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Gao N, Wu H, Li B, Yu H, Wu L, Zhang J, Zhang N, Lin B, Zhao Q, Gao Z. Nucleos(t)ide analogs continuation is not associated with a lower risk of HBsAg seroreversion following PEG-IFN-induced HBsAg loss. Virol J 2025; 22:80. [PMID: 40108632 PMCID: PMC11924841 DOI: 10.1186/s12985-025-02700-2] [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: 01/11/2025] [Accepted: 03/09/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND/AIMS It is unclear whether nucleos(t)ide analogs (NUCs) continuation provides clinical benefits following HBsAg seroclearance with pegylated interferon (PEG-IFN)-based therapy. This study aims to investigate the role of NUCs continuation in HBsAg seroreversion. METHODS Patients who experienced serum HBsAg loss after PEG-IFN-based therapy were enrolled and followed up for 96 weeks. Propensity score matching (PSM) was performed using a 1:1 ratio to adjust for the associated factors. A multivariate logistic regression analysis was used to determine the factors associated with HBsAg seroreversion. RESULTS In total, 220 patients with HBsAg seroclearance were divided into NUCs (n = 54) and non-NUCs (n = 166) consolidation therapy groups. At week 96, the HBsAg seroreversion (12/54 vs. 31/166, P = 0.709) and virological relapse (2/54 vs. 10/166, P = 0.759) rates were similar in the NUCs and non-NUCs groups. After PSM, HBsAg seroreversion (12/53 vs. 13/53; P = 1.000) and virological relapse (2/53 vs. 4/53; P = 0.674) rates were not significantly different between the two groups. Serum hepatitis B surface antibody titer (odds ratio, 0.388; 95% confidence interval, 0.245-0.616; P < 0.001) was found to be associated with HBsAg seroreversion, while NUCs continuation was not related to HBsAg seroreversion. CONCLUSIONS NUCs continuation is not associated with a lower risk of HBsAg seroreversion in patients with serum HBsAg loss following PEG-IFN-based therapy.
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Affiliation(s)
- Na Gao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Number 600 Tianhe Road, Guangzhou, Guangdong, 510630, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, Guangdong, 510080, China
| | - Haishi Wu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Number 600 Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Bin Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Number 600 Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Huiying Yu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Number 600 Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Lili Wu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Number 600 Tianhe Road, Guangzhou, Guangdong, 510630, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, Guangdong, 510080, China
| | - Jing Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Number 600 Tianhe Road, Guangzhou, Guangdong, 510630, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, Guangdong, 510080, China
| | - Nan Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Number 600 Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Bingliang Lin
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Number 600 Tianhe Road, Guangzhou, Guangdong, 510630, China
| | - Qiyi Zhao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Number 600 Tianhe Road, Guangzhou, Guangdong, 510630, China.
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, Guangdong, 510080, China.
| | - Zhiliang Gao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Number 600 Tianhe Road, Guangzhou, Guangdong, 510630, China.
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, Guangdong, 510080, China.
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Qiu Z, Xu Y, Qi W, Shen J, Wen T, Li C. Tenofovir vs Entecavir on the Prognosis of Patients With Hepatitis B Virus-Related Hepatocellular Carcinoma After Liver Resection: The Role of HBsAg Levels. Clin Transl Gastroenterol 2025; 16:e00814. [PMID: 39791573 PMCID: PMC11932590 DOI: 10.14309/ctg.0000000000000814] [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: 08/12/2024] [Accepted: 12/20/2024] [Indexed: 01/12/2025] Open
Abstract
INTRODUCTION Our study aimed to explore whether hepatitis B surface antigen (HBsAg) levels affected the role of nucleot(s)ide analog treatment (entecavir [ETV] and tenofovir disoproxil fumarate [TDF]) in improving the prognosis of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after liver resection. METHODS A total of 865 patients with HBV-related HCC after hepatectomy treated with TDF or ETV were included in our study. Patients were divided into the high HBsAg cohort (n = 681) and the low HBsAg cohort (n = 184). Propensity score matching (PSM) analysis was used to reduce the impact of potential confounding factors. Kaplan-Meier method and competing risk analysis were used to compare the survival outcomes. RESULTS In the high HBsAg cohort, patients in the TDF group had better recurrence-free survival (RFS) and overall survival (OS) compared with patients in the ETV group both before (RFS: P < 0.001; OS: P < 0.001) and after (RFS: P = 0.005; OS: P = 0.035) PSM. TDF treatment was a favorable factor independently associated with RFS (hazard ratio: 0.58, 95% confidence interval: 0.45-0.75, P < 0.001) and OS (hazard ratio: 0.43, 95% confidence interval: 0.28-0.66, P < 0.001). In the low HBsAg cohort, no difference was observed in RFS and OS between the TDF group and the ETV group both before (RFS: P = 0.140; OS: P = 0.640) and after (RFS: P = 0.480; OS: P = 0.920) PSM. TDF treatment remained superiority after controlling for competing events by competing risk analysis in the high HBsAg cohort. DISCUSSION TDF treatment was superior to ETV treatment in improving RFS and OS of HBV-related HCC patients with high HBsAg level after liver resection. Even after controlling for survival competing events, the advantage of TDF treatment remained. Our findings may better help clinicians to assign individualized antiviral regimens to patients with HBV-related HCC after liver resection.
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Affiliation(s)
- Zhancheng Qiu
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yueqing Xu
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Weili Qi
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Junyi Shen
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tianfu Wen
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Chuan Li
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
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Wu M, Mai J, Zhang H, Zhang G, Mao J, Tang Y, Yan W, Wu W, Hou J, Liang X, Liu Z, Ding Y, Niu J. Safety, pharmacokinetics, and antiviral efficacy of the novel capsid assembly modulator GST-HG141 in patients with chronic hepatitis B: a phase 1 trial with a randomized, placebo-controlled design. Virol J 2024; 21:328. [PMID: 39707469 DOI: 10.1186/s12985-024-02584-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 11/21/2024] [Indexed: 12/23/2024] Open
Abstract
In preclinical studies, GST-HG141, a novel hepatitis B virus (HBV) capsid assembly modulator displayed potent anti-HBV activity in vitro and strong efficacy in HBV animal models. A randomized, double-blind, ascending phase 1b trial assessed the pharmacokinetics, safety, and efficacy of GST-HG141 in chronic hepatitis B (CHB) individuals. Thirty treatment-naïve CHB patients were enrolled in three cohorts (25, 50, and 100 mg twice orally after meals daily) over 28 days, with 10 subjects per cohort (8:2 ratio for GST-HG141 and placebo). Dose-related safety and tolerability, pharmacokinetic profiles, and drug responses were evaluated. GST-HG141 exhibited a generally favorable safety profile across all doses with predominantly mild adverse reactions, including three cases of grade 1 transaminase elevations. Significant reductions in HBV DNA and pregenomic RNA (pgRNA) levels were observed across all doses of (25, 50, and 100 mg of GST-HG141, twice-daily) after 28 days of treatment. Pharmacokinetic analysis showed a consistent linear trend in GST-HG141 concentrations, with mean trough concentrations ranging from 75 to 240 ng/mL. These concentrations adequately covered the protein binding-adjusted EC50 (16.89 ng/mL) by factors of 4.4, 11.1, and 14.6 for doses of 25, 50, and 100 mg, respectively. Our study demonstrated GST-HG141's well-tolerated profile up to 100 mg over 4 weeks, alongside robust antiviral activity in CHB patients, supporting its progression into further clinical investigation for CHB management.
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Affiliation(s)
- Min Wu
- Phase I Clinical Trial Unit, First Hospital, Jilin University, Jilin, China
| | - Jiajia Mai
- Phase I Clinical Trial Unit, First Hospital, Jilin University, Jilin, China
| | - Hong Zhang
- Phase I Clinical Trial Unit, First Hospital, Jilin University, Jilin, China
| | - George Zhang
- Fujian Akeylink Biotechnology Co., Ltd., Shanghai, China
| | - John Mao
- Fujian Akeylink Biotechnology Co., Ltd., Shanghai, China
| | - Yanan Tang
- Fujian Akeylink Biotechnology Co., Ltd., Shanghai, China
| | - Wenhao Yan
- Fujian Akeylink Biotechnology Co., Ltd., Shanghai, China
| | - Wenqiang Wu
- Fujian Akeylink Biotechnology Co., Ltd., Shanghai, China
| | - Jinlin Hou
- Department of Infectious Diseases and Hepatology Unit, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xieer Liang
- Department of Infectious Diseases and Hepatology Unit, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhihong Liu
- Department of Infectious Diseases and Hepatology Unit, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanhua Ding
- Phase I Clinical Trial Unit, First Hospital, Jilin University, Jilin, China.
- Phase I Clinical Research Center, The First Hospital of Jilin University, Changchun, Jilin, China.
| | - Junqi Niu
- Department of Hepatology, Center of Infectious Disease and Pathogen Biology, The First Hospital of Jilin University, Changchun, China.
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Vecchi A, Rossi M, Tiezzi C, Fisicaro P, Doselli S, Gabor EA, Penna A, Montali I, Ceccatelli Berti C, Reverberi V, Montali A, Fletcher SP, Degasperi E, Sambarino D, Laccabue D, Facchetti F, Schivazappa S, Loggi E, Coco B, Cavallone D, Rosselli Del Turco E, Massari M, Pedrazzi G, Missale G, Verucchi G, Andreone P, Brunetto MR, Lampertico P, Ferrari C, Boni C. HBcrAg values may predict virological and immunological responses to pegIFN-α in NUC-suppressed HBeAg-negative chronic hepatitis B. Gut 2024; 73:1737-1748. [PMID: 39033025 PMCID: PMC11423235 DOI: 10.1136/gutjnl-2024-332290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 06/10/2024] [Indexed: 07/23/2024]
Abstract
OBJECTIVE Selected populations of patients with chronic hepatitis B (CHB) may benefit from a combined use of pegylated interferon-alpha (pegIFN-α) and nucleos(t)ides (NUCs). The aim of our study was to assess the immunomodulatory effect of pegIFN-α on T and natural killer (NK) cell responses in NUC-suppressed patients to identify cellular and/or serological parameters to predict better T cell-restoring effect and better control of infection in response to pegIFN-α for a tailored application of IFN-α add-on. DESIGN 53 HBeAg-negative NUC-treated patients with CHB were randomised at a 1:1 ratio to receive pegIFN-α-2a for 48 weeks, or to continue NUC therapy and then followed up for at least 6 months maintaining NUCs. Serum hepatitis B surface antigen (HBsAg) and hepatitis B core-related antigen (HBcrAg) levels as well as peripheral blood NK cell phenotype and function and HBV-specific T cell responses upon in vitro stimulation with overlapping HBV peptides were measured longitudinally before, during and after pegIFN-α therapy. RESULTS Two cohorts of pegIFN-α treated patients were identified according to HBsAg decline greater or less than 0.5 log at week 24 post-treatment. PegIFN-α add-on did not significantly improve HBV-specific T cell responses during therapy but elicited a significant multispecific and polyfunctional T cell improvement at week 24 post-pegIFN-α treatment compared with baseline. This improvement was maximal in patients who had a higher drop in serum HBsAg levels and a lower basal HBcrAg values. CONCLUSIONS PegIFN-α treatment can induce greater functional T cell improvement and HBsAg decline in patients with lower baseline HBcrAg levels. Thus, HBcrAg may represent an easily and reliably applicable parameter to select patients who are more likely to achieve better response to pegIFN-α add-on to virally suppressed patients.
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Affiliation(s)
- Andrea Vecchi
- Unit of Infectious Diseases and Hepatology, University Hospital of Parma, Parma, Italy
| | - Marzia Rossi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Camilla Tiezzi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Paola Fisicaro
- Unit of Infectious Diseases and Hepatology, University Hospital of Parma, Parma, Italy
| | - Sara Doselli
- Unit of Infectious Diseases and Hepatology, University Hospital of Parma, Parma, Italy
| | | | - Amalia Penna
- Unit of Infectious Diseases and Hepatology, University Hospital of Parma, Parma, Italy
| | - Ilaria Montali
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | | | | | - Anna Montali
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Simon P Fletcher
- Department of Biology, Gilead Sciences, Foster City, California, USA
| | - Elisabetta Degasperi
- Division of Gastroenterology and Hepatology, IRCCS Foundation Maggiore Policlinico Hospital, Milan, Italy
| | - Dana Sambarino
- Division of Gastroenterology and Hepatology, IRCCS Foundation Maggiore Policlinico Hospital, Milan, Italy
| | - Diletta Laccabue
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Floriana Facchetti
- Division of Gastroenterology and Hepatology, IRCCS Foundation Maggiore Policlinico Hospital, Milan, Italy
| | - Simona Schivazappa
- Unit of Infectious Diseases and Hepatology, University Hospital of Parma, Parma, Italy
| | - Elisabetta Loggi
- Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Barbara Coco
- Hepatology Unit, Pisa University Hospital, Pisa, Italy
| | | | - Elena Rosselli Del Turco
- Department of Infectious Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna Policlinico di Sant'Orsola, Bologna, Italy
| | - Marco Massari
- Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Giuseppe Pedrazzi
- Department of Medicine and Surgery, Unit of Neuroscience, Interdepartmental Center of Robust Statistics (Ro.S.A.), University of Parma, Parma, Italy
| | - Gabriele Missale
- Unit of Infectious Diseases and Hepatology, University Hospital of Parma, Parma, Italy
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Gabriella Verucchi
- Department of Infectious Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna Policlinico di Sant'Orsola, Bologna, Italy
| | - Pietro Andreone
- Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Maurizia Rossana Brunetto
- Hepatology Unit, Pisa University Hospital, Pisa, Italy
- Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, IRCCS Foundation Maggiore Policlinico Hospital, Milan, Italy
- CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Carlo Ferrari
- Unit of Infectious Diseases and Hepatology, University Hospital of Parma, Parma, Italy
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Carolina Boni
- Unit of Infectious Diseases and Hepatology, University Hospital of Parma, Parma, Italy
- Department of Medicine and Surgery, University of Parma, Parma, Italy
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Pondé RADA, Amorim GDSP. Elimination of the hepatitis B virus: A goal, a challenge. Med Res Rev 2024; 44:2015-2034. [PMID: 38528684 DOI: 10.1002/med.22030] [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: 10/06/2023] [Revised: 01/24/2024] [Accepted: 02/05/2024] [Indexed: 03/27/2024]
Abstract
The hepatitis B elimination is a goal proposed by the WHO to be achieved by 2030 through the adoption of synergistic measures for the prevention and chronic HBV infection treatment. Complete cure is characterized by the HBV elimination from the body and is the goal of the chronic hepatitis B treatment, which once achieved, will enable the hepatitis B elimination. This, today, has been a scientific challenge. The difficulty in achieving a complete cure is due to the indefinite maintenance of a covalently closed episomal circular DNA (cccDNA) reservoir and the maintenance and persistence of an insufficient and dysfunctional immune response in chronically infected patients. Among the measures adopted to eliminate hepatitis B, two have the potential to directly interfere with the virus cycle, but with limited effect on HBV control. These are conventional vaccines-blocking transmission and antiviral therapy-inhibiting replication. Vaccines, despite their effectiveness in protecting against horizontal transmission and preventing mother-to-child vertical transmission, have no effect on chronic infection or potential to eliminate the virus. Treatment with antivirals suppresses viral replication, but has no curative effect, as it has no action against cccDNA. Therapeutic vaccines comprise an additional approach in the chronic infection treatment, however, they have only a modest effect on the immune system, enhancing it temporarily. This manuscript aims to address (1) the cccDNA persistence in the hepatocyte nucleus and the immune response dysfunction in chronically infected individuals as two primary factors that have hampered the treatment and HBV elimination from the human body; (2) the limitations of antiviral therapy and therapeutic vaccines, as strategies to control hepatitis B; and (3) the possibly promising therapeutic approaches for the complete cure and elimination of hepatitis B.
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Affiliation(s)
- Robério Amorim de Almeida Pondé
- Secretaria de Estado da Saúde-SES, Superintendência de Vigilância em Saúde-SUVISA/GO, Gerência de Vigilância Epidemiológica de Doenças Transmissíveis-GVEDT/Coordenação de Análises e Pesquisas-CAP, Goiânia, Goiás, Brazil
- Department of Microbiology, Laboratory of Human Virology, Institute of Tropical Pathology and Public Health, Federal University of Goiás, Goiânia, Goiás, Brazil
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Quan D, Wang P, Wu W, Li J. Investigating the role of GTPase in inhibiting HBV replication and enhancing interferon therapy efficacy in chronic hepatitis B patients. Microb Pathog 2024; 194:106821. [PMID: 39084309 DOI: 10.1016/j.micpath.2024.106821] [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: 01/27/2024] [Revised: 07/20/2024] [Accepted: 07/21/2024] [Indexed: 08/02/2024]
Abstract
BACKGROUND Interferon-alpha (IFNα) is a common treatment for chronic hepatitis B virus (HBV) infection, but its efficacy varies widely among patients. GTPASE, an interferon-stimulated gene (ISG), has recently been identified as a factor in antiviral immunity, though its role in HBV infection is not fully understood. OBJECTIVE This study investigates the role of GTPASE in enhancing the antiviral effects of IFNα against HBV and elucidates its mechanism of action. METHODS We analyzed the impact of GTPASE overexpression and silencing on HBV replication and clearance in HBV-infected cells. Molecular docking studies assessed the interaction between GTPASE and HBV surface antigens (HBs). Clinical samples from HBV patients undergoing Peg-IFNα treatment were also evaluated for GTPASE expression and its correlation with treatment efficacy. RESULTS Overexpression of GTPASE led to significant inhibition of HBV replication, increased HBeAg seroconversion, and enhanced HBsAg clearance. GTPASE directly bound to HBs proteins, reducing their levels and affecting viral particle formation. Silencing GTPASE reduced these effects, while combined treatment with Peg-IFNα and GTPASE overexpression further improved antiviral outcomes. Mutational analysis revealed that specific sites in GTPASE are crucial for its antiviral activity. CONCLUSIONS GTPASE acts as a positive regulator in IFNα-induced antiviral immunity against HBV. It enhances the therapeutic efficacy of IFNα by targeting HBs and modulating viral replication. GTPASE levels may serve as a predictive biomarker for response to Peg-IFNα therapy, highlighting its potential for improving individualized treatment strategies for chronic HBV infection.
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Affiliation(s)
- Dongmei Quan
- Hepatobiliary Surgery, The Sixth People's Hospital of Shenyang, Shenyang, China
| | - Pengfei Wang
- The Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine/Medical Management Office, China
| | - Wei Wu
- Hepatobiliary Surgery, The Sixth People's Hospital of Shenyang, Shenyang, China
| | - Jing Li
- Teaching and Research Section of the Internal Medicine of Traditional Chinese Medicine, The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, China.
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Li Y, Luo H, Hu X, Gong J, Tan G, Luo H, Wang R, Pang H, Yu R, Qin B. Guanylate-Binding Protein 1 (GBP1) Enhances IFN-α Mediated Antiviral Activity against Hepatitis B Virus Infection. Pol J Microbiol 2024; 73:217-235. [PMID: 38905278 PMCID: PMC11192456 DOI: 10.33073/pjm-2024-021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 05/08/2024] [Indexed: 06/23/2024] Open
Abstract
Interferon-alpha (IFN-α) is a first-line drug for treating chronic hepatitis B (CHB). Guanylate-binding protein 1 (GBP1) is one of the interferon-stimulating factors, which participates in the innate immunity of the host and plays an antiviral and antibacterial role. In this study, we explored how GBP1 is involved in IFN-α antiviral activity against HBV. Before being gathered, HepG2-NTCP and HepG2 2.15 cells were transfected with the wild-type hGBP1 plasmid or si-GBP1, respectively, and followed by stimulation with Peg-IFNα-2b. We systematically explored the role of GBP1 in regulating HBV infection in cell models. Additionally, we also examined GBP1 levels in CHB patients. GBP1 activity increased, and its half-life was prolonged after HBV infection. Overexpression of GBP1 inhibited the production of HBsAg and HBeAg, as well as HBs protein and HBV total RNA levels, whereas silencing of GBP1 inhibited its ability to block viral infections. Interestingly, overexpressing GBP1 co-treatment with Peg-IFNα-2b further increased the antiviral effect of IFN-α, while GBP1 silencing co-treatment with Peg-IFNα-2b partly restored its inhibitory effect on HBV. Mechanistically, GBP1 mediates the anti-HBV response of Peg-IFNα-2b by targeting HBs. Analysis of clinical samples revealed that GBP1 was elevated in CHB patients and increased with Peg-IFNα-2b treatment, while GBP1 showed good stability in the interferon response group. Our study demonstrates that GBP1 inhibits HBV replication and promotes HBsAg clearance. It is possible to achieve antiviral effects through the regulation of IFN-α induced immune responses in response to HBV.
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Affiliation(s)
- Yadi Li
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Haiying Luo
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoxia Hu
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiaojiao Gong
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Central Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guili Tan
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Central Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Huating Luo
- Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Rui Wang
- 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
- Central Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Renjie Yu
- 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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Wen C, Wang Y, Tian H, Lei Y, Wang Z, Cai D, Zhou Z, Shi X. Clinical cure induced by pegylated interferon α-2b in the advantaged population of chronic hepatitis B virus infection: a retrospective cohort study. Front Cell Infect Microbiol 2024; 13:1332232. [PMID: 38292859 PMCID: PMC10824921 DOI: 10.3389/fcimb.2023.1332232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 12/22/2023] [Indexed: 02/01/2024] Open
Abstract
Background Among the advantaged population with clinical cure of chronic hepatitis B, chronic inactive hepatitis B virus carriers (IHCs) and nucleoside analog-experienced patients have similar serological manifestations. This study established non-interferon-treated groups as controls to compare the efficacy of pegylated interferon α-2b (Peg-IFNα-2b) in achieving clinical cure between IHCs and nucleoside analog (NA)-experienced patients. Method A total of 270 patients were enrolled in this observational study. The IHC cohort comprised 55 patients who received Peg-IFNα-2b (Peg-IFN group), and the other 70 patients did not receive any antiviral treatment (untreated group). Patients treated with NAs were divided into two groups: one group (70 patients) receiving NA add-on Peg-IFNα-2b therapy regimen (NA add-on Peg-IFN group) and another group (75 patients) receiving continuous NA monotherapy (NA group). The primary endpoints were hepatitis B surface antigen (HBsAg) clearance and HBsAg seroconversion at 48 weeks and 72 weeks. Results At 48 weeks, 65.5% (36/55) and 52.9% (37/70) patients achieved HBsAg clearance in the Peg-IFN group and NA add-on Peg-IFN group, respectively (p = 0.156). HBsAg seroconversion was achieved in 47.3% (26/55) of the Peg-IFN group and 34.3% (24/70) of the NA add-on Peg-IFN group (p = 0.141). At the follow-up of 72 weeks, 36 patients in the Peg-IFN group achieved HBsAg loss (65.5%, 36/55), and 33 patients in the NA add-on Peg-IFN group achieved HBsAg clearance (47.1%, 33/70), which were significantly higher than in the Peg-IFN group (p = 0.041). The HBsAg seroconversion rates in the Peg-IFN group and NA add-on Peg-IFN group at 72 weeks were 45.5% (25/55) and 32.9% (23/70), respectively (p = 0.151). No patient achieved HBsAg clearance or seroconversion in the NA group and untreated group. Furthermore, the receiver operating characteristic curve showed baseline HBsAg< 72 IU/mL, and the decline of HBsAg of more than 80% and 98% from baseline to 12 and 24 weeks provided good predictions for HBsAg clearance. Meanwhile, 77% of patients with baseline HBsAg< 100 IU/mL achieved a clinical cure at 48 weeks. Conclusion Peg-IFNα-2b results in a high rate of HBsAg clearance and seroconversion in both IHCs and NA-experienced patients, especially for those patients who have HBsAg below 100 IU/mL.
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Affiliation(s)
| | | | | | | | | | | | | | - Xiaofeng Shi
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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9
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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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10
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Liu Z, Zhao Z, Ma X, Liu S, Xin Y. Renal and bone side effects of long-term use of entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide fumarate in patients with Hepatitis B: a network meta-analysis. BMC Gastroenterol 2023; 23:384. [PMID: 37950196 PMCID: PMC10638829 DOI: 10.1186/s12876-023-03027-4] [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: 04/07/2023] [Accepted: 11/01/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND Nucleoside analogues are currently applied as a first-line treatment for chronic hepatitis B (CHB) patients. However, the long-term effects of this type of treatment on kidney and bone tissue need to be further investigated. METHODS We conducted a search of entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF) for treatment of CHB patients through October 29, 2023. Side effects of the three drugs were compared. Standardized mean difference (SMD), 95% confidence interval (95%CI), and surface under the cumulative ranking curve (SUCRA) were reported for each outcome. Further subgroup analysis was conducted according to duration of administration. RESULTS ETV and TAF exhibited less effect on estimated glomerular filtration rate (eGFR) than TDF (SMD = -3.60 (95%CI: -1.94 ~ -5.26) and SMD = -4.27 (95%CI: -2.62 ~ -5.93)). ETV also exhibited less effect on creatinine rise than TAF and TDF (SMD = -0.55 (95%CI: -0.09 ~ -1.01) and SMD = -0.61 (95%CI: -0.15 ~ -1.06)). Moreover, the effect of TAF on bone mineral density (BMD) was less than that of TDF (SMD = -0.02 (95%CI: -0.01 ~ -0.02)). The probabilities of the three drugs changing relevant indicators exhibited similar patterns: eGFR (TDF (100.0%) > ETV (41.2%) > TAF (8.8%)), creatinine (TDF (94.7%) > TAF (54.7%) > ETV (0.6%)), BMD (TDF (79.7%) > ETV (50.6%) > TAF (19.6%)), and blood phosphorus (TDF (90.6%) > TAF (49.8%) > ETV (9.7%)). After 6 and 24 months of treatment, no statistically significant difference in renal function or bone tissue was observed between ETV and TDF. However, greater adverse effects on renal function were observed for TDF than ETV at 60 months compared to 12 months. TDF also exhibited greater adverse effects on bone tissue than ETV at 36 months than at 12 months. CONCLUSIONS Long-term administration of TDF has resulted in stronger adverse effects than TAF and ETV in regard to both renal function and bone tissue in CHB patients. The effect of TAF on creatinine increase was greater than ETV. The difference in side effects between ETV and TDF was independent of treatment duration.
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Affiliation(s)
- Zekun Liu
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, 266071, Shandong, China
| | - Zhenzhen Zhao
- Clinical Research Center, Qingdao Municipal Hospital, Qingdao, 266071, Shandong, China
| | - Xuefeng Ma
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, 266071, Shandong, China
| | - Shousheng Liu
- Clinical Research Center, Qingdao Municipal Hospital, Qingdao, 266071, Shandong, China
| | - Yongning Xin
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, 266071, Shandong, China.
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11
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Boni C, Rossi M, Montali I, Tiezzi C, Vecchi A, Penna A, Doselli S, Reverberi V, Ceccatelli Berti C, Montali A, Schivazappa S, Laccabue D, Missale G, Fisicaro P. What Is the Current Status of Hepatitis B Virus Viro-Immunology? Clin Liver Dis 2023; 27:819-836. [PMID: 37778772 DOI: 10.1016/j.cld.2023.05.001] [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] [Indexed: 10/03/2023]
Abstract
The natural history of hepatitis B virus (HBV) infection is closely dependent on the dynamic interplay between the host immune response and viral replication. Spontaneous HBV clearance in acute self-limited infection is the result of an adequate and efficient antiviral immune response. Instead, it is widely recognized that in chronic HBV infection, immunologic dysfunction contributes to viral persistence. Long-lasting exposure to high viral antigens, upregulation of multiple co-inhibitory receptors, dysfunctional intracellular signaling pathways and metabolic alterations, and intrahepatic regulatory mechanisms have been described as features ultimately leading to a hierarchical loss of effector functions up to full T-cell exhaustion.
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Affiliation(s)
- Carolina Boni
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
| | - Marzia Rossi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Ilaria Montali
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Camilla Tiezzi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Andrea Vecchi
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Amalia Penna
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Sara Doselli
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Valentina Reverberi
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | | | - Anna Montali
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Simona Schivazappa
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Diletta Laccabue
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Gabriele Missale
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Paola Fisicaro
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
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12
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Chen J, Li L, Yin Q, Shen T. A review of epidemiology and clinical relevance of Hepatitis B virus genotypes and subgenotypes. Clin Res Hepatol Gastroenterol 2023; 47:102180. [PMID: 37479136 DOI: 10.1016/j.clinre.2023.102180] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/07/2023] [Accepted: 07/13/2023] [Indexed: 07/23/2023]
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a global public health burden, affecting nearly 300 million people around the world. Due to HBV population is considered to be represented as a viral quasispecies with genetic diversity, some reports showed that different genotypes of HBV have different viral effects, though the emergence of antiviral drugs that effectively inhibit viral replication, however, HBV infection has still not been eradicated and further research is needed. SUMMARY HBV has been classified into at least ten genotypes (A-J) and more than 40 subgenotypes based on an intergroup or intragroup nucleotide difference across the whole genome, respectively. Inter genotypic recombinants were also observed during the HBV evolution. HBV genotypes and subgenotypes have distinct ethno-geographical distributions, as well as evident differences in their biological characteristics. HBV genotypes and subgenotypes also have close association with disease severity, long-term clinical outcomes, and response to antiviral therapy. KEYMESSAGES In this review, we up-dated the epidemiological characteristics, clinical features and prognosis of HBV infection with dissimilar genotype/subgenotypes, to better understanding and developing individualized prevention and treatment strategies.
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Affiliation(s)
- Jing Chen
- Medical school, Kunming University of Science and Technology, Kunming, 650500, Yunnan Province, PR China; Department of Pulmonary and Critical Care Medicine, Yunnan Provincial Key Laboratory for Clinical Virology, Institute of Basic and Clinical Medicine, The First People's Hospital of Yunnan Province, Kunming, 650032, PR China
| | - Li Li
- Department of Pulmonary and Critical Care Medicine, Yunnan Provincial Key Laboratory for Clinical Virology, Institute of Basic and Clinical Medicine, The First People's Hospital of Yunnan Province, Kunming, 650032, PR China
| | - Qi Yin
- Medical school, Kunming University of Science and Technology, Kunming, 650500, Yunnan Province, PR China; Department of Pulmonary and Critical Care Medicine, Yunnan Provincial Key Laboratory for Clinical Virology, Institute of Basic and Clinical Medicine, The First People's Hospital of Yunnan Province, Kunming, 650032, PR China
| | - Tao Shen
- Medical school, Kunming University of Science and Technology, Kunming, 650500, Yunnan Province, PR China; Department of Pulmonary and Critical Care Medicine, Yunnan Provincial Key Laboratory for Clinical Virology, Institute of Basic and Clinical Medicine, The First People's Hospital of Yunnan Province, Kunming, 650032, PR China; Department of Infectious Diseases and Hepatic Disease, Yunnan Province Innovation Team of Intestinal Microecology Related Disease Research and Technological Transformation, the First People's Hospital of Yunnan Province, Kunming 650032, PR China.
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13
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Abstract
Hepatitis B virus (HBV) infection is a major public health problem, with an estimated 296 million people chronically infected and 820 000 deaths worldwide in 2019. Diagnosis of HBV infection requires serological testing for HBsAg and for acute infection additional testing for IgM hepatitis B core antibody (IgM anti-HBc, for the window period when neither HBsAg nor anti-HBs is detected). Assessment of HBV replication status to guide treatment decisions involves testing for HBV DNA, whereas assessment of liver disease activity and staging is mainly based on aminotransferases, platelet count, and elastography. Universal infant immunisation, including birth dose vaccination is the most effective means to prevent chronic HBV infection. Two vaccines with improved immunogenicity have recently been approved for adults in the USA and EU, with availability expected to expand. Current therapies, pegylated interferon, and nucleos(t)ide analogues can prevent development of cirrhosis and hepatocellular carcinoma, but do not eradicate the virus and rarely clear HBsAg. Treatment is recommended for patients with cirrhosis or with high HBV DNA levels and active or advanced liver disease. New antiviral and immunomodulatory therapies aiming to achieve functional cure (ie, clearance of HBsAg) are in clinical development. Improved vaccination coverage, increased screening, diagnosis and linkage to care, development of curative therapies, and removal of stigma are important in achieving WHO's goal of eliminating HBV infection by 2030.
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Affiliation(s)
- Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - George V Papatheodoridis
- Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Anna S F Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
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14
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Yang H, Yao W, Yang J. Overview of the development of HBV small molecule inhibitors. Eur J Med Chem 2023; 249:115128. [PMID: 36709647 DOI: 10.1016/j.ejmech.2023.115128] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/13/2023] [Accepted: 01/15/2023] [Indexed: 01/28/2023]
Abstract
Like tuberculosis and Acquired Immune Deficiency Syndrome (AIDS), hepatitis B is a globally recognized major public health threat. Although there are many small-molecule drugs for the treatment of hepatitis B, the approved drugs cannot eradicate the pathogenic culprit covalently closed circular DNA in patients, so the patients need long-term medication to control HBV amplification. Driven by a high unmet medical need, many pharmaceutical companies and research institutions have been engaged in the development of anti-HBV drugs to achieve a functional cure for chronic hepatitis B as soon as possible. This review summarizes the pathogenesis of hepatitis B virus and the research progress in the development of anti-HBV small molecule drugs, and introduces the cccDNA formation and transcription inhibitors and core inhibitors in detail, especially emphasizes the role of chinese herbal medicine in the treatment of chronic hepatitis B. Furthermore, this review proposes three potential strategies for cccDNA eradication in the future. We believe this review will provide meaningful guidance to achieve a functional cure for viral hepatitis B in the future.
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Affiliation(s)
- Huihui Yang
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, 266001, China
| | - Weiwei Yao
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, 266001, China
| | - Jinfei Yang
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, 266001, China.
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15
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Al Mahtab M, Akbar SMF, Aguilar JC, Yoshida O, Khan S, Gerardo GN, Hiasa Y. Safety profile, antiviral capacity, and liver protection of a nasal therapeutic vaccine in patients with chronic hepatitis B: Five-year-follow-up outcomes after the end of treatment. Front Med (Lausanne) 2023; 10:1032531. [PMID: 36844221 PMCID: PMC9945514 DOI: 10.3389/fmed.2023.1032531] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 01/19/2023] [Indexed: 02/11/2023] Open
Abstract
Introduction There is a pressing need to develop novel drugs for treating patients with chronic hepatitis B (CHB), as commercially available antiviral drugs are endowed with safety and efficacy concerns. Methods A phase III clinical trial was conducted with a therapeutic vaccine containing two antigens of the hepatitis B virus (HBV; named NASVAC) in 78 patients with CHB expressing both HBV DNA and elevated levels of alanine aminotransferase (ALT) in the blood. Five years after the end of treatment (EOT), 60 NASVAC-recipient patients were enrolled in this long-term follow-up study to evaluate the safety, antiviral potential, and liver-protective capacity of NASVAC. Results NASVAC exhibited an excellent safety profile 5 years after EOT. The levels of HBV DNA in the sera were reduced in 55 of the 60 patients, and 45 of them were negative for HBV DNA in the sera. ALT levels were also normalized in 40 of the 60 patients 5 years after EOT. None of the patients receiving NASVAC developed liver cirrhosis or cancer. Discussion The present study is the first to exhibit long-term follow-up data of a finite immune therapy for CHB that is safe and endowed with potent antiviral and liver-protecting capacities.
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Affiliation(s)
- Mamun Al Mahtab
- Department of Hepatology, Interventional Hepatology Division, Bangabandhu Sheikh Mujib Medical University, BSMMU, Dhaka, Bangladesh
| | - Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan,*Correspondence: Sheikh Mohammad Fazle Akbar, ✉
| | | | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Sakirul Khan
- Department of Microbiology, Faculty of Medicine, Oita University, Oita, Japan
| | | | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
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16
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IFIT3 Is Increased in Serum from Patients with Chronic Hepatitis B Virus (HBV) Infection and Promotes the Anti-HBV Effect of Interferon Alpha via JAK-STAT2 In Vitro. Microbiol Spectr 2022; 10:e0155722. [PMID: 36314949 PMCID: PMC9769971 DOI: 10.1128/spectrum.01557-22] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Increasing evidence indicates that interferon alpha (IFN-α) therapy is an effective treatment option for a subgroup of patients with chronic hepatitis B virus (HBV) infection. It has been confirmed that interferon-induced protein with tetratricopeptide repeats 3 (IFIT3), a member of the interferon-stimulated genes (ISGs), could inhibit the replication of various viruses. However, its effect on HBV replication is unclear. The present study sought to explore the role and mechanism of IFIT3 in IFN-α antiviral activities against HBV. IFIT3 mRNA levels in the peripheral blood of 108 treatment-naive patients and 70 healthy controls were analyzed first. The effect of IFIT3 on the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway under the dual intervention of IFN-α and HBV was also explored in vitro. Treatment-naive individuals exhibited elevated levels of IFIT3 mRNA compared to the controls (P < 0.0001). Mechanistically, the knockdown of IFIT3 inhibited the phosphorylation of signal transducer and activator of transcription 2 (STAT2), whereas the overexpression of IFIT3 produced the opposite effect in vitro. Meanwhile, the overexpression of IFIT3 enhanced the expression of IFN-α-triggered ISGs, including myxovirus resistance A (MxA), 2'-5'-oligoadenylate synthetase 1 (OAS1), and double-stranded RNA-activated protein kinase (PKR), while a weaker induction of IFN-α-triggered ISGs was observed in ruxolitinib-treated cells. After decreasing IFIT3 expression by validated small hairpin RNAs (shRNAs), the levels of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and HBV DNA secreted by HepG2 cells transiently transfected with the pHBV1.2 plasmid were increased. Our findings suggest that IFIT3 works in a STAT2-dependent manner to promote the antiviral effect of IFN-α through the JAK-STAT pathway in HBV infection in both human hepatocytes and hepatocarcinoma cells. IMPORTANCE Our study contributes new insights into the understanding of the functions and roles of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3), which is one of the interferon-stimulated genes induced by hepatitis B virus infection in human hepatocytes and hepatocarcinoma cells, and may help to identify targeted genes promoting the efficacy of interferon alpha.
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17
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Fisicaro P. Engineered IFN-α and anti-PDL1 containing compounds to target the liver and restore antiviral protection for HBV cure. Gut 2022; 72:gutjnl-2022-328902. [PMID: 36591618 DOI: 10.1136/gutjnl-2022-328902] [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: 11/28/2022] [Accepted: 12/05/2022] [Indexed: 01/03/2023]
Affiliation(s)
- Paola Fisicaro
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
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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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Virological Changes of Chronic Hepatitis B Patients with Minimally Elevated Levels of Alanine Aminotransferase: A Meta-Analysis and Systematic Review. Can J Gastroenterol Hepatol 2022; 2022:7499492. [PMID: 36439633 PMCID: PMC9683979 DOI: 10.1155/2022/7499492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 10/17/2022] [Accepted: 11/02/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Chronic hepatitis B (CHB) patients with normal or minimally increased levels of alanine aminotransferase (ALT) are still at the risk of hepatocellular carcinoma, cirrhotic events, and mortality. However, there is a debate over the initiation of antiviral treatment for these patients. This systematic review and mate-analysis aimed to explore this problem. METHODS MEDLINE (PubMed), EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science databases were systematically searched for retrieving relevant studies with risk ratios (RRs) or risk differences (RDs) for virological changes between antivirus-treated and no antivirus-treated CHB patients with ALT levels less than two-fold of the upper limit of normal. Retrieved data ranged from January 1990 to October 2020. RESULTS Of 6783 abstracts screened, 9 studies met the criteria for inclusion in the systematic review and had a low risk of bias. Among studies that were involved in the meta-analyses, it was found that the rates of HBsAg loss (RR = 12.22, 95% confidence interval (CI): 4.28-34.95, P < 0.001), HBsAg seroconversion (RR = 19.90, 95% CI: 2.75-144.09, P=0.003), and undetectable HBV DNA (RR = 11.89, 95% CI: 2.44-57.89, P=0.002) were both higher in the antiviral treatment group compared with placebo or no treatment group. Subgroup analysis suggested that patients who received interferon (IFN)-based therapy were more inclined to achieve HBsAg loss (P=0.010), HBsAg seroconversion (P=0.020), and HBeAg loss (P=0.002). CONCLUSION From a sizable population, it was revealed that CHB patients with normal or minimally increased levels of ALT could benefit from the antiviral therapy, especially those who received IFN-based treatment.
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Akbar SMF, Mahtab MA, Khan S, Yoshida O, Hiasa Y. Development of Therapeutic Vaccine for Chronic Hepatitis B: Concept, Cellular and Molecular Events, Design, Limitation, and Future Projection. Vaccines (Basel) 2022; 10:vaccines10101644. [PMID: 36298512 PMCID: PMC9612083 DOI: 10.3390/vaccines10101644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 09/20/2022] [Accepted: 09/28/2022] [Indexed: 12/02/2022] Open
Abstract
Four decades have passed since the first usage of the therapeutic vaccine in patients with chronic hepatitis B (CHB). However, there is no approved regimen of vaccine therapy for the treatment of CHB. This is mainly attributable to faulty conception, an improper understanding of the cellular and molecular mechanisms of CHB, and the impaired design of vaccine therapy for CHB. With the advent of new techniques and a better understanding of cellular and molecular mechanisms underlying the genesis of CHB, the limitations and failures of previous regimens of therapeutic vaccines have been primarily understood. Additionally, the importance of immune therapy for treating millions of CHB patients and achieving the target of "Elimination of Hepatitis by 2030" has been focused on in the international arena. This has been amplified by the apparent limitation of commercially available antiviral drugs that are infinite in duration, endowed with safety concerns, and unable to cure liver damage due to their minimal immune modulation capacities. The proposed review article comprehensively discusses each of these points and proposes evidence-based approaches for viable types of vaccine therapy for the treatment of CHB.
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Affiliation(s)
- Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Graduate School of Medicine, Ehime University, Ehime 791-0295, Japan
- Correspondence: ; Tel.: +81-89-960-5308; Fax: +81-89-960-5310
| | - Mamun Al Mahtab
- Interventional Hepatology Division, Department of Hepatology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka 1000, Bangladesh
| | - Sakirul Khan
- Department of Microbiology, Oita University, Oita 879-5593, Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Graduate School of Medicine, Ehime University, Ehime 791-0295, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Graduate School of Medicine, Ehime University, Ehime 791-0295, Japan
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21
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Konya P, Demirtürk N. Evaluation of Tenofovir Disoproxil Fumarate Treatment in Patients with Chronic Hepatitis B. INFECTIOUS DISEASES & CLINICAL MICROBIOLOGY 2022; 4:47-54. [PMID: 38633545 PMCID: PMC11022821 DOI: 10.36519/idcm.2022.78] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 02/20/2022] [Indexed: 04/19/2024]
Abstract
Objective The main purpose of chronic hepatitis B (CHB) treatment is to improve the patients' life quality and prevent the disease from progressing to cirrhosis or hepatocellular carcinoma. Continuous suppression of hepatitis B virus (HBV) DNA with nucleoside or nucleotide analogues is the most critical way to achieve this goal. This study aimed to evaluate the CHB patients retrospectively followed up with tenofovir disoproxil fumarate (TDF) treatment. Materials and Methods The study was planned as retrospective research by Afyonkarahisar Health Sciences University, Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology between January 2001 and December 2020. We evaluated all treatment-naive and treatment-experienced patients who received TDF (245 mg/day) treatment with the diagnosis of CHB. The data were obtained by reviewing the file information registered in the hospital automation system. HBsAg, Anti-HBs, HBeAg, Anti-HBe, HBV DNA, aspartate aminotransferase (AST), alanine aminotransferase (ALT) values of the patients were evaluated at 1st, 3rd, 6th, 12th months, and 6-month follow-ups throughout the treatment. Virological (HBV-DNA of < 50 IU/ml), biochemical (decrease below 40 IU/Ml in patients with pre-treatment value of ALT >40 IU/ml) and serological (Anti-HBe seroconversion in HBeAg positives and HBsAg negative and anti-HBs seroconversion in all patients) responses were examined. Adverse effects were also assessed during the treatment. Results Data from 131 patients who received TDF treatment were evaluated. Virological responses were determined as 78.6%, 81.3%, 94.2%, and 100% in the patients at 24th week, 48th week, 4th year, and 8th year, respectively. While there was no Anti-HBs seroconversion in any patients in four years of the treatment, it was observed at a rate of 10.5% in the eighth year. We did not determine any significant adverse effects requiring discontinuation of the treatment in the long-term follow-up of 131 patients under TDF treatment. Conclusion As a result of our study, TDF was an effective and well-tolerated choice for CHB treatment.
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Affiliation(s)
- Petek Konya
- Department of Infectious Disease and Clinical Microbiology, Afyonkarahisar Health Sciences University School of Medicine, Afyonkarahisar, Turkey
| | - Neşe Demirtürk
- Department of Infectious Disease and Clinical Microbiology, Afyonkarahisar Health Sciences University School of Medicine, Afyonkarahisar, Turkey
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22
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Lim SG, Yang WL, Ngu JH, Chang J, Tan J, Ahmed T, Dan YY, Lim K, Lee YM, Lee GH, Tan PS, Wai KL, Phyo WW, Khine HHTW, Lee C, Tay A, Chan E. Switching to or Add-on Peginterferon in Patients on Nucleos(t)ide Analogues for Chronic Hepatitis B: The SWAP RCT. Clin Gastroenterol Hepatol 2022; 20:e228-e250. [PMID: 33895361 DOI: 10.1016/j.cgh.2021.04.031] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/19/2021] [Accepted: 04/20/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The optimal therapeutic strategy in nucleoside analogue (NA) experienced chronic hepatitis B (CHB) using peginterferon is still unclear; hence we explored a switch to or add-on peginterferon strategy versus continued NA. METHODS We conducted a randomized controlled trial of CHB patients on NA >12 months with HBV DNA(-) randomized to switch or add-on peginterferon-alpha2b (1.5 μg/kg/weekly) for 48 weeks versus continuing NA (controls) (allocation 2:2:1; Clinicaltrial.gov: NCT01928511) in tertiary Singapore hospitals. The primary composite endpoint at week 72 was hepatitis B e antigen (HBeAg) loss or quantitative HBsAg (qHBsAg) >1 log IU/mL reduction, and secondary endpoints were HBsAg loss, HBsAg seroconversion, qHBsAg <200 IU/mL, qHBsAg <100 IU/mL, HBV DNA(-), viral relapse, and safety. Analysis was by intention-to-treat (ITT). RESULTS A total of 253 patients (controls 51, switch 103, add-on 99) were randomized. The primary ITT endpoint was achieved in 3.9% of controls, 33.3% of switch, and 26.7% of add-on (P < .0001, switch/add-on versus controls). HBsAg loss occurred in 0% of controls, 7.8% of switch, and 10.1% of add-on (ITT, P < .001, switch/add-on versus controls). HBeAg(+) patients on peginterferon had higher HBeAg loss than controls but poor HBsAg responses, whereas HBeAg(-) patients on peginterferon achieved better HBsAg responses than controls. Reduction in qHBsAg in HBeAg(+) was 0.14 log IU/mL versus 0.51 log IU/mL in HBeAg(-) (P < .0001) in peginterferon-treated patients. Clinical relapse was higher in switch (13.6% overall, 27% in HBeAg(+)) versus 1% add-on and 0% controls. Adverse events were typically interferon-related symptoms, with one death (myocardial infarction unrelated to therapy). CONCLUSIONS ITT analysis showed that either peginterferon strategies were superior to NA for the primary endpoint and HBsAg loss, but add-on peginterferon is preferred to switch due to improved safety and similar efficacy. ClincialTrials.gov number: NCT01928511.
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Affiliation(s)
- Seng Gee Lim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
| | - Wei Lyn Yang
- Department of Gastroenterology, Tan Tock Seng Hospital, Singapore
| | - Jing Hieng Ngu
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
| | - Jason Chang
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
| | - Jessica Tan
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore
| | - Taufique Ahmed
- Department of Medicine, Khoo Teck Puat Hospital, Singapore
| | - Yock Young Dan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Kieron Lim
- Mount Elizabeth Medical Centre, Singapore
| | - Yin Mei Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Guan Huei Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Poh Seng Tan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Khin Lay Wai
- Department of Obstetrics and Gynaecology, Kandang Kerbau Women's and Children's Hospital, Singapore; Duke-NUS Medical School, Singapore
| | - Wah Wah Phyo
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Htet Htet Toe Wai Khine
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Chris Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Amy Tay
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Edwin Chan
- Duke-NUS Medical School, Singapore; Singapore Clinical Research Institute, Singapore
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23
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Cellular and Molecular Mechanisms Underlying Scope and Limitation of Ongoing and Innovative Therapies for Treating Chronic Hepatitis B. LIVERS 2022. [DOI: 10.3390/livers2010001] [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: 11/16/2022] Open
Abstract
Millions of people of the world suffer from chronic hepatitis B (CHB), a pathological entity in which the patients are chronically infected with hepatitis B virus (HBV) and express hepatitis B surface antigen (HBsAg) and HBV DNA, as well as evidence of liver damages. Considerable numbers of CHB patients develop cirrhosis of the liver and hepatocellular carcinoma if untreated. Two groups of drugs (interferons and nucleoside analogs) are used to treat CHB patients, but both are endowed with considerable adverse effects, increased costs, extended duration of therapy, and limited efficacy. Thus, there is a pressing need to develop new and innovative therapeutics for CHB patients, and many such drugs have been developed during the last four decades. Some of these drugs have inspired considerable optimism to be a game-changer for the treatment of CHB. Here, we first discuss why ongoing therapeutics such as interferon and nucleoside analogs could not stand the test of time. Next, we dissect the scope and limitation of evolving therapies for CHB by dissecting the cellular and molecular mechanisms of some of these innovative therapeutics.
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Abstract
Hepatitis B virus (HBV) infects 240 million people worldwide. Current therapy profoundly suppresses HBV replication but requires long-term maintenance therapy. Therefore, there is still a medical need for an efficient HBV cure. HBV enters host cells by binding via the preS1 domain of the viral L protein to the Na+/taurocholate cotransporting polypeptide (NTCP). Thus, NTCP should be a key target for the development of anti-HBV therapeutics. Indeed, myrcludex B, a synthetic form of the myristoylated preS1 peptide, effectively reduces HBV/hepatitis D virus (HDV) infection and has been approved as Hepcludex in Europe for the treatment of patients with chronic HDV infection. We established a monoclonal antibody (MAb), N6HB426-20, that recognizes the extracellular domain of human NTCP and blocks HBV entry in vitro into human liver cells but has much less of an inhibitory effect on bile acid uptake. In vivo, administration of the N6HB426-20 MAb prevented HBV viremia for an extended period of time after HBV inoculation in a mouse model system without strongly inhibiting bile acid absorption. Among the extracellular loops (ECLs) of NTCP, regions of amino acids (aa) 84 to 87 in ECL1 and aa 157 to 165 near ECL2 of transmembrane domain 5 are critically important for HBV/HDV infection. Epitope mapping and the three-dimensional (3D) model of the NTCP structure suggested that the N6HB426-20 MAb may recognize aa 276/277 at the tip of ECL4 and interfere with binding of HBV to the region from aa 84 to 87. In summary, we identified an in vivo neutralizing NTCP-targeting antibody capable of preventing HBV infection. Further improvements in efficacy of this drug will pave the way for its clinical applications. IMPORTANCE A number of entry inhibitors are being developed to enhance the treatment of HBV patients with oral nucleoside/nucleotide analogues (NA). To amplify the effectiveness of NA therapy, several efforts have been made to develop therapeutic MAbs with neutralizing activity against HBs antigens. However, the neutralizing effect of these MAbs may be muted by a large excess of HBsAg-positive noninfectious particles in the blood of infected patients. The advantage of NTCP-targeted HBV entry inhibitors is that they remain effective regardless of viral genotype, viral mutations, and the presence of subviral particles. Although N6HB426-20 requires a higher dose than myrcludex to obtain equivalent suppression of HBV in a model mouse system, it maintained the inhibitory effect for a long time postadministration in proportion to the half-life of an IgG MAb. We believe that further improvements will make this antibody a promising treatment option for patients with chronic hepatitis B.
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25
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Detection and Prevention of Virus Infection. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1368:21-52. [DOI: 10.1007/978-981-16-8969-7_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Cheng K, Chen Y, Wang X, Xu M, Liao W, Duan X, Zhao X, Sun Y, Duan Z, Wang L. Entecavir combined with interferon-α is superior to entecavir monotherapy in reducing hepatic and extrahepatic cancer in patients with chronic hepatitis B. Cancer 2021; 128:558-569. [PMID: 34623636 DOI: 10.1002/cncr.33949] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/30/2021] [Accepted: 09/07/2021] [Indexed: 11/10/2022]
Abstract
BACKGROUND The objective of this study was to assess whether entecavir (ETV) in combination with interferon-α (IFN-α) could reduce hepatocellular cancer (HCC) and extrahepatic cancers (EHCs) in patients with chronic hepatitis B (CHB). METHODS The cohort consisted of 4194 patients with CHB treated with ETV combined with IFN-α or ETV monotherapy at a tertiary hospital in Beijing, China, from January 2009 to December 2017. The risks, hazard ratios (HRs), and 95% confidence intervals (CIs) of HCC and EHCs were compared in the 2 groups. RESULTS In a multivariate Cox regression analysis, a significantly lower risk of HCC (HR, 0.6; 95% CI, 0.3-0.9; P = .0310) and a marginally significantly lower risk of EHCs (HR, 0.2; 95% CI, 0.02-1.3; P = .0854) were observed in the group receiving ETV combined with IFN-α in comparison with the ETV monotherapy group. The annual virological response rates were significantly higher in the combination therapy group versus the monotherapy group (33.8% vs 21.2%; P < .0001), but the hepatitis B surface antigen (HBsAg) seroclearance rates were not (1.2% vs 0.9%; P = .8537). The HRs were consistent with propensity score-based matching, inverse probability weighting adjustments, and adjustments for virological response and HBsAg seroclearance. CONCLUSIONS ETV combined with IFN-α therapy is superior to ETV monotherapy in reducing the risk of HCC and EHCs for patients with CHB. People who can tolerate and benefit from IFN-α therapy could consider combination therapy.
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Affiliation(s)
- Kailiang Cheng
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yu Chen
- Fourth Department of Liver Disease (Difficult and Complicated Liver Diseases and Artificial Liver Center), Beijing You'an Hospital, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Xiaomo Wang
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Manman Xu
- Fourth Department of Liver Disease (Difficult and Complicated Liver Diseases and Artificial Liver Center), Beijing You'an Hospital, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Wei Liao
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | | | - Xinyu Zhao
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yuanyuan Sun
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Zhongping Duan
- Fourth Department of Liver Disease (Difficult and Complicated Liver Diseases and Artificial Liver Center), Beijing You'an Hospital, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Li Wang
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
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Akbar SMF, Al Mahtab M, Cesar Aguilar J, Uddin MH, Khan MSI, Yoshida O, Penton E, Gerardo GN, Hiasa Y. Exploring evidence-based innovative therapy for the treatment of chronic HBV infection: experimental and clinical. EXPLORATION OF MEDICINE 2021. [DOI: 10.37349/emed.2021.00058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 08/03/2021] [Indexed: 01/02/2025] Open
Abstract
With the advent of various vaccines and antimicrobial agents during the 20th century, the control and containment of infectious diseases appeared to be a matter of time. However, studies unveiled the diverse natures of microbes, their lifestyle, and pathogenetic potentials. Since the ground-breaking discovery of the hepatitis B virus (HBV) by Baruch Blumberg and the subsequent development of a vaccine in the early 1980s, the main task of the scientific community has been to develop a proper management strategy for HBV-induced chronic liver diseases. In the early 1980’s, standard interferon (IFN) induced a reduction of HBV DNA levels, followed by the normalization of serum transaminases (alanine aminotransferase, ALT), in some chronic hepatitis B (CHB) patients. However, in the course of time, the limitations of standard IFN became evident, and the search for an alternative began. In the late 1980’s, nucleoside analogs entered the arena of CHB treatment as oral drugs with potent antiviral capacities. At the beginning of the 21st century, insights were developed into the scope and limitations of standard IFN, pegylated-IFN as well as nucleoside analogs for treating CHB. Considering the non-cytopathic nature of the HBV, the presence of covalently closed circular DNA (cccDNA) in the nucleus of the infected hepatocytes and HBV-induced immune-mediated liver damages, a new field of CHB management was initiated by modulating the hosts’ immune system through immune therapy. This review will discuss the nature and design of innovative immune therapy for CHB.
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Affiliation(s)
- Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime 7910295, Japan
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka 1000, Bangladesh
| | - Julio Cesar Aguilar
- Center for Genetic Engineering and Biotechnology, Havana, Havana 10600, Cuba
| | | | - Md. Sakirul Islam Khan
- Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Ehime 7910295, Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime 7910295, Japan
| | - Eduardo Penton
- Center for Genetic Engineering and Biotechnology, Havana, Havana 10600, Cuba
| | | | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime 7910295, Japan
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28
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Tsounis EP, Tourkochristou E, Mouzaki A, Triantos C. Toward a new era of hepatitis B virus therapeutics: The pursuit of a functional cure. World J Gastroenterol 2021; 27:2727-2757. [PMID: 34135551 PMCID: PMC8173382 DOI: 10.3748/wjg.v27.i21.2727] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/23/2021] [Accepted: 04/13/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection, although preventable by vaccination, remains a global health problem and a major cause of chronic liver disease. Although current treatment strategies suppress viral replication very efficiently, the optimal endpoint of hepatitis B surface antigen (HBsAg) clearance is rarely achieved. Moreover, the thorny problems of persistent chromatin-like covalently closed circular DNA and the presence of integrated HBV DNA in the host genome are ignored. Therefore, the scientific community has focused on developing innovative therapeutic approaches to achieve a functional cure of HBV, defined as undetectable HBV DNA and HBsAg loss over a limited treatment period. A deeper understanding of the HBV life cycle has led to the introduction of novel direct-acting antivirals that exert their function through multiple mechanisms, including inhibition of viral entry, transcriptional silencing, epigenetic manipulation, interference with capsid assembly, and disruption of HBsAg release. In parallel, another category of new drugs aims to restore dysregulated immune function in chronic hepatitis B accompanied by lethargic cellular and humoral responses. Stimulation of innate immunity by pattern-recognition receptor agonists leads to upregulation of antiviral cytokine expression and appears to contribute to HBV containment. Immune checkpoint inhibitors and adoptive transfer of genetically engineered T cells are breakthrough technologies currently being explored that may elicit potent HBV-specific T-cell responses. In addition, several clinical trials are attempting to clarify the role of therapeutic vaccination in this setting. Ultimately, it is increasingly recognized that elimination of HBV requires a treatment regimen based on a combination of multiple drugs. This review describes the rationale for progressive therapeutic interventions and discusses the latest findings in the field of HBV therapeutics.
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Affiliation(s)
- Efthymios P Tsounis
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
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29
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Cheng X, Uchida T, Xia Y, Umarova R, Liu CJ, Chen PJ, Gaggar A, Suri V, Mücke MM, Vermehren J, Zeuzem S, Teraoka Y, Osawa M, Aikata H, Tsuji K, Mori N, Hige S, Karino Y, Imamura M, Chayama K, Liang TJ. Diminished hepatic IFN response following HCV clearance triggers HBV reactivation in coinfection. J Clin Invest 2021; 130:3205-3220. [PMID: 32163375 DOI: 10.1172/jci135616] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 03/05/2020] [Indexed: 12/12/2022] Open
Abstract
In patients with HBV and HCV coinfection, HBV reactivation leading to severe hepatitis has been reported with the use of direct-acting antivirals (DAAs) to treat HCV infection. Here we studied the molecular mechanisms behind this viral interaction. In coinfected cell culture and humanized mice, HBV replication was suppressed by HCV coinfection. In vitro, HBV suppression was attenuated when interferon (IFN) signaling was blocked. In vivo, HBV viremia, after initial suppression by HCV superinfection, rebounded following HCV clearance by DAA treatment that was accompanied by a reduced hepatic IFN response. Using blood samples of coinfected patients, IFN-stimulated gene products including C-X-C motif chemokine 10 (CXCL10), C-C motif chemokine ligand 5 (CCL5), and alanine aminotransferase (ALT) were identified to have predictive value for HBV reactivation after HCV clearance. Taken together, our data suggest that HBV reactivation is a result of diminished hepatic IFN response following HCV clearance and identify serologic markers that can predict HBV reactivation in DAA-treated HBV-HCV-coinfected persons.
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Affiliation(s)
- Xiaoming Cheng
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Takuro Uchida
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.,Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuchen Xia
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Regina Umarova
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Chun-Jen Liu
- Graduate Institute of Clinical Medicine, Hepatitis Research Center and Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, Hepatitis Research Center and Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Anuj Gaggar
- Gilead Sciences, Foster City, California, USA
| | | | - Marcus M Mücke
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany
| | - Johannes Vermehren
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Mitsutaka Osawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Keiji Tsuji
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Nami Mori
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Shuhei Hige
- Department of Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Yoshiyasu Karino
- Department of Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Michio Imamura
- 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
| | - T Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
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Lee SK, Kwon JH, Lee SW, Jang JW, Nam H, Baik KW, Yoo SH, Nam SW, Sung PS, Bae SH, Choi JY, Yoon SK. Sustained off therapy response after peglyated interferon favours functional cure and no disease progression in chronic hepatitis B. Liver Int 2021; 41:288-294. [PMID: 33043567 DOI: 10.1111/liv.14701] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/31/2020] [Accepted: 10/06/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB) patients reduces liver-related mortality. However, long-term outcomes after pegylated interferon (PEG-IFN) therapy remain to be elucidated. Therefore, we aimed to investigate the long-term effectiveness and clinical outcomes of PEG-IFN therapy. METHODS A total of 190 patients treated with PEG-IFN for CHB or compensated cirrhosis were consecutively enrolled between 2005 and 2014, and 122 patients who completed the treatment were analysed. The initial response was assessed at 6 months post-treatment and defined as achieving both <2000 IU/mL HBV DNA and HBeAg loss or seroconversion in the HBeAg-positive group, and <2000 IU/mL HBV DNA in the HBeAg-negative group. The rates of HBsAg loss, disease progression to cirrhosis or HCC, and sustained off-therapy response, defined as not requiring further NAs because of low viremia and liver enzymes, were analysed. RESULTS The median follow-up period was 7.2 years. Forty-three (35.2%) patients achieved an initial response and 53 patients (43.4%) achieved a sustained response. Initial responders displayed higher rates of sustained response than noninitial responders (69.6% vs 32.5%, P < .001). A higher rate of HBsAg loss was observed in patients who achieved a sustained response than in non-sustained responders (16.2% vs 2.5%, P = .01). Disease progression to cirrhosis or HCC was observed in eight patients (6.6%) who were nonsustained responders. CONCLUSIONS During long-term follow-up after PEG-IFN treatment, nearly half of patients achieved sustained response without the need of further NA and these patients displayed favourable outcomes, including HBsAg loss and no disease progression.
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Affiliation(s)
- Soon Kyu Lee
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.,The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea
| | - Jung Hyun Kwon
- The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea.,Division of Hepatology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea
| | - Sung Won Lee
- The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea.,Division of Hepatology, Department of Internal Medicine, Bucheon St. Mary's Hospital, The Catholic University of Korea, Bucheon, Korea
| | - Jeong Won Jang
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.,The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea
| | - Heechul Nam
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.,The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea
| | - Kyoung Won Baik
- The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea.,Division of Hepatology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea
| | - Sun Hong Yoo
- The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea.,Division of Hepatology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea
| | - Soon Woo Nam
- The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea.,Division of Hepatology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea
| | - Pil Soo Sung
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.,The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea
| | - Si Hyun Bae
- The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea.,Division of Hepatology, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Jong Young Choi
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.,The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea
| | - Seung Kew Yoon
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.,The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea
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31
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Dandri M, Petersen J. cccDNA Maintenance in Chronic Hepatitis B - Targeting the Matrix of Viral Replication. Infect Drug Resist 2020; 13:3873-3886. [PMID: 33149632 PMCID: PMC7605611 DOI: 10.2147/idr.s240472] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 10/02/2020] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B is a numerically important cause of cirrhosis and hepatocellular carcinoma, despite an effective prophylactic vaccine and well-tolerated and effective oral antivirals. Both the incapacity of the immune system to clear hepatitis B virus (HBV) infection and the unique replication strategies adopted by HBV are considered key determinants of HBV chronicity. In this regard, the formation of the HBV DNA minichromosome, the covalently closed circular DNA (cccDNA), in the nucleus of infected hepatocytes, is essential not only for the production of all viral proteins but also for HBV persistence even after long-term antiviral therapy. Licensed polymerase inhibitors target the HBV reverse transcriptase activity, control the disease with long-term therapy but fail to eliminate the cccDNA. Consequently, the production of viral RNAs and proteins, including the hepatitis B surface antigen (HBsAg), is not abolished. Novel therapeutic efforts that are in the pipeline for early clinical trials explore novel targets and molecules. Such therapeutic efforts focus on achieving a functional cure, which is defined by the loss of HBsAg and undetectable HBV DNA levels in serum. Since a true cure of HBV infection requires the elimination of the cccDNA from infected cells, comprehension of the mechanisms implicated in cccDNA biogenesis, regulation and stability appears necessary to achieve HBV eradication. In this review, we will summarize the state of knowledge on cccDNA metabolism, focusing on insights suggesting potential weak points of the cccDNA that may be key for the development of therapeutic approaches and design of clinical trials aiming at lowering cccDNA loads and activity.
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Affiliation(s)
- Maura Dandri
- Department of Internal Medicine, University Medical Center Hamburg - Eppendorf, Hamburg, Germany.,German Center for Infection Research (DZIF), Hamburg-Luebeck-Borstel-Riems Site, Germany
| | - Joerg Petersen
- Institute for Interdisciplinary Medicine, Asklepios Klinik St Georg, University of Hamburg, Hamburg, Germany
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Mo S, Gu L, Xu W, Liu J, Ding D, Wang Z, Yang J, Kong L, Zhao Y. Bifunctional macromolecule activating both OX40 and interferon-α signaling displays potent therapeutic effects in mouse HBV and tumor models. Int Immunopharmacol 2020; 89:107099. [PMID: 33091819 DOI: 10.1016/j.intimp.2020.107099] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 10/10/2020] [Accepted: 10/10/2020] [Indexed: 11/16/2022]
Abstract
Combinatory enhancement of innate and adaptive immune responses is a promising strategy in immunotherapeutic drug development. Bifunctional macromolecules that simultaneously target two mechanisms may provide additional advantages over the combination of targeting two single pathways. Interferon alpha (IFNα) has been used clinically against viral infection such as the chronic infection of hepatitis B virus (CHB) as well as some types of cancers. OX40 is a costimulatory immune checkpoint molecule involved in the activation of T lymphocytes. To test whether simultaneously activating IFNα and OX40 signaling pathway could produce a synergistic therapeutic effect on CHB and tumors, we designed a bifunctional fusion protein composed of a mouse OX40 agonistic monoclonal antibody (OX86) and a mouse IFNα4, joined by a flexible (GGGGS)3 linker. This fusion protein, termed OX86-IFN, can activate both IFNα and OX40. We demonstrated that OX86-IFN could effectively activate T lymphocytes in the peripheral blood of mice. Furthermore, we showed that OX86-IFN had superior therapeutic effect to monotherapies in HBV hydrodynamic transfection and syngeneic tumor models. Collectively, our data suggests that simultaneously targeting interferon and OX40 signaling pathways by bifunctional molecule OX86-IFN elicits potent antiviral and antitumor activities, which could provide a new strategy in developing therapeutic agents against viral infection and tumors.
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Affiliation(s)
- Shifu Mo
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu 210023, PR China; Nanjing U-Mab Biopharma Co., Ltd, 699-8 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China
| | - Liyun Gu
- Nanjing U-Mab Biopharma Co., Ltd, 699-8 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China
| | - Wei Xu
- Nanjing U-Mab Biopharma Co., Ltd, 699-8 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Dong Ding
- Nanjing U-Mab Biopharma Co., Ltd, 699-8 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China
| | - Zhichao Wang
- Nanjing U-Mab Biopharma Co., Ltd, 699-8 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China
| | - Jie Yang
- Nanjing U-Mab Biopharma Co., Ltd, 699-8 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China
| | - Lingdong Kong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu 210023, PR China.
| | - Yong Zhao
- Nanjing U-Mab Biopharma Co., Ltd, 699-8 Xuanwu Avenue, Nanjing, Jiangsu 210042, PR China.
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Fonseca MA, Ling JZJ, Al-Siyabi O, Co-Tanko V, Chan E, Lim SG. The efficacy of hepatitis B treatments in achieving HBsAg seroclearance: A systematic review and meta-analysis. J Viral Hepat 2020; 27:650-662. [PMID: 32170983 DOI: 10.1111/jvh.13283] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 11/20/2019] [Accepted: 01/13/2020] [Indexed: 02/06/2023]
Abstract
Current therapies for chronic hepatitis B (CHB) include nucleos(t)ide analogues (NAs) and interferon (IFN), but their relative efficacy as monotherapy or in combination has not been examined systematically for HBsAg loss (functional cure). Hence, we systematically reviewed the evidence for HBsAg loss in CHB patients treated with IFN, NA or the combination. We searched PubMed, EMBASE and abstracts from EASL, Asia Pacific Association for study of the Liver and American Association for the Study of Liver Disease for randomized controlled trials of CHB patients, comparing NA, IFN or the combination. The Cochrane Risk of Bias tool v2.0 and GRADE method were used. Analyses were stratified by NA genetic barrier, cirrhosis, type of combination therapy, HBeAg, treatment naivety, IFN dosage/duration and outcome duration. Sensitivity analysis was performed for selected strata, and HBsAg loss was measured at the end-of-study (EOS), end-of-treatment (EOT) or end-of-follow-up (EOF). Effects were reported as risk differences (RD) with 95% confidence intervals (CI) using a random-effects model. Forty-five studies were included, all with low risk of bias. For HBsAg loss at EOS, when comparing combination vs IFN, RD = 1%, 95%CI-1%, 2%; combination vs NA, RD = 5%, 95%CI 3%,7%; IFN vs NA, RD = 3%, 95%CI 2%,5%. Subgroup analysis showed a significant effect of standard IFN dose vs nonstandard; IFN duration ≥48 weeks vs <48 weeks, and loss of efficacy >2 years of follow-up. Similar findings were seen in HBsAg seroconversion, but only three studies reported HBsAg seroreversion. In conclusion, IFN monotherapy/combination had a small but significant increase in HBsAg loss over NA, associated with standard dose of IFN and ≥48 weeks of therapy, although this effect faded over time.
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Affiliation(s)
- Mariana Alves Fonseca
- Hospital DivinaProvidência, Porto Alegre, Brazil.,Hospital Moinhos de Vento, Porto Alegre, Brazil
| | - Joanna Zhi Jie Ling
- Royal Melbourne Institute of Technology, Melbourne, Vic., Australia.,Singapore Clinical Research Institute, Singapore City, Singapore
| | - Omar Al-Siyabi
- Division of Gastroenterology and Hepatology, Department of Medicine, Royal Hospital, Oman Muscat, Oman
| | - Vanessa Co-Tanko
- Division of Gastroenterology and Hepatology, Department of Medicine, UP-Philippine General Hospital, Manila, Philippines
| | - Edwin Chan
- Singapore Clinical Research Institute, Singapore City, Singapore.,Duke-NUS Medical School, Singapore City, Singapore
| | - Seng Gee Lim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore City, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore
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Chen MB, Wang H, Zheng QH, Cui WY, Xu HL, Zheng XW. Comparative efficacy of the front-line anti-HBV drugs in nucleos(t)ide analogue-naive chronic hepatitis B: A protocol for systematic review and network meta-analysis. Medicine (Baltimore) 2020; 99:e20160. [PMID: 32384507 PMCID: PMC7220057 DOI: 10.1097/md.0000000000020160] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND: During the COVID-19 period, there was a huge gap in the understanding of masks between east and west. At the same time, the mechanism of the mask and the effect after use, also appeared differences. The Objective of this Meta-analysis is to systematically evaluate the efficacy of masks for influenza in the community. METHODS: The Web of Science, PubMed, The Cochrane Library, EMBASE and Clinical Trials will be electronically searched to collect randomized controlled trials regarding the efficacy of masks for influenza in the community through Apr 2020. Two researchers independently screened and evaluated the obtained studies and extracted the outcome indexes. Revman 5.3 software will be used for the meta-analysis. RESULTS: The outbreak is continuing, and we need to be prepared for a long fight. If masks are effective, we need to promote their use as soon as possible. If masks are ineffective, strong evidence should be given. This is an urgent task and our team will finish it as soon as possible. CONCLUSION: Provide stronger evidence to solve the problem, should we wear masks or not right now.
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Affiliation(s)
| | - Hua Wang
- Department of ICU, Wujin People Hospital Affiliated with Jiangsu University and Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, PR China
| | | | - Wei-yan Cui
- Department of ICU, Wujin People Hospital Affiliated with Jiangsu University and Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, PR China
| | - Hua-lan Xu
- Department of ICU, Wujin People Hospital Affiliated with Jiangsu University and Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, PR China
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35
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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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Păcurar D, Dijmărescu I, Dijmărescu A, Pavelescu M, Andronie M, Becheanu C. Autoimmune phenomena in treated and naive pediatric patients with chronic viral hepatitis. Exp Ther Med 2019; 18:5101-5104. [PMID: 31819772 PMCID: PMC6895782 DOI: 10.3892/etm.2019.8144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 10/07/2019] [Indexed: 12/16/2022] Open
Abstract
Chronic viral hepatitis has been incriminated for inducing autoimmune events, but it is a known fact that interferon-based therapies also promote autoimmunity. We conducted an observational prospective study which included 114 pediatric patients with chronic viral hepatitis B and C. The patients were divided in 2 groups, the first group consisted of treatment-naive patients; the second group included patients who had received interferon-based therapy. We aimed to determine whether the ones who received treatment are more predisposed to developing autoimmune manifestations when compared to those naive. Fifty percent of the study group was found to have serological autoimmune phenomenon. Our research shows that the occurrence of the autoimmune phenomenon is delayed when the patient is treated with interferon-based regimens when compared to naive patients. Hence, even though interferon treatment has been reported to promote autoimmunity, the viruses themselves are more likely to induce the appearance of autoimmune markers over time in patients who do not receive treatment.
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Affiliation(s)
- Daniela Păcurar
- Department of Pediatrics, 'Grigore Alexandrescu' Emergency Children's Hospital, 011743 Bucharest, Romania.,Department of Pediatrics, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Irina Dijmărescu
- Department of Pediatrics, 'Grigore Alexandrescu' Emergency Children's Hospital, 011743 Bucharest, Romania.,Department of Pediatrics, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Adrian Dijmărescu
- Department of Radiology, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania.,Department of Radiology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Mirela Pavelescu
- Department of Pediatrics, 'Grigore Alexandrescu' Emergency Children's Hospital, 011743 Bucharest, Romania.,Department of Pediatrics, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Mihai Andronie
- Department of Economic Sciences, Faculty of Economic Sciences, Spiru Haret University, 030045 Bucharest, Romania
| | - Cristina Becheanu
- Department of Pediatrics, 'Grigore Alexandrescu' Emergency Children's Hospital, 011743 Bucharest, Romania.,Department of Pediatrics, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
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Xiong F, Bao X, Gu N, Guo J, Wang J, Ma Y, Yu L, Gao Y, Tan B, Lu J. The combination therapy of Peginterferonα and entecavir for HBeAg-positive chronic hepatitis B with high HCC risk. INFECTION GENETICS AND EVOLUTION 2019; 78:104101. [PMID: 31689542 DOI: 10.1016/j.meegid.2019.104101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 10/27/2019] [Accepted: 10/30/2019] [Indexed: 02/06/2023]
Abstract
The population of HBV infection with family history of hepatocellular carcinoma (HCC) is the high risk group for the development of HCC. The aim of this study was to evaluate the effect of the de novo combination therapy including pegylated-interferon α-2a (PEG-IFNα-2a) and entecavir (ETV) in this high risk population. The study recruited 58 Hepatitis B e Antigen (HBeAg)-Positive CHB patients patients with HBV-DNA > 107 IU/mL, genotype B or C and HCC family history and were treated for 48 weeks. Patients without HBeAg loss at the 48th week were 40 patients and extended the combination therapy to 96 weeks. All patients were followed up to 120 weeks. The rate of HBeAg loss and HBsAg loss was 12/40(30.0%) and 2/40(5.0%) at week 120 respectively. When logistic regression analysis was used to identify viables of HBeAg loss, HBV-DNA levels <20 IU/mL at week 48 was found to have a 6.02 fold increased probability (95% CI = 1.17-30.40, P = .03) of HBeAg loss. Patients with HBV-DNA levels <20 IU/mL at week 48 had a high probability of HBeAg loss 8/17(47.1%), HBsAg loss 2/17(11.8%), compared to 4/23(17.4%), 0/23(0%) in patients with HBV-DNA ≥ 20 IU/mL. Combination therapy for 96 weeks was well tolerated. During the combination therapy, low-level viremia during treatment is reversely associated with response. The combination therapy of PEG-IFNα and ETV was suggested to extend to 96 weeks when HBV-DNA was completed suppressed at week 48.
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Affiliation(s)
- Fang Xiong
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Xuli Bao
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Na Gu
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Jia Guo
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Jinhuan Wang
- International Medical Department, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Yanpin Ma
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Lele Yu
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Yao Gao
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Bingqin Tan
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Jun Lu
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
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Chen Q, Zhang J, Huang J, Quan B, Wu X, Deng S, Han W. Early Serum HBsAg Drop Is a Strong Predictor of HBeAg Seroconversion and HBsAg Loss to Pegylated Interferon Alfa-2a in Chronic Hepatitis B Patients with Prior Nucleos(t)ide Analogue Exposure. Med Sci Monit 2019; 25:4665-4674. [PMID: 31230063 PMCID: PMC6604672 DOI: 10.12659/msm.916441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background High rates of HBeAg and/or HBsAg seroconversion or clearance have been achieved in chronic hepatitis B (CHB) patients receiving pegylated interferon (pegIFN) in addition to ongoing nucleos(t)ide analogue (NUC) treatment. In the present study, we aimed to evaluate HBsAg kinetics to predict HBeAg seroconversion and HBsAg clearance in these patients. Material/Methods A total of 33 HBeAg-positive and 17 HBeAg-negative patients were enrolled between January 2010 and January 2018. At the end of pegIFN treatment, 9 of 50 patients achieved HBsAg clearance, and 9 of 33 HBeAg-positive patients achieved HBeAg seroconversion. Results The cutoff value of 0.41 log10 IU/mL in HBsAg decline at week 12 had a positive predictive value (PPV) of 58.3% and a negative predictive value (NPV) of 94.6% for HBsAg clearance. The cutoff value of 1.94 log10 IU/mL in HBsAg decline at week 24 had a PPV of 80.0% and an NPV of 97.5% for HBsAg clearance. The cutoff value of 0.47 log10 IU/mL in HBsAg decline at week 12 had a PPV of 83.3% and an NPV of 85.2% for HBeAg seroconversion. The cutoff value of 1.29 log10 IU/mL in in HBsAg decline at week 24 had a PPV of 85.7% and an NPV of 88.5% for HBeAg seroconversion. Conclusions Early HBsAg drop has a high predictive value for HBsAg clearance and HBeAg seroconversion in patients who were treated with combination therapy of pegIFN and NUCs.
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Affiliation(s)
- Qing Chen
- Department of Nuclear Medicine, The First Affiliated Hospital of Wanan Medical College, Wuhu, Anhui, China (mainland)
| | - Jun Zhang
- Clinical Blood Laboratory, The First Affiliated Hospital of Wanan Medical College, Wuhu, Anhui, China (mainland)
| | - Jianjun Huang
- Clinical Laboratory, The First Affiliated Hospital of Wanan Medical College, Wuhu, Anhui, China (mainland)
| | - Bin Quan
- Department of Infectious Diseases, The First Affiliated Hospital of Wanan Medical College, Wuhu, Anhui, China (mainland)
| | - Xiaoxin Wu
- State Key Laboratory for Infectious Diseases Diagnosis and Treatment, Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China (mainland)
| | - Shengming Deng
- Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China (mainland)
| | - Wenzheng Han
- Clinical Laboratory, The First Affiliated Hospital of Wanan Medical College, Wuhu, Anhui, China (mainland)
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2019; 25:93-159. [PMID: 31185710 PMCID: PMC6589848 DOI: 10.3350/cmh.2019.1002] [Citation(s) in RCA: 161] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
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Leoni MC, Ustianowski A, Farooq H, Arends JE. HIV, HCV and HBV: A Review of Parallels and Differences. Infect Dis Ther 2018; 7:407-419. [PMID: 30182282 PMCID: PMC6249183 DOI: 10.1007/s40121-018-0210-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Indexed: 02/06/2023] Open
Abstract
Elimination of the three blood-borne viruses-human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV)-as public health issues may be plausible in the near future. Spectacular advances have been made with the introduction of highly effective antiviral agents into clinical practice, and prevention strategies are available for all three infections. Effective disease control, laid out by WHO global strategies, is currently feasible for all three viruses. However, for worldwide elimination of these viruses, effective vaccines are required that are currently only available for HBV. In this review differences and parallels among HIV, HCV and HBV will be discussed with a focus on virologic and therapeutic issues, and prospects for the future of HBV will be presented.
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Affiliation(s)
- Maria C Leoni
- Department of Internal Medicine, Section Infectious Diseases, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
- Infectious Diseases Department, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
| | - Andrew Ustianowski
- Regional Infectious Diseases Unit, North Manchester General Hospital, Manchester, UK
- School of Medical Sciences, University of Manchester, Manchester, UK
| | - Hamzah Farooq
- Regional Infectious Diseases Unit, North Manchester General Hospital, Manchester, UK
| | - Joop E Arends
- Department of Internal Medicine, Section Infectious Diseases, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands.
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Increased CCR7 loPD-1 hiCXCR5 +CD4 + T Cells in Peripheral Blood Mononuclear Cells Are Correlated with Immune Activation in Patients with Chronic HBV Infection. Can J Gastroenterol Hepatol 2018; 2018:1020925. [PMID: 30402448 PMCID: PMC6196997 DOI: 10.1155/2018/1020925] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 07/06/2018] [Accepted: 09/30/2018] [Indexed: 02/07/2023] Open
Abstract
T follicular helper cells (Tfh cells) affect essential immune pathogenesis in chronic hepatitis B virus (HBV) infection. The CCR7loPD-1hi Tfh subset has a partial Tfh effector phenotype and is associated with active Tfh differentiation, whereas the CCR7hiPD-1lo Tfh subset is a resting phenotype. We recruited 20 healthy volunteers and 77 patients with chronic HBV infection, including those in the immune tolerant (IT) phase (n=19), immune clearance (IC) phase (n=20), low replicative (LR) phase (n=18), and reactivation (RA) phase (n=20). The expression of CD4, CXCR5, PD-1, and CCR7 was detected in T cells from peripheral blood by flow cytometry. The frequency of the CCR7loPD-1hi T subset was significantly higher in the patients than in the healthy controls (14.92±4.87% vs 12.23±2.95%, p=0.018). The frequency of this Tfh subset in the IC group (18.42%±3.08) was increased compared with the IT group (11.94±2.87%, p=0.001) and LR group (13.65±4.93%, p=0.031) and was higher in the RA group than in the IT group (16.03±5.37% vs 11.94±2.87%, p=0.030). We observed a weak positive correlation between the CCR7loPD-1hi Tfh subset population and the alanine transaminase (ALT) level (r=0.370, p=0.001). The CCR7loPD-1h Tfh subset in the chronic HBV-infected patients was elevated to various degrees among the different immune phases. CCR7loPD-1hiCXCR5+CD4+ T cells are correlated with the immune status of chronic HBV infection patients and may be developed as a potential indicator for antiviral treatment.
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