeling analysis. Virol J 2025; 22:158. [PMID: 40405187 PMCID: PMC12100987 DOI: 10.1186/s12985-025-02788-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2025] [Accepted: 05/12/2025] [Indexed: 05/24/2025] Open
Abstract
BACKGROUND Chronic hepatitis B (CHB) is a significant global health challenge, with tenofovir disoproxil fumarate (TDF) widely used as an effective treatment option. Despite TDF's efficacy in suppressing hepatitis B virus (HBV) DNA, it rarely achieves functional cure, requiring hepatitis B surface antigen (HBsAg) clearance or seroconversion, which are an optimal goal of CHB treatment. This study aimed to evaluate the long-term effects of TDF monotherapy on HBsAg clearance rates through a systematic review and meta-analysis, combined with a longitudinal modeling analysis to investigate HBsAg dynamics. METHODS Eligible studies published between January 1st, 2008, and September 28th, 2023, in PubMed, EMBASE, and Web of Science were included in the systematic review and meta-analysis. The longitudinal model was developed based on data from 123 subjects in a Phase III trial cohort. RESULTS Twenty-three studies were selected for meta-analysis. The summarized HBsAg clearance rate was near zero and unlikely to increase with extended treatment. The longitudinal model of HBsAg dynamic in CHB patients receiving TDF monotherapy showed a good fitting performance and extrapolation predictive ability. Model-based simulation confirmed that HBsAg clearance remained unlikely with prolonged therapy, with median HBsAg levels reducing by 21% after 168 weeks. CONCLUSIONS The consistency between meta-analysis and model simulation outcomes indicated that TDF monotherapy can achieve a limited reduction in HBsAg levels but did not result in functional cure, which reinforced the limited role of TDF monotherapy in comprehensive CHB management.
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Affiliation(s)
- Weizhe Jian
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Yalin Yin
- Xiamen Amoytop Biotech Co., LTD, Xiamen, China
| | - Junsheng Xue
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Rong Chen
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | | | - Jiayao Zeng
- Xiamen Amoytop Biotech Co., LTD, Xiamen, China
| | - Ruoyi He
- Xiamen Amoytop Biotech Co., LTD, Xiamen, China.
| | - Tianyan Zhou
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China.
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Shan Y, Pang H, Tang Y, Yang N, Wang R, Yang F, Qin B. Altered LY6E and TRIM6 expression in PBMCs correlated with HBsAg clearance and response to Peg-IFN-α treatment in HBeAg-negative chronic hepatitis B patients. Virol J 2025; 22:74. [PMID: 40089754 PMCID: PMC11909810 DOI: 10.1186/s12985-025-02689-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 03/01/2025] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND Pegylated interferon alpha (Peg-IFN-α) has the potential to eradicate hepatitis B surface antigen (HBsAg). This study aimed to investigate whether the expression levels of lymphocyte antigen 6 family member E (LY6E) and tripartite motif-containing protein 6 (TRIM6) mRNAs in peripheral blood mononuclear cells (PBMCs) of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) patients is associated with the response to Peg-IFN-α treatment and HBsAg clearance. METHODS In this prospective study, HBeAg-negative chronic HBV patients treated with Peg-IFN-α were followed for 48 weeks. The participants were classified into two groups, the virological response (VR) group and nonvirological response (NVR) group, according to the changes in HBV DNA and HBsAg levels observed at week 48 of treatment. Furthermore, these patients were divided into a serological response (SR) group and a nonserological response (NSR) group, depending on whether they exhibited a loss of serum HBsAg or evidence of seroconversion. The expression levels of LY6E and TRIM6 mRNAs in PBMCs were evaluated using real-time quantitative PCR with fluorescence detection. The diagnostic performance of LY6E and TRIM6 was assessed by analyzing the receiver operating characteristic (ROC) curve and calculating the area under the ROC curve (AUC). RESULTS After the treatment period, the observed VR and SR rates were 44.64% and 28.57%, respectively. Dynamic changes in LY6E and TRIM6 mRNA levels were significantly different between the VR and NVR groups and between the SR and NSR groups. Multivariate analysis revealed that TRIM6 was independently associated with VR at weeks 12 and 24 of Peg-IFN-α therapy and with SR at week 12; in addition, LY6E was independently associated with VR at week 12 and SR at week 24. At week 24, the area under the curve (AUC) for LY6E in the prediction of VR was 0.6942, and the AUC for the prediction of SR was 0.7766; at week 12, TRIM6 had AUCs of 0.7600 for the prediction of VR and 0.8469 for the prediction of SR. CONCLUSIONS LY6E and TRIM6 are important biomarkers for early therapeutic responses to Peg-IFN-α and HBsAg clearance. TRIAL REGISTRATION Registration number: 2023 - 311. Date of registration: 1 October 2023.
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Affiliation(s)
- Yiru Shan
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hao Pang
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yao Tang
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Na Yang
- Central Laboratory, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Rui Wang
- Central Laboratory, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Fan Yang
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Bo Qin
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 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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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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Huang Q, Xiao X, Zhuang X, Chen W, Huang Y, Liao J, Wang W, Wang Y, Lu L, Liu Z, Huang J. Peripheral Circulating Exosomal-miRNAs Potentially Mediate the Sensitivity to Interferon Treatment in Chronic Hepatitis B Virus Patients. Viral Immunol 2023; 36:209-221. [PMID: 36944116 DOI: 10.1089/vim.2022.0130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2023] Open
Abstract
Pegylated interferon alfa-2b (Peg-IFN α-2b), a first-line treatment for hepatitis B virus (HBV) infection, can significantly achieve HBsAg clearance in clinic. However, only 30-40% of patients had achieved HBsAg clearance after Peg-IFN α-2b administration. The biological targets and the underline mechanisms that distinguish sensitive and insensitive populations to interferon therapy are still unclear. In the present study, only 33.33% of patients achieved HBsAg loss after 48 weeks of Peg-IFN α-2b therapy. Thirty-six exosomal-microRNAs (miRNAs) in the sensitive group were identified that might induce sensitivity specifically, whereas 32 exosomal-miRNAs in the insensitive group were identified that might induce insensitive specifically. Among these miRNAs, five miRNAs (miR-425-5p, miR-8485, miR-619-5p, miR-181a-5p, and miR-484) might increase the sensitivity to Peg-IFN α-2b therapy by regulating key genes GSK3B, KRAS, FLT1, or GRB2, whereas, 13 miRNAs (miR-195-5p, miR-215-5p, miR-9-5p, miR-130a-3p, miR-214-3p, miR-149-5p, miR-429, miR-200b-3p, miR-200c-3p, miR-16-2-3p, miR-141-3p, miR-200a-3p, and miR-218-5p) might decrease the sensitivity to Peg-IFN α-2b therapy by regulating key genes, FGF2, GSK3B, PDGFRA, FGFR1, KRAS, FLT1, MYC, TGFB2, EFNA1, MAPK9, or GRB2. Furthermore, seven novel miRNAs, namely Novel_352, Novel_459, Novel_527, Novel_677, Novel_717, Novel_749, and Novel_801 were found to be downregulated specifically in the sensitive group, whereas, Novel_142 and Novel_664 were found to be downregulated specifically in the insensitive group. Our data indicate that the serum exosomal-miRNAs could be involved in regulating the sensitivity of chronic HBV (CHB) patients to Peg-IFN α-2b therapy, which might suggest potential novel therapeutic biomarkers and standard options for CHB patients. Clinical Trials.gov ID: NCT04035837.
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Affiliation(s)
- Qiuju Huang
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, College of Pharmacy, Guangxi Medical University, Nanning, China
| | - Xin Xiao
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xuerong Zhuang
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wenli Chen
- Department of Infectious Diseases, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yanfang Huang
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jinyao Liao
- Department of Infectious Diseases, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Wensheng Wang
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying Wang
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Linlin Lu
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhongqiu Liu
- Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jing Huang
- Department of Infectious Diseases, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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Zheng JR, Wang ZL, Feng B. Hepatitis B functional cure and immune response. Front Immunol 2022; 13:1075916. [PMID: 36466821 PMCID: PMC9714500 DOI: 10.3389/fimmu.2022.1075916] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 11/02/2022] [Indexed: 07/30/2023] Open
Abstract
Hepatitis B virus (HBV) is a hepatotropic virus, which damage to hepatocytes is not direct, but through the immune system. HBV specific CD4+ T cells can induce HBV specific B cells and CD8+ T cells. HBV specific B cells produce antibodies to control HBV infection, while HBV specific CD8+ T cells destroy infected hepatocytes. One of the reasons for the chronicity of HBV infection is that it cannot effectively activate adoptive immunity and the function of virus specific immune cells is exhausted. Among them, virus antigens (including HBV surface antigen, e antigen, core antigen, etc.) can inhibit the function of immune cells and induce immune tolerance. Long term nucleos(t)ide analogues (NAs) treatment and inactive HBsAg carriers with low HBsAg level may "wake up" immune cells with abnormal function due to the decrease of viral antigen level in blood and liver, and the specific immune function of HBV will recover to a certain extent, thus becoming the "dominant population" for functional cure. In turn, the functional cure will further promote the recovery of HBV specific immune function, which is also the theoretical basis for complete cure of hepatitis B. In the future, the complete cure of chronic HBV infection must be the combination of three drugs: inhibiting virus replication, reducing surface antigen levels and specific immune regulation, among which specific immunotherapy is indispensable. Here we review the relationship, mechanism and clinical significance between the cure of hepatitis B and immune system.
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Affiliation(s)
| | | | - Bo Feng
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People’s Hospital, Peking University Hepatology Institute, Beijing, China
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Suresh M, Menne S. Recent Drug Development in the Woodchuck Model of Chronic Hepatitis B. Viruses 2022; 14:v14081711. [PMID: 36016334 PMCID: PMC9416195 DOI: 10.3390/v14081711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/22/2022] [Accepted: 07/31/2022] [Indexed: 11/24/2022] Open
Abstract
Infection with hepatitis B virus (HBV) is responsible for the increasing global hepatitis burden, with an estimated 296 million people being carriers and living with the risk of developing chronic liver disease and cancer. While the current treatment options for chronic hepatitis B (CHB), including oral nucleos(t)ide analogs and systemic interferon-alpha, are deemed suboptimal, the path to finding an ultimate cure for this viral disease is rather challenging. The lack of suitable laboratory animal models that support HBV infection and associated liver disease progression is one of the major hurdles in antiviral drug development. For more than four decades, experimental infection of the Eastern woodchuck with woodchuck hepatitis virus has been applied for studying the immunopathogenesis of HBV and developing new antiviral therapeutics against CHB. There are several advantages to this animal model that are beneficial for performing both basic and translational HBV research. Previous review articles have focused on the value of this animal model in regard to HBV replication, pathogenesis, and immune response. In this article, we review studies of drug development and preclinical evaluation of direct-acting antivirals, immunomodulators, therapeutic vaccines, and inhibitors of viral entry, gene expression, and antigen release in the woodchuck model of CHB since 2014 until today and discuss their significance for clinical trials in patients.
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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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Ferrando-Martinez S, Snell Bennett A, Lino E, Gehring AJ, Feld J, Janssen HLA, Robbins SH. Functional Exhaustion of HBV-Specific CD8 T Cells Impedes PD-L1 Blockade Efficacy in Chronic HBV Infection. Front Immunol 2021; 12:648420. [PMID: 34589081 PMCID: PMC8473828 DOI: 10.3389/fimmu.2021.648420] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 08/24/2021] [Indexed: 01/12/2023] Open
Abstract
Background A functional cure for chronic HBV could be achieved by boosting HBV-specific immunity. In vitro studies show that immunotherapy could be an effective strategy. However, these studies include strategies to enrich HBV-specific CD8 T cells, which could alter the expression of the anti-PD-1/anti-PD-L1 antibody targets. Our aim was to determine the efficacy of PD-L1 blockade ex vivo. Methods HBV-specific CD8 T cells were characterized ex vivo by flow cytometry for the simultaneous analysis of six immune populations and 14 activating and inhibitory receptors. Ex vivo functionality was quantified by ELISpot and by combining peptide pool stimulation, dextramers and intracellular flow cytometry staining. Results The functionality of HBV-specific CD8 T cells is associated with a higher frequency of cells with low exhaustion phenotype (LAG3-TIM3-PD-1+), independently of the clinical parameters. The accumulation of HBV-specific CD8 T cells with a functionally exhausted phenotype (LAG3+TIM3+PD-1+) is associated with lack of ex vivo functionality. PD-L1 blockade enhanced the HBV-specific CD8 T cell response only in patients with lower exhaustion levels, while response to PD-L1 blockade was abrogated in patients with higher frequencies of exhausted HBV-specific CD8 T cells. Conclusion Higher levels of functionally exhausted HBV-specific CD8 T cells are associated with a lack of response that cannot be restored by blocking the PD-1:PD-L1 axis. This suggests that the clinical effectiveness of blocking the PD-1:PD-L1 axis as a monotherapy may be restricted. Combination strategies, potentially including the combination of anti-LAG-3 with other anti-iR antibodies, will likely be required to elicit a functional cure for patients with high levels of functionally exhausted HBV-specific CD8 T cells.
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Affiliation(s)
- Sara Ferrando-Martinez
- Microbial Sciences, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
| | - Angie Snell Bennett
- Microbial Sciences, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
| | - Elisabete Lino
- Microbial Sciences, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
| | - Adam J Gehring
- Toronto Center for Liver Disease, Toronto General Hospital, University Health Network, Toronto, ON, Canada.,Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Jordan Feld
- Toronto Center for Liver Disease, Toronto General Hospital, University Health Network, Toronto, ON, Canada
| | - Harry L A Janssen
- Toronto Center for Liver Disease, Toronto General Hospital, University Health Network, Toronto, ON, Canada
| | - Scott H Robbins
- Late Stage Oncology Development, Oncology R&D, AstraZeneca, Gaithersburg, MD, United States
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Ohsaki E, Suwanmanee Y, Ueda K. Chronic Hepatitis B Treatment Strategies Using Polymerase Inhibitor-Based Combination Therapy. Viruses 2021; 13:v13091691. [PMID: 34578273 PMCID: PMC8473100 DOI: 10.3390/v13091691] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/19/2021] [Accepted: 08/25/2021] [Indexed: 12/12/2022] Open
Abstract
Viral polymerase is an essential enzyme for the amplification of the viral genome and is one of the major targets of antiviral therapies. However, a serious concern to be solved in hepatitis B virus (HBV) infection is the difficulty of eliminating covalently closed circular (ccc) DNA. More recently, therapeutic strategies targeting various stages of the HBV lifecycle have been attempted. Although cccDNA-targeted therapies are attractive, there are still many problems to be overcome, and the development of novel polymerase inhibitors remains an important issue. Interferons and nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are the only therapeutic options currently available for HBV infection. Many studies have reported that the combination of interferons and NRTI causes the loss of hepatitis B surface antigen (HBsAg), which is suggestive of seroconversion. Although NRTIs do not directly target cccDNA, they can strongly reduce the serum viral DNA load and could suppress the recycling step of cccDNA formation, improve liver fibrosis/cirrhosis, and reduce the risk of hepatocellular carcinoma. Here, we review recent studies on combination therapies using polymerase inhibitors and discuss the future directions of therapeutic strategies for HBV infection.
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Goh ZY, Ren EC, Ko HL. Intracellular interferon signalling pathways as potential regulators of covalently closed circular DNA in the treatment of chronic hepatitis B. World J Gastroenterol 2021; 27:1369-1391. [PMID: 33911462 PMCID: PMC8047536 DOI: 10.3748/wjg.v27.i14.1369] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/23/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
Infection with the hepatitis B virus (HBV) is still a major global health threat as 250 million people worldwide continue to be chronically infected with the virus. While patients may be treated with nucleoside/nucleotide analogues, this only suppresses HBV titre to sub-detection levels without eliminating the persistent HBV covalently closed circular DNA (cccDNA) genome. As a result, HBV infection cannot be cured, and the virus reactivates when conditions are favorable. Interferons (IFNs) are cytokines known to induce powerful antiviral mechanisms that clear viruses from infected cells. They have been shown to induce cccDNA clearance, but their use in the treatment of HBV infection is limited as HBV-targeting immune cells are exhausted and HBV has evolved multiple mechanisms to evade and suppress IFN signalling. Thus, to fully utilize IFN-mediated intracellular mechanisms to effectively eliminate HBV, instead of direct IFN administration, novel strategies to sustain IFN-mediated anti-cccDNA and antiviral mechanisms need to be developed. This review will consolidate what is known about how IFNs act to achieve its intracellular antiviral effects and highlight the critical interferon-stimulated gene targets and effector mechanisms with potent anti-cccDNA functions. These include cccDNA degradation by APOBECs and cccDNA silencing and transcription repression by epigenetic modifications. In addition, the mechanisms that HBV employs to disrupt IFN signalling will be discussed. Drugs that have been developed or are in the pipeline for components of the IFN signalling pathway and HBV targets that detract IFN signalling mechanisms will also be identified and discussed for utility in the treatment of HBV infections. Together, these will provide useful insights into design strategies that specifically target cccDNA for the eradication of HBV.
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Affiliation(s)
- Zhi Yi Goh
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
- Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore 119077, Singapore
| | - Ee Chee Ren
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Singapore
| | - Hui Ling Ko
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
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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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Wigfield P, Sbarigia U, Hashim M, Vincken T, Heeg B. Are Published Health Economic Models for Chronic Hepatitis B Appropriately Capturing the Benefits of HBsAg Loss? A Systematic Literature Review. PHARMACOECONOMICS - OPEN 2020; 4:403-418. [PMID: 31428938 PMCID: PMC7426349 DOI: 10.1007/s41669-019-00175-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
OBJECTIVES Sustained hepatitis B surface antigen (HBsAg) loss or 'functional cure' (FC) is considered an optimal treatment endpoint by international clinical guidelines for chronic hepatitis B (CHB), yet rarely is this achieved with current standard of care (SoC). This leads to an under-reporting of FC in clinical trials, observational studies and health economic (HE) models. This paper systematically identifies and assesses how FC is incorporated in published HE models of CHB. METHODS A systematic literature review was conducted in PubMed and Embase (conducted February 2019) to review how HBsAg loss is captured in HE models. The following items were extracted: rate of (and transition probabilities to) HBsAg loss, HBsAg loss health state costs, and HBsAg loss health state utilities. RESULTS Sixty-five economics evaluations were identified, and < 50% of these (27/65) incorporated HBsAg loss in their models. Only 15/27 stated HBsAg loss health state costs, 15/27 stated HBsAg loss health state utilities, and 11/27 mentioned treatment-specific transition probabilities to HBsAg loss. The majority of sources these inputs were derived from are not transparent. CONCLUSIONS The benefits of FC in current HE models are not well captured, as FC is often not reported or not directly related to modelled treatments. This has the potential for novel agents with higher efficacy compared with SoC to be overlooked and undervalued if their worth is not appropriately communicated. In order to ensure optimal access for patients to new and effective therapies, it is important that the benefits of FC are better assessed and captured within HE models.
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Affiliation(s)
- Peter Wigfield
- Ingress-health Nederland, Hofplein 20, 3032 AC Rotterdam, The Netherlands
| | - Urbano Sbarigia
- Janssen Pharmaceutica, Turnhoutseweg 30, 2340 Beerse, Belgium
| | - Mahmoud Hashim
- Ingress-health Nederland, Hofplein 20, 3032 AC Rotterdam, The Netherlands
| | - Talitha Vincken
- Ingress-health Nederland, Hofplein 20, 3032 AC Rotterdam, The Netherlands
| | - Bart Heeg
- Ingress-health Nederland, Hofplein 20, 3032 AC Rotterdam, The Netherlands
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Ma Y, Wang J, Xiong F, Lu J. Extended duration therapy regimens based on Pegylated interferon for chronic hepatitis B patients focusing on hepatitis B surface antigen loss: A systematic review and meta-analysis. INFECTION GENETICS AND EVOLUTION 2020; 85:104492. [PMID: 32763441 DOI: 10.1016/j.meegid.2020.104492] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 07/31/2020] [Accepted: 08/01/2020] [Indexed: 02/08/2023]
Abstract
AIMS Hepatitis B surface antigen (HBsAg) loss is associated with disease control and improvement of prognosis. Therefore, it is regarded as the optimal treatment endpoint for chronic hepatitis B (CHB) patients. Pegylated interferon (PegIFN)-based extended therapy regimens was assessed in several studies. In order to summarize a conclusion on the HBsAg loss rate and safety in this regimen, a systematic review and meta-analysis was performed. METHODS Studies on Hepatitis B and PegIFN were searched thoroughly in Pubmed, EMBASE, and the Cochrane Library from inception to November 18, 2019. The primary endpoint of this study was the HBsAg loss rate at the end of the extended duration therapy. The secondary endpoint was safety. All analyses were performed by using the R3.6.1 version Software. Quality assessment of RCTs was carried out by using Review manager 5.3. RESULTS A total of nine studies, including 545 CHB patients met the inclusion criteria. The pooled HBsAg loss rate after PegIFN-based extended duration therapy was 11% (95% CI: 0.05-0.19), I2 = 82%, P < 0.01(Q test). The extended duration therapy regimen was safe and tolerable. Subgroup analysis showed HBsAg loss rates were 14% (95% CI: 0.04-0.29) and 10% (95% CI: 0.02-0.20) respectively for HBeAg positive and HBeAg negative patients (P = 0.52). HBsAg loss rates were 11%(95%CI:0.03-0.22)and 12%(95%CI:0.04-0.24)respectively for PegIFN monotherapy and PegIFN with Nucleos(t)ide analogs (NAs) therapy (P = 0.84). HBsAg loss rates were 25% (95% CI: 0.19-0.31) and 8% (95% CI: 0.03-0.15) respectively for the advantageous group and non-advantageous group (P = 0.001). CONCLUSIONS For CHB patients, extended duration of PegIFNα-based treatment for more than 48 weeks is likely to improve HBsAg clearance rate. Specially, the advantageous group will benefit a lot. In addition, the extended duration therapy regimen is safe and tolerable.
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Affiliation(s)
- Yanpin Ma
- International Medical Department, Beijing You-an Hospital, Capital Medical University, Beijing, China
| | - Jinhuan Wang
- International Medical Department, Beijing You-an Hospital, Capital Medical University, Beijing, China
| | - Fang Xiong
- International Medical Department, Beijing You-an Hospital, Capital Medical University, Beijing, China
| | - Jun Lu
- International Medical Department, Beijing You-an Hospital, Capital Medical University, Beijing, China.
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Jiang YC, Li YF, Zhou L, Zhang DP. Comparative metabolomics unveils molecular changes and metabolic networks of syringin against hepatitis B mice by untargeted mass spectrometry. RSC Adv 2020; 10:461-473. [PMID: 35492557 PMCID: PMC9048208 DOI: 10.1039/c9ra06332c] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 12/09/2019] [Indexed: 12/18/2022] Open
Abstract
Untargeted metabolomics technology was used to discover the metabolic pathways and biomarkers for revealing the potential biological mechanism of syringin on hepatitis B virus. Serum samples were analyzed by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS)-based comparative metabolomics coupled with pattern recognition methods and network pathway. In addition, the histopathology, HBV DNA detection of liver tissue, and biochemical indicators of liver function change were also explored for investigating the antiviral effect of syringin. In comparison to the model group, the metabolic profiles of the turbulence in transgenic mice tended to recover to the same as the control group after syringin therapy. A total of 33 potential biomarkers were determined to explore the metabolic disorders in the hepatitis B animal model, of which 25 were regulated by syringin, and 8 metabolic pathways, such as phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, arachidonic acid metabolism, glyoxylate and dicarboxylate metabolism, were involved. Syringin markedly reduced the liver pathology change, inhibited HBV DNA replication, and improved liver function. Amino acid metabolism is a potential target for the treatment of hepatitis B. The hepatoprotective effect of syringin may contribute to ameliorating oxidative stress and preventing protein and DNA replication. Comparative metabolomics is a promising tool for discovering metabolic pathways and biomarkers of the hepatitis B animal model as targets to reveal the effects and mechanism of syringin, which benefits the development of natural products and advances the treatment of diseases. Untargeted metabolomics technology was used to discover the metabolic pathways and biomarkers for revealing the potential biological mechanism of syringin on hepatitis B virus.![]()
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Affiliation(s)
- Yi-chang Jiang
- Third Department of Orthopedics
- First Affiliated Hospital
- Heilongjiang University of Chinese Medicine
- Harbin 150040
- China
| | - Yuan-feng Li
- Third Department of Orthopedics
- First Affiliated Hospital
- Heilongjiang University of Chinese Medicine
- Harbin 150040
- China
| | - Ling Zhou
- First Affiliated Hospital
- Heilongjiang University of Chinese Medicine
- Harbin 150040
- China
| | - Da-peng Zhang
- Third Department of Orthopedics
- First Affiliated Hospital
- Heilongjiang University of Chinese Medicine
- Harbin 150040
- China
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16
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Ning Q, Wu D, Wang GQ, Ren H, Gao ZL, Hu P, Han MF, Wang Y, Zhang WH, Lu FM, Wang FS. Roadmap to functional cure of chronic hepatitis B: An expert consensus. J Viral Hepat 2019; 26:1146-1155. [PMID: 31087479 DOI: 10.1111/jvh.13126] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 04/25/2019] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) infection continues to be a major public health issue worldwide. HBsAg loss is associated with functional remission and improved long-term outcome, and is considered to be a 'functional cure' (also referred to as clinical or immunologic cure) for chronic hepatitis B. This ideal goal of therapy can be achieved using optimized combination regimens with direct-acting antivirals [eg nucleos(t)ide analogues (NAs)] and immunomodulators [eg pegylated interferon alpha2a (Peg-IFN)] in selected patients with chronic hepatitis B. Among different combination therapies currently available, those with NA lead-in followed by Peg-IFN in virally suppressed patients has been demonstrated to be effective. This review provides an updated overview of the evidence supporting the use of combination therapies and summarizes expert consensus on the roadmap to attain functional cure for chronic hepatitis B patients.
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Affiliation(s)
- Qin Ning
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Di Wu
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gui-Qiang Wang
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing, China
| | - Hong Ren
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhi-Liang Gao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Peng Hu
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mei-Fang Han
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Wang
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing, China
| | - Wen-Hong Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Feng-Min Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Fu-Sheng Wang
- Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of the General Hospital of PLA, Beijing, China
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Ma Z, Zhang E, Gao S, Xiong Y, Lu M. Toward a Functional Cure for Hepatitis B: The Rationale and Challenges for Therapeutic Targeting of the B Cell Immune Response. Front Immunol 2019; 10:2308. [PMID: 31608073 PMCID: PMC6769125 DOI: 10.3389/fimmu.2019.02308] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 09/12/2019] [Indexed: 12/13/2022] Open
Abstract
The central role of the cellular immune response in the control and clearance of the hepatitis B virus (HBV) infection has been well-established. The contribution of humoral immunity, including B cell and antibody responses against HBV, has been investigated for a long time but has attracted increasing attention again in recent years. The anti-HBs antibody was first recognized as a marker of protective immunity after the acute resolution of the HBV infection (or vaccination) and is now defined as a biomarker for the functional cure of chronic hepatitis B (CHB). In this way, therapies targeting HBV-specific B cells and the induction of an anti-HBs antibody response are essential elements of a rational strategy to terminate chronic HBV infection. However, a high load of HBsAg in the blood, which has been proposed to induce antigen-specific immune tolerance, represents a major obstacle to curing CHB. Long-term antiviral treatment by nucleoside analogs, by targeting viral translation by siRNA, by inhibiting HBsAg release via nucleic acid polymers, or by neutralizing HBsAg via specific antibodies could potentially reduce the HBsAg load in CHB patients. A combined strategy including a reduction of the HBsAg load via the above treatments and the therapeutic targeting of B cells by vaccination may induce the appearance of anti-HBs antibodies and lead to a functional cure of CHB.
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Affiliation(s)
- Zhiyong Ma
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Ejuan Zhang
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Shicheng Gao
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yong Xiong
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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Sequential combination therapy with interferon, interleukin-2 and therapeutic vaccine in entecavir-suppressed chronic hepatitis B patients: the Endeavor study. Hepatol Int 2019; 13:573-586. [PMID: 31172415 DOI: 10.1007/s12072-019-09956-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 05/18/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Switching from nucleos(t)ide analogues to interferon (IFN) improves hepatitis B surface antigen (HBsAg) loss. We aimed to evaluate whether combining immunomodulators such as interleukin-2 (IL-2) and therapeutic vaccine with IFN enhances HBsAg loss in entecavir (ETV)-suppressed patients. METHODS Ninety-four patients exhibiting virological suppression and hepatitis B e antigen (HBeAg) loss following ETV treatment were randomized 1:1:1 to receive ETV (group I) or IFN (group II) for 48 weeks, or IFN and vaccine for 48 weeks plus IL-2 for 12 weeks (group III). The primary endpoint was HBsAg loss at week 48. Peripheral natural killer (NK) cells and regulatory T cells (Treg) were measured as immune checkpoint indicators. RESULTS Mean HBsAg decline at week 48 was significantly greater in group III (0.85 log 10 IU/mL) and group II (0.74 log 10 IU/mL), than in group I (0.13 log 10 IU/mL). At week 48, 9.38%, 3.03%, and 3.70% of subjects in group III, II, and I, respectively, achieved HBsAg loss. Among patients with baseline HBsAg titers ranging from 100 to 1500 IU/mL, HBsAg loss rate was 27.3, 7.1, and 0% in group III, II, and I, respectively. Responders in group III showed a significantly higher increase in CD56bright CD16-NK cells from week 24 to 36, and a significant decline in Treg from week 12 to 24 than non-responders. CONCLUSION For ETV-suppressed patients, particularly those with low baseline HBsAg levels, combination therapy with IFN and other immunomodulators may enhance HBsAg loss, while successful response correlates with partial restoration of NK cells and Tregs.
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