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Xie Y, Li M, Ou X, Zheng S, Gao Y, Xu X, Yang Y, Ma A, Li J, Nan Y, Zheng H, Liu J, Wei L, Feng B. IP10 and Anti-HBc can Predict Virological Relapse and HBsAg Loss in Chronic Hepatitis B Patients after Nucleos(t)ide Analog Discontinuation. Dig Dis 2023; 41:922-931. [PMID: 37586356 DOI: 10.1159/000533515] [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: 02/14/2023] [Accepted: 07/27/2023] [Indexed: 08/18/2023]
Abstract
INTRODUCTION To assess predictive ability of serum interferon-inducible protein 10 (IP10) and hepatitis B core antibody (anti-HBc) levels for virological relapse (VR) and hepatitis B surface antigen (HBsAg) loss after nucleos(t)ide analog (NA) discontinuation. METHODS In this multicenter prospective study, overall 139 patients were followed up for 24 months after NA discontinuation. RESULTS End of treatment (EOT) IP10 and anti-HBc were 29.2 (5.1-66.4) pg/mL and 193.6 (136.9-221.4) IU/mL. EOT IP10 and anti-HBc were independent predictors for VR and HBsAg loss in Cox regression analysis. Cumulative rates of VR in patients with EOT IP10 > 26.99 pg/mL was 31.9% (vs. 70.1%, hazard ratio [HR] 2.998, p < 0.001). Cumulative incidences of VR in patients with EOT anti-HBc ≤141.35 IU/mL was 49.1% (vs. 60.6%, HR 2.99, p < 0.001). Cumulative probabilities of VR was 16.7% in patients with EOT IP10 > 26.99 pg/mL plus anti-HBc ≤141.35 IU/mL (vs. 73.6%, HR 6.464, p < 0.001). Cumulative probabilities of HBsAg loss in patients with EOT IP10 > 93.5 pg/mL was 46.2% (vs. 4.7%, HR 10.94, p < 0.001). Cumulative probabilities of HBsAg loss in patients with EOT anti-HBc ≤78.42 IU/mL were 47.1% (vs. 5%, HR 12.27, p < 0.001). Patients with EOT IP10 > 93.5 pg/mL plus anti-HBc ≤78.42 IU/mL had the highest 24-month cumulative HBsAg loss rate (53.8% vs. 4%, HR 16.83, p < 0.001). CONCLUSION High EOT IP10 and low EOT anti-HBc levels were related to both lower risk of VR and higher probability of HBsAg loss.
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Affiliation(s)
- Yandi Xie
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China,
| | - Minghui Li
- Department of Hepatology Division, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Sujun Zheng
- Complicated Liver Diseases and Artificial Liver Treatment and Training Center, Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment and Research, Beijing Youan Hospital, Capital Medical University Beijing, Beijing, China
| | - Yinjie Gao
- Department of Infectious Diseases, The Fifth Medical Center, General Hospital of PLA, Beijing, China
| | - Xiaoyuan Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Ying Yang
- Department of Infectious Diseases, The Second Hospital of Xingtai, Xingtai, China
| | - Anlin Ma
- Department of Infectious Disease, China-Japan Friendship Hospital, Beijing, China
| | - Jia Li
- Department of Liver Disease, Tianjin Second People's Hospital, Tianjin, China
| | - Yuemin Nan
- Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Huanwei Zheng
- Department of Liver Disease, Shijiazhuang Fifth Hospital, Shijiazhuang, China
| | - Juan Liu
- Research Center for Technologies in Nucleic Acid-Based Diagnostics, Changsha, China
| | - Lai Wei
- Department of Hepatopancreatobiliary Disease, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Bo Feng
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
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Abstract
Chronic hepatitis B virus (HBV) infection remains a global health burden. Timely and effective antiviral therapy is beneficial for patients with HBV infection. With existing antiviral drugs, including nucleos(t)ide analogs and interferon-alfa, patients can achieve viral suppression with improved prognosis. However, the rate of hepatitis B surface antigen loss is low. To achieve a functional cure and even complete cure in chronic hepatitis B patients, new antivirals need to be developed. In this review, we summarized the advantages and disadvantages of existing antiviral drugs and focused on new antivirals including direct-acting antiviral drugs and immunotherapeutic approaches.
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Almeida PH, Matielo CEL, Curvelo LA, Rocco RA, Felga G, Della Guardia B, Boteon YL. Update on the management and treatment of viral hepatitis. World J Gastroenterol 2021; 27:3249-3261. [PMID: 34163109 PMCID: PMC8218370 DOI: 10.3748/wjg.v27.i23.3249] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/11/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
This review aims to summarize the current evidence on the treatment of viral hepatitis, focusing on its clinical management. Also, future treatment options and areas of potential research interest are detailed. PubMed and Scopus databases were searched for primary studies published within the last ten years. Keywords included hepatitis A virus, hepatitis B virus (HBV), hepatitis C virus, hepatitis D virus (HDV), hepatitis E virus, and treatment. Outcomes reported in the studies were summarized, tabulated, and synthesized. Significant advances in viral hepatitis treatment were accomplished, such as the advent of curative therapies for hepatitis C and the development and improvement of hepatitis A, hepatitis B, and hepatitis E vaccination. Drugs that cure hepatitis B, going beyond viral suppression, are so far unavailable; however, targeted antiviral drugs against HBV (immunomodulatory therapies and gene silencing technologies) are promising approaches to eradicating the virus. Ultimately, high vaccination coverage and large-scale test-and-treat programmes with high screening rates may eliminate viral hepatitis and mitigate their burden on health systems. The development of curative hepatitis C treatment renewed the enthusiasm for curing hepatitis B, albeit further investigation is required. Novel therapeutic options targeting HDV life cycle are currently under clinical investigation.
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Affiliation(s)
| | - Celso E L Matielo
- Liver Unit, Hospital Israelita Albert Einstein, São Paulo 05652-900, Brazil
| | - Lilian A Curvelo
- Liver Unit, Hospital Israelita Albert Einstein, São Paulo 05652-900, Brazil
| | - Rodrigo A Rocco
- Liver Unit, Hospital Israelita Albert Einstein, São Paulo 05652-900, Brazil
| | - Guilherme Felga
- Liver Unit, Hospital Israelita Albert Einstein, São Paulo 05652-900, Brazil
| | | | - Yuri L Boteon
- Liver Unit, Hospital Israelita Albert Einstein, São Paulo 05652-900, Brazil
- Instituto Israelita de Ensino e Pesquisa Albert Einstein, Faculdade Israelita de Ciências da Saúde Albert Einstein, São Paulo 05652-900, Brazil
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Ning Q, Wu D, Wang GQ, Ren H, Gao ZL, Hu P, Han MF, Wang Y, Zhang WH, Lu FM, Wang FS. Roadmap to functional cure of chronic hepatitis B: An expert consensus. J Viral Hepat 2019; 26:1146-1155. [PMID: 31087479 DOI: 10.1111/jvh.13126] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 04/25/2019] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) infection continues to be a major public health issue worldwide. HBsAg loss is associated with functional remission and improved long-term outcome, and is considered to be a 'functional cure' (also referred to as clinical or immunologic cure) for chronic hepatitis B. This ideal goal of therapy can be achieved using optimized combination regimens with direct-acting antivirals [eg nucleos(t)ide analogues (NAs)] and immunomodulators [eg pegylated interferon alpha2a (Peg-IFN)] in selected patients with chronic hepatitis B. Among different combination therapies currently available, those with NA lead-in followed by Peg-IFN in virally suppressed patients has been demonstrated to be effective. This review provides an updated overview of the evidence supporting the use of combination therapies and summarizes expert consensus on the roadmap to attain functional cure for chronic hepatitis B patients.
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Affiliation(s)
- Qin Ning
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Di Wu
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gui-Qiang Wang
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing, China
| | - Hong Ren
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhi-Liang Gao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Peng Hu
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mei-Fang Han
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Wang
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing, China
| | - Wen-Hong Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Feng-Min Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Fu-Sheng Wang
- Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of the General Hospital of PLA, Beijing, China
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Antiviral Therapy for AECHB and Severe Hepatitis B (Liver Failure). ACUTE EXACERBATION OF CHRONIC HEPATITIS B 2019. [PMCID: PMC7498919 DOI: 10.1007/978-94-024-1603-9_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This chapter describes the principles of antiviral therapy, treatment strategies, medications and recommendations for AECHB, HBV-ACLF, HBV-related liver cirrhosis, HBV-related HCC, and liver transplantation.
Severe exacerbation of chronic hepatitis B is closely related to continuous HBV replication. Therefore, inhibiting HBV replication to reduce viral load may block disease progression and improve the quality of life of these patients. ETV or TDF has been recommend first-line drug for the treatment of AECHB. A hyperactive immune response due to continuous HBV replication is the main mechanism for development of severe hepatitis B. In addition to comprehensive treatment, early administration of potent nucleoside analogs can rapidly reduce HBV DNA concentration, relieve immune injury induced by HBV, and reduce liver inflammation and patient mortality. Antiviral agents have become important in the treatment of severe exacerbation of chronic hepatitis B. Long-term antiviral treatment with nucleoside analogs can delay or reverse the progress of liver cirrhosis. Virologic response, viral resistance and adverse drug reactions should be closely monitored during treatment. The treatment should be optimized for maximum effect based on each patient’s responses. Effective antiviral therapy can suppress HBV replication and reduce the incidence of HBV-related HCC. Patients with HBV-related HCC should receive individualized and optimal multidisciplinary comprehensive treatment. Anti-viral drugs with high efficacy, low resistance and low adverse drug reactions should be selected to improve the patient’s quality of life and prolong survival time. Methods to prevent HBV reinfection after liver transplantation include passive immunization (HBIG), antiviral treatment (nucleoside analogs) and active immunization (hepatitis B vaccine). Clinical trials involving sequential combination therapy with NUC and Peg-IFN have shown statistically significant decline in HBsAg levels on treatment and high rates of sustained post-treatment serologic response. Combination therapy with novel DAA and immunotherapeutic approach may hold promise to overcome both cccDNA persistence and immune escape, representing a critical step towards HBV cure.
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Kao JH. Hepatitis B: From control to cure. J Formos Med Assoc 2018; 117:868-870. [DOI: 10.1016/j.jfma.2018.08.020] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Accepted: 08/23/2018] [Indexed: 02/07/2023] Open
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Zhang X, Wang J, Lu J, Li R, Zhao S. Immunogenicity of adenovirus-vector vaccine targeting hepatitis B virus: non-clinical safety assessment in non-human primates. Virol J 2018; 15:111. [PMID: 30041659 PMCID: PMC6056916 DOI: 10.1186/s12985-018-1026-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 07/16/2018] [Indexed: 12/19/2022] Open
Abstract
Background A new promising therapeutic approach has emerged for patients chronically infected by the hepatitis B virus (HBV) with the development of a non-replicative adenovirus vector vaccine candidate (Ad-HBV). The vaccine encodes a fusion protein composed of a truncated HBV core protein, mutated polymerase protein, and two envelope domains. In this study, we assessed the immunogenicity of Ad-HBV administered to cynomolgus monkeys during a non-clinical safety assessment. Methods The virus was subcutaneously administered at 1.0 × 109 viral particles (VP)/animal (low-dose group), 1.0 × 1010 VP/animal (mid-dose group), and 1.0 × 1011 VP/animal (high-dose group); the control groups were administered an Ad5-null virus (1.0 × 1011 VP/animal) and saline only. Results Except for inflammatory cell infiltration under the skin at the injection sites and transient elevation of body temperature and serum albumin, no Ad-HBV-related toxic effects were noted in any treatment group. Moreover, interferon (IFN)-γ enzyme-linked immunospot assays showed that Ad-HBV induced the targeting of T cells to a broad spectrum of HBV-specific epitopes spanning all three of the selected HBV immunogens (core, polymerase, and envelope domains) in a dose-dependent manner. Although anti-Ad antibody was produced in all groups (except for the saline control), the antibody titers were significantly lower in the high-dose Ad-HBV group than in the group that received the same dose of the Ad-null empty vector. In addition, the IFN-γ and IL-2 expression levels in the liver were significantly improved for the mid-dose, high-dose, and Ad-null control group (p < 0.05), but not for the low-dose group. Conclusions Taken together, this safety assessment indicates that the Ad-HBV candidate vaccine is a potent specific immunotherapeutic agent, supporting its further clinical development as an anti-HBV infection vaccine. Electronic supplementary material The online version of this article (10.1186/s12985-018-1026-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xuefeng Zhang
- Jiangsu Tripod Preclinical Research Laboratories Co., Ltd., Nanjing, 211800, China
| | - Jing Wang
- Jiangsu Tripod Preclinical Research Laboratories Co., Ltd., Nanjing, 211800, China
| | - Jing Lu
- Jiangsu Tripod Preclinical Research Laboratories Co., Ltd., Nanjing, 211800, China
| | - Rongrong Li
- Jiangsu Tripod Preclinical Research Laboratories Co., Ltd., Nanjing, 211800, China
| | - Shuli Zhao
- Jiangsu Tripod Preclinical Research Laboratories Co., Ltd., Nanjing, 211800, China. .,Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China.
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Chulanov VP, Zueva AP, Kostyushev DS, Brezgin SA, Volchkova EV, Maleyev VV. [Hepatitis C can be cured: will hepatitis B become next?]. TERAPEVT ARKH 2018; 89:4-13. [PMID: 29260740 DOI: 10.17116/terarkh201789114-13] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Chronic hepatitis B (CHB) and C (CHC) are one of the leading causes of cirrhosis and liver cancer with over a million of people dying annually from their consequences. In Russia CHB and CHC morbidity and related mortality show an upward trend. As a result of recent breakthroughs in antiviral therapeutics CHC became a curable disease. Modern therapeutics effectively suppress viral replication in CHB patients, but withdrawal of antivirals usually results in disease relapse. Loss of HBsAg required for the so called 'functional cure' is a very rare event. Moreover, 'complete cure' when the virus is entirely eliminated from the body is not possible due to a persistent form of covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) in hepatocytes refractory to modern antivirals. Today, there is a plethora of new promising medications being at different stages of development that target different steps of viral life cycle, including inhibitors of interaction between HBV and its entry receptor NTCP, inhibitors of HBV cccDNA, inhibitors of nucleocapsid assembly, technologies of genome editing (TALENs, CRISPR/Cas etc) and RNA-interference. In addition to direct acting antivirals, there is a number of approaches aimed at enhancement of the innate and adaptive immune responses. In experimental conditions, some of these approaches or their combinations help to achieve functional cure. However, complete elimination of the virus is possible only using technologies of genome editing, capable of specific cccDNA degradation. Nuclease systems are currently at their early stages of development, and there is a long way to prove their efficacy and safety. Nevertheless, highly promising results of the recent years leave no doubt that CRISPR/Cas systems and similar technologies can become the basis of CHB therapy.
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Affiliation(s)
- V P Chulanov
- Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russia; I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russian Federation, Moscow, Russia
| | - A P Zueva
- Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russia; M.V. Lomonosov Moscow State University, Moscow, Russia
| | - D S Kostyushev
- Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russia
| | - S A Brezgin
- Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russia
| | - E V Volchkova
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russian Federation, Moscow, Russia
| | - V V Maleyev
- Central Research Institute of Epidemiology of Rospotrebnadzor, Moscow, Russia
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Tseng CH, Hsu YC, Chang CY, Tseng TC, Wu MS, Lin JT, Kao JH. Quantification of serum hepatitis B core antibody to predict off-entecavir relapse in patients with chronic hepatitis B. J Formos Med Assoc 2017; 117:915-921. [PMID: 29249417 DOI: 10.1016/j.jfma.2017.11.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 10/21/2017] [Accepted: 11/23/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/PURPOSE The predictors of off-therapy response in patients treated with neucleos(t)ide analogue (NA) have not been elucidated. It remained unexplored whether serum level of hepatitis B core antibody (anti-HBc) at the end of NA therapy was associated with relapse risks. METHODS This prospective study monitored 82 chronic hepatitis B (CHB) patients after discontinuing entecavir. All patients had been treated for 3 years or longer and serologically negative for viral DNA and HBeAg at treatment cessation. Patients were monitored for virological relapse (viral DNA > 2000 IU/mL), and clinical relapse (serum alanine aminotransferase > 80 U/L plus virological relapse). The association between anti-HBc levels and the risk of relapse was assessed by the Cox analysis. RESULTS Clinical and virological relapses occurred in 29 and 60 participants, respectively, with the cumulative incidences of 23.7% (95% CI, 15.8-34.6%) and 62.0% (95% CI, 51.5-72.5%) at 1 year, and 36.2% (95% CI, 26.2-48.4%) and 78.8% (95% CI, 68.2-87.8%) at 2 years, respectively. There was a trend for an inverse association between anti-HBc and clinical relapse (crude hazard ratio [HR], 0.50; 95% CI, 0.24-1.05). All 3 patients with the level <100 IU/mL had a rapid clinical relapse (P = 0.002). This trend remained after adjustment for HBsAg and age (adjusted HR 0.50, 95% CI, 0.24-1.03). On the other hand, anti-HBc quantity was unrelated to virological relapse (crude HR, 0.97; 95% CI, 0.58-1.62; adjusted HR, 0.97; 95% CI, 0.58-1.60). CONCLUSION This pilot study suggests a trend for an inverse association between anti-HBc levels and clinical relapse in CHB patients off entecavir.
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Affiliation(s)
- Cheng-Hao Tseng
- Division of Gastroenterology and Hepatology, E-DA Cancer Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan; School of Medicine and Big Data Research Center, Fu-Jen Catholic University, New Taipei, Taiwan; Graduate Institute of Clinical Medicine, China Medical University, Taichung, Taiwan
| | - Chi-Yang Chang
- Division of Gastroenterology and Hepatology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan; School of Medicine and Big Data Research Center, Fu-Jen Catholic University, New Taipei, Taiwan
| | - Tai-Chung Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Ming-Shiang Wu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Jaw-Town Lin
- Division of Gastroenterology and Hepatology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan; School of Medicine and Big Data Research Center, Fu-Jen Catholic University, New Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.
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Su TH, Kao JH. Unmet Needs in Clinical and Basic Hepatitis B Virus Research. J Infect Dis 2017; 216:S750-S756. [PMID: 29156048 DOI: 10.1093/infdis/jix382] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Chronic hepatitis B (CHB) has become a treatable and controllable disease. The current nucleos(t)ide analogue (NUC) and pegylated interferon therapies effectively help slow disease progression and reduce the risk of cirrhosis, hepatocellular carcinoma (HCC), and CHB-associated mortality. Long-term viral suppression is easily achievable by NUC therapy, with limited adverse reactions. However, several unmet requirements still exist, including safety and risk-stratified HCC surveillance among patients who received long-term NUC therapy. Criteria for determining which patients should receive finite-duration NUC therapy and which should receive combination therapy with both NUC and pegylated interferon remain unsettled. The management of hepatitis B virus (HBV) e antigen-positive viremic patients with normal liver function and the incorporation of new biomarkers to help manage CHB require further exploration. To achieve functional cure (ie, HBV surface antigen seroclearance) and complete cure (ie, eradication of covalently closed circular DNA) of CHB, several challenges in basic research must be addressed, including the development of an efficient cell culture system and animal models for HBV investigation, development of treatment to eradicate covalently closed circular HBV DNA, and development of immunotherapy for CHB. This brief review focuses on unmet needs in both clinical and basic HBV research.
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Affiliation(s)
- Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine.,Hepatitis Research Center
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine.,Hepatitis Research Center.,Department of Medical Research, National Taiwan University Hospital.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei
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Wu D, Ning Q. Toward a Cure for Hepatitis B Virus Infection: Combination Therapy Involving Viral Suppression and Immune Modulation and Long-term Outcome. J Infect Dis 2017; 216:S771-S777. [PMID: 29156046 DOI: 10.1093/infdis/jix355] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains a major global health burden. Currently, the approved therapeutic regimens include nucleos(t)ide analogues (NAs) and either interferon or pegylated interferon. NA therapy is generally safe and well tolerated, but the rate of posttreatment virologic relapse is high, making NA treatment a lifetime commitment. The benefits of pegylated interferon treatment include a finite duration, more-durable response and absence of viral resistance. However, sustained response to interferon alone is achieved only in a minority of patients, and side effects are common, which limit its clinical use. Given that HBV covalently closed circular DNA and the integrated HBV genome persist stably in the nuclei of infected hepatocytes, elimination (complete cure) of HBV is rarely achieved. After completion of treatment, sustained HBV surface antigen loss, with or without seroconversion to HBV surface antibody positivity (ie, functional cure), is therefore recommended as the ideal end point for anti-HBV treatment, despite the lack of complete eradication of HBV. Theoretically, combination of antiviral agents with differential mechanisms of actions on HBV, including viral suppression combined with immune modulation (as occurs during treatment with NA plus pegylated interferon), is an encouraging strategy to treat chronic hepatitis B. Recent studies have confirmed certain virological and serological advantages of simultaneous administration of NA and pegylated interferon (de novo combination therapy) or addition of pegylated interferon to ongoing NA therapy (sequential combination therapy) over monotherapy. Few data exist, however, on the long-term outcomes of patients receiving combination therapy. This review summarizes current combination therapy developed to cure chronic HBV infection.
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Affiliation(s)
- Di Wu
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qin Ning
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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12
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Enhanced antiviral and antifibrotic effects of short hairpin RNAs targeting HBV and TGF-β in HBV-persistent mice. Sci Rep 2017. [PMID: 28634402 PMCID: PMC5478661 DOI: 10.1038/s41598-017-04170-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The hepatitis B virus (HBV) causes acute and chronic liver infection, which may lead to liver cirrhosis and hepatocellular carcinoma. Current treatments including interferons and nucleotide analogs, have limited therapeutic effects, underscoring the need to identify effective therapeutic options to inhibit HBV replication and prevent complications. Previous animal models mimicking chronic HBV infection do not faithfully reflect disease progression in humans. Here, we used our established HBV-persistent mouse line with liver fibrosis to evaluate the efficacy of novel therapies. The combination of two short hairpin RNAs (dual-shRNA) against different coding regions of HBV delivered by a self-complementary AAV vector showed better antiviral effects than single shRNA both in vitro and in HBV-persistent mice. The dual-shRNA also exhibited stronger antifibrotic activity in vivo. Vector carrying shRNA against TGF-β, though did not inhibit HBV replication alone, enhanced the antiviral and antifibrotic activities of single and dual HBV shRNAs. Co-administration of TGF-β shRNA and HBV dual-shRNA decreased HBV DNA, HBV RNA, HBsAg, HBeAg, and liver fibrosis markers in serum and tissues, and improved liver morphology more effectively than single treatments. Our results suggest that the combination of shRNAs against HBV and TGF-β could be developed into a viable treatment for human HBV infection.
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Soriano V, Barreiro P, Benitez L, Peña JM, de Mendoza C. New antivirals for the treatment of chronic hepatitis B. Expert Opin Investig Drugs 2017; 26:843-851. [PMID: 28521532 DOI: 10.1080/13543784.2017.1333105] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Vincent Soriano
- Infectious Diseases Unit, La Paz University Hospital & Autonomous University, Madrid, Spain
| | - Pablo Barreiro
- Infectious Diseases Unit, La Paz University Hospital & Autonomous University, Madrid, Spain
| | - Laura Benitez
- Department of Internal Medicine, Puerta de Hierro Research Institute, Majadahonda, Spain
| | - Jose M. Peña
- Infectious Diseases Unit, La Paz University Hospital & Autonomous University, Madrid, Spain
| | - Carmen de Mendoza
- Department of Internal Medicine, Puerta de Hierro Research Institute, Majadahonda, Spain
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Abstract
Chronic hepatitis B virus (HBV) infection is a global public health issue. Although the disease cannot be cured effectively, disease management has been improved over the past decade. The introduction of potent nucleos(t)ide analogues (NAs) to suppress viral replication represented a giant leap in the control of this disease. It has been shown that tenofovir treatment, a potent NA, complements current immunoprophylaxis to diminish mother-to-infant transmission in pregnant women with a high viral load. For patients with chronic HBV infection, quantitative hepatitis B surface antigen is a useful tool to define inactive carriers and to guide antiviral therapy. Quantification of HBV mutants is also useful in predicting long-term outcomes more precisely than ever. The next challenge is how to achieve an HBV cure; although immunotherapy is a promising strategy, the current results from two clinical trials using therapeutic vaccines to induce HBV-specific immune response in patients with chronic HBV infection are disappointing. In the coming years, we are expecting to see a combination of therapeutic agents with various modes of action to complete the mission of HBV elimination.
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Affiliation(s)
- Tai-Chung Tseng
- Department of Internal Medicine, National Taiwan University Hospital Jinshan Branch, New Taipei City, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. .,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te St., Taipei, 10002, Taiwan. .,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan. .,Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
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15
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Golsaz-Shirazi F, Shokri F. Hepatitis B immunopathogenesis and immunotherapy. Immunotherapy 2016; 8:461-77. [PMID: 26973127 DOI: 10.2217/imt.16.3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Worldwide there are over 248 million chronic carriers of HBV of whom about a third eventually develop severe HBV-related complications. Due to the major limitations of current therapeutic approaches, the development of more effective strategies to improve therapeutic outcomes in chronic hepatitis B (CHB) patients seems crucial. Immune activation plays a critical role in spontaneous viral control; therefore, new modalities based on stimulation of the innate and adaptive immune responses could result in the resolution of infection and are promising approaches. Here, we summarize the HBV immunopathogenesis, and discuss the encouraging results obtained from the promising immune-based innovations, such as therapeutic vaccination, cytokine therapy, cell-based therapies and blocking inhibitory receptors, as current and future immunotherapeutic interventions.
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Affiliation(s)
- Forough Golsaz-Shirazi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Fazel Shokri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.,Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
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16
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17
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Tian L, Fu Q, Huang F. Effect of adefovir dipivoxil on T cell immune function in the treatment of chronic hepatitis B and hepatocirrhosis. Exp Ther Med 2016; 12:2511-2514. [PMID: 27698751 PMCID: PMC5038382 DOI: 10.3892/etm.2016.3623] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 08/18/2016] [Indexed: 01/29/2023] Open
Abstract
The aim of the present study was to investigate the T cell immune function in chronic hepatitis B hepatocirrhosis patients at the compensated and decompensated stage following treatment with adefovir dipivoxil. A total of 104 patients diagnosed with hepatitis B hepatocirrhosis during the period from October 2013 to October 2014 were enrolled in the study. Among the cases, there were 56 cases at compensated stage, and another 48 at decompensated stage. Adefovir dipivoxil was administered for antiviral therapy (10 mg/time, 1 time/day, for a total of 24 weeks), and we compared the virus disappearance rate, liver function improvement and T cell immune function between the two groups before and after treatment. The difference between the virus disappearance rate in the two groups was not statistically significant (P>0.05). The decreased level of ALT decrease in the compensated group was significantly higher than that in the decompensated group, while the increased level of albumin in the compensated group was significantly higher as well. The differences showed statistical significance (P<0.05). After treatment, the level of CD4+ and CD4+/CD8+ ratio were higher than before treatment, while the level of CD8+ was lower after treatment than before treatment in the two groups. The differences all showed statistical significance (P<0.05). The CD4+CXCR5+ T follicular helper (TFH) cell level in the two groups was higher after treatment, as was interleukin-2 and interferon-γ. The differences all showed statistical significance (P<0.05). As for comparison between groups, the difference had no statistical significance (P>0.05). Adefovir dipivoxil treatment can improve T cell immune function at the compensated and decompensated stages in chronic hepatitis B hepatocirrhosis patients. This may be associated with virus disappearance and liver function improvement.
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Affiliation(s)
- Liting Tian
- Department of Liver Disease, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi'an, Shaanxi 710003, P.R. China
| | - Qilin Fu
- Department of Liver Disease, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi'an, Shaanxi 710003, P.R. China
| | - Fu Huang
- Department of Gastroenterology, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi'an, Shaanxi 710003, P.R. China
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18
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Lin CL, Kao JH. Review article: novel therapies for hepatitis B virus cure - advances and perspectives. Aliment Pharmacol Ther 2016; 44:213-22. [PMID: 27302653 DOI: 10.1111/apt.13694] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Revised: 03/26/2016] [Accepted: 05/21/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND Current anti-viral therapies, interferon and nucleos(t)ide analogues, have been proven to reduce the progression of chronic hepatitis B (CHB). However, covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) persists, resulting in viral relapse after the discontinuation of treatment. AIM To discuss and review novel therapies for chronic hepatitis B infection. METHODS Recent published studies which searched from PubMed were comprehensive reviewed. The key words include chronic hepatitis B, hepatitis B virus cure, covalently closed circular DNA, direct acting anti-virals and host targeting agents. RESULTS Several novel agents through viral and host targets approaches are under investigations towards functional cure of HBV. On the one hand, direct acting anti-virals targeting virus itself, such as HBV new polymerase inhibitor, entry inhibitor, engineered site-specific nucleases and RNA interference, could inhibit amplification of cccDNA as well as intrahepatic HBV infection and eliminate or silence cccDNA transcription. Inhibitors of HBV nucleocapsid assembly suppress capsid formation and prevent synthesis of HBV DNA. On the other hand, host targeting agents (HTA) include lymphotoxin-β receptor agonist, toll-like receptor agonist, immune checkpoint inhibitors and adenovirus-based therapeutic vaccine. Through enhancing innate and adaptive immune responses, these agents could induce noncytolytic destruction of cccDNA or attack HBV-infected hepatocytes. CONCLUSION With these promising approaches, we hope to reach global hepatitis B virus control in the middle of this century.
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Affiliation(s)
- C-L Lin
- Department of Gastroenterology, Renai branch, Taipei City Hospital, Taipei, Taiwan.,Department of Psychology, National Chengchi University, Taipei, Taiwan
| | - J-H Kao
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Research, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan
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19
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Lamontagne RJ, Bagga S, Bouchard MJ. Hepatitis B virus molecular biology and pathogenesis. HEPATOMA RESEARCH 2016; 2:163-186. [PMID: 28042609 PMCID: PMC5198785 DOI: 10.20517/2394-5079.2016.05] [Citation(s) in RCA: 117] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
As obligate intracellular parasites, viruses need a host cell to provide a milieu favorable to viral replication. Consequently, viruses often adopt mechanisms to subvert host cellular signaling processes. While beneficial for the viral replication cycle, virus-induced deregulation of host cellular signaling processes can be detrimental to host cell physiology and can lead to virus-associated pathogenesis, including, for oncogenic viruses, cell transformation and cancer progression. Included among these oncogenic viruses is the hepatitis B virus (HBV). Despite the availability of an HBV vaccine, 350-500 million people worldwide are chronically infected with HBV, and a significant number of these chronically infected individuals will develop hepatocellular carcinoma (HCC). Epidemiological studies indicate that chronic infection with HBV is the leading risk factor for the development of HCC. Globally, HCC is the second highest cause of cancer-associated deaths, underscoring the need for understanding mechanisms that regulate HBV replication and the development of HBV-associated HCC. HBV is the prototype member of the Hepadnaviridae family; members of this family of viruses have a narrow host range and predominately infect hepatocytes in their respective hosts. The extremely small and compact hepadnaviral genome, the unique arrangement of open reading frames, and a replication strategy utilizing reverse transcription of an RNA intermediate to generate the DNA genome are distinguishing features of the Hepadnaviridae. In this review, we provide a comprehensive description of HBV biology, summarize the model systems used for studying HBV infections, and highlight potential mechanisms that link a chronic HBV-infection to the development of HCC. For example, the HBV X protein (HBx), a key regulatory HBV protein that is important for HBV replication, is thought to play a cofactor role in the development of HBV-induced HCC, and we highlight the functions of HBx that may contribute to the development of HBV-associated HCC.
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Affiliation(s)
- R. Jason Lamontagne
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
- The Wistar Institute, Philadelphia, PA 19104, USA
| | - Sumedha Bagga
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
| | - Michael J. Bouchard
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
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20
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Leng XJ, Yan XB. Status and development of anti-HBV drugs based on "HBF drug watch". Shijie Huaren Xiaohua Zazhi 2016; 24:2336-2346. [DOI: 10.11569/wcjd.v24.i15.2336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a major public health threat globally. Present therapies can only suppress viral replication instead of viral elimination. With the application of direct anti-viral agents (DAAs) to hepatitis C virus (HCV) infection, many pharmaceutical industries pay their attention to investigating anti-HBV drugs. As a result, the update of anti-HBV drugs at the website http://www.hepb.org/professionals/hbf_drug_watch.htm speeds up. In this review, we summarize all the drugs available in the market and those in clinical trials based on this website.
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21
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Lin CL, Yang HC, Kao JH. Hepatitis B virus: new therapeutic perspectives. Liver Int 2016; 36 Suppl 1:85-92. [PMID: 26725903 DOI: 10.1111/liv.13003] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 10/30/2015] [Indexed: 12/12/2022]
Abstract
Current antiviral therapies have dramatically improved the long-term outcomes of patients with chronic hepatitis B virus (HBV) infection. Both interferon (IFN) and nucleos(t)ide analogue (NA) treatments have been shown to reduce the progression of liver disease in chronic hepatitis B (CHB) patients. However, persistent covalently closed circular DNA (cccDNA) can result in a viral relapse after discontinuation of antiviral treatment. On the basis of extensive research on the HBV lifecycle and virus-host interactions, several new agents focusing on viral and host targets are under development to cure HBV. New polymerase inhibitors, tenofovir alafenamide and besifovir provide effective and safer treatment for CHB patients. Agents targeting cccDNA, such as engineered site-specific nucleases and RNA interference therapeutics could eliminate cccDNA or silence cccDNA transcription. Inhibitors of HBV nucleocapsid assembly suppress capsid formation and prevent synthesis of HBV DNA. The HBV entry inhibitor, Myrcludex-B, has been shown to effectively inhibit amplification of cccDNA as well as the spread of intrahepatic infection. Agents targeting host factors that enhance innate and adaptive immune responses, including the lymphotoxin-β receptor agonist, toll-like receptor agonist, immune checkpoint inhibitors and adenovirus-based therapeutic vaccine, could play a critical role in the elimination of HBV-infected cells. With all of these promising approaches, we hope to reach the ultimate goal of a cure to HBV in the near future.
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Affiliation(s)
- Chih-Lin Lin
- Department of Gastroenterology, Ren-Ai branch, Taipei City Hospital, Taipei, Taiwan.,Department of Psychology, National Chengchi University, Taipei, Taiwan
| | - Hung-Chih Yang
- Department of Microbiology, National Taiwan University, College of Medicine, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University, College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University, College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University, College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Research, National Taiwan University, College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
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22
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Kao JH. Hepatitis B vaccination and prevention of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 2015; 29:907-17. [PMID: 26651252 DOI: 10.1016/j.bpg.2015.09.011] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Accepted: 09/02/2015] [Indexed: 01/31/2023]
Abstract
Hepatitis B virus (HBV) infection is a global health threat; with 240 million people are chronic carriers of the virus. The infection can cause acute and chronic liver disease including liver cirrhosis and hepatocellular carcinoma (HCC). On the basis of disease burden and the availability of safe and effective vaccines, World Health Organization has recommended that hepatitis B vaccine be incorporated into routine infant and childhood immunization programs for all countries. The efficacy of universal immunization has been proven in many countries, with substantial reductions of the prevalence of HBV carriage in children, adolescents and young adults. Most important, hepatitis B vaccination can protect them from HCC, as has been demonstrated in Taiwan and other countries. Nevertheless, the implementation of worldwide vaccination against HBV indeed requires more effort to overcome the social and economic challenges. To have a global control of HBV infection, we have to continue the universal HBV vaccination, interrupt the possible transmission routes and treat eligible patients with antiviral agents. However, current treatments are still far from ideal as they cannot eradicate intrahepatic HBV cccDNA, and lifelong administration of these agents will pose a major economic burden, especially in the endemic Asia-Pacific region. Thus we need innovative treatment strategies and novel agents with difference modes of action to overcome the unmet medical need for an efficient HBV cure with subsequent global eradication of HBV infection, hopefully by the first half of 21st century.
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Affiliation(s)
- Jia-Horng Kao
- Hepatitis Research Center, Graduate Institute of Clinical Medicine and Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.
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23
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Lin CL, Kao JH. Perspectives and control of hepatitis B virus infection in Taiwan. J Formos Med Assoc 2015; 114:901-9. [PMID: 26184565 DOI: 10.1016/j.jfma.2015.06.003] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Revised: 06/04/2015] [Accepted: 06/08/2015] [Indexed: 02/06/2023] Open
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24
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Guo Z, King T. Therapeutic Strategies and New Intervention Points in Chronic Hepatitis Delta Virus Infection. Int J Mol Sci 2015; 16:19537-52. [PMID: 26295228 PMCID: PMC4581312 DOI: 10.3390/ijms160819537] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 08/05/2015] [Accepted: 08/07/2015] [Indexed: 12/18/2022] Open
Abstract
Chronic hepatitis delta virus infection (CHD) is a condition arising from super-infection of hepatitis B virus (HBV)-infected patients, resulting in a more rapid advance in liver pathology and hepatocellular carcinoma than is observed for HBV mono-infection. Although hepatitis delta virus (HDV) is structurally simple, its life cycle involves the complex participation of host enzymes, HBV-derived surface antigen (HBsAg), and HDV-auto-ribozyme and hepatitis delta antigen (HDAg) activities. Unsatisfactory clinical trial results with interferon-based therapies are motivating researchers to adjust and redirect the approach to CHD drug development. This new effort will likely require additional structural and functional studies of the viral and cellular/host components involved in the HDV replication cycle. This review highlights recent work aimed at new drug interventions for CHD, with interpretation of key pre-clinical- and clinical trial outcomes and a discussion of promising new technological approaches to antiviral drug design.
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Affiliation(s)
- Zhimin Guo
- Huron Peak Ave., Superior, CO 80027, USA.
| | - Thomas King
- Allevagen, LLC, 4105 Perry St., Denver, CO 80212, USA.
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