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1
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Lam R, Lim JK. Advances in discovery of novel investigational agents for functional cure of chronic hepatitis B: A comprehensive review of phases II and III therapeutic agents. World J Hepatol 2024; 16:331-343. [PMID: 38577537 PMCID: PMC10989302 DOI: 10.4254/wjh.v16.i3.331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 01/23/2024] [Accepted: 02/29/2024] [Indexed: 03/27/2024] Open
Abstract
Chronic hepatitis B virus (HBV) infection affects over 295 million people globally and an estimated 1.6 million people in the United States. It is associated with significant morbidity and mortality due to cirrhosis, liver failure, and liver cancer. Antiviral therapy with oral nucleos(t)ide analogues is associated with high rates of virologic suppression, which in turn has been associated with a decreased risk of liver complications. However, current antiviral regimens are limited by concerns with adverse effects, adherence, resistance, long-term treatment, and ongoing risk for liver events. Novel investigational agents are currently in development and are targeted at achieving functional cure with sustained hepatitis B surface antigen (HBsAg) loss and suppression of HBV DNA. Herein we review key evidence from phases II and III trials defining the efficacy and safety profiles for key investigational agents for functional cure of chronic hepatitis B, including core/capsid inhibitors, entry inhibitors, RNA interference (siRNA/ASO), HBsAg inhibitors, Toll-like receptor agonists, checkpoint inhibitors, and therapeutic vaccines.
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Affiliation(s)
- Robert Lam
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, United States
| | - Joseph K Lim
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, United States.
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2
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Kou B, Zhang Z, Han X, Zhou Z, Xu Z, Zhou X, Shen F, Zhou Y, Tian X, Yang G, Young JAT, Qiu H, Ottaviani G, Mayweg A, Zhu W, Shen HC, Liu H, Hu T. Discovery of 4,5,6,7-Tetrahydropyrazolo[1.5-a]pyrizine Derivatives as Core Protein Allosteric Modulators (CpAMs) for the Inhibition of Hepatitis B Virus. J Med Chem 2023; 66:14116-14132. [PMID: 37801325 DOI: 10.1021/acs.jmedchem.3c01145] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/07/2023]
Abstract
Hepatitis B Virus (HBV) core protein allosteric modulators (CpAMs) are an attractive class of potential anti-HBV therapeutic agents. Here we describe the efforts toward the discovery of a series of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (THPP) compounds as HBV CpAMs that effectively inhibit a broad range of nucleos(t)ide-resistant HBV variants. The lead compound 45 demonstrated inhibition of HBV DNA viral load in a HBV AAV mouse model by oral administration.
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Affiliation(s)
- Buyu Kou
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Zhisen Zhang
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Xingchun Han
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Zheng Zhou
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Lead Discovery, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Zhiheng Xu
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Lead Discovery, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Xue Zhou
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Discovery Virology, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Fang Shen
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Discovery Virology, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Yuan Zhou
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Discovery Virology, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Xiaojun Tian
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Discovery Virology, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Guang Yang
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Discovery Virology, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - John A T Young
- Roche Innovation Center Basel, Roche Pharma Research and Early Development, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Discovery Virology, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Hongxia Qiu
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Pharmaceutical Sciences, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Giorgio Ottaviani
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Pharmaceutical Sciences, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Alexander Mayweg
- Roche Innovation Center Basel, Roche Pharma Research and Early Development, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Wei Zhu
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Hong C Shen
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Haixia Liu
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
| | - Taishan Hu
- China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China
- Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China
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Shiue SJ, Cheng CL, Shiue HS, Chen CN, Cheng SW, Wu LW, Jargalsaikhan G, Chan TS, Lin HY, Wu MS. Arthrospira Enhances Seroclearance in Patients with Chronic Hepatitis B Receiving Nucleos(t)ide Analogue through Modulation of TNF-α/IFN-γ Profile. Nutrients 2022; 14:2790. [PMID: 35889747 PMCID: PMC9325115 DOI: 10.3390/nu14142790] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/30/2022] [Accepted: 07/04/2022] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B (CHB) virus infection, causing immune dysfunction and chronic hepatitis, is one of the leading risk factors for hepatocellular cancer. We investigated how Arthrospira affected hepatitis B surface antigen (HBsAg) reduction in CHB patients under continued nucleos(t)ide analogues (NA). Sixty CHB patients who had been receiving NA for at least one year with undetectable HBV DNA were randomized into three groups: control and oral Arthrospira at 3 or 6 g daily add-on therapy groups. Patients were followed up for 6 months. Oral Arthrospira-diet mice were established to investigate the possible immunological mechanism of Arthrospira against HBV. Within 6 months, mean quantitative HBsAg (qHBsAg) decreased in the oral Arthrospira add-on therapy group. Interestingly, interferon gamma (IFN-γ) increased but TNF-α, interleukin 6 (IL-6), hepatic fibrosis, and steatosis decreased in the add-on groups. In mice, Arthrospira enhanced both innate and adaptive immune system, especially natural killer (NK) cell cytotoxicity, B cell activation, and the interleukin 2 (IL-2), IFN-γ immune response. Arthrospira may modulate IL-2- and TNF-α/IFN-γ-mediated B and T cell activation to reduce HBsAg. Also, Arthrospira has the potential to restore immune tolerance and enhance HBsAg seroclearance in CHB patients through promoting T, B, and NK cell activation.
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Affiliation(s)
- Sheng-Jie Shiue
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan; (S.-J.S.); (C.-L.C.); (H.-S.S.); (C.-N.C.); (S.-W.C.); (T.-S.C.)
- Integrative Therapy Center for Gastroenterologic Cancers, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
| | - Chao-Ling Cheng
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan; (S.-J.S.); (C.-L.C.); (H.-S.S.); (C.-N.C.); (S.-W.C.); (T.-S.C.)
| | - Han-Shiang Shiue
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan; (S.-J.S.); (C.-L.C.); (H.-S.S.); (C.-N.C.); (S.-W.C.); (T.-S.C.)
| | - Chun-Nan Chen
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan; (S.-J.S.); (C.-L.C.); (H.-S.S.); (C.-N.C.); (S.-W.C.); (T.-S.C.)
| | - Sheng-Wei Cheng
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan; (S.-J.S.); (C.-L.C.); (H.-S.S.); (C.-N.C.); (S.-W.C.); (T.-S.C.)
- Division of Gastroenterology, Department of Internal Medicine, Taiwan Adventist Hospital, Taipei 105, Taiwan
| | - Li-Wei Wu
- Department of Internal Medicine, National Taiwan University Hospital, YunLin Branch, YunLin 640, Taiwan;
| | | | - Tze-Sian Chan
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan; (S.-J.S.); (C.-L.C.); (H.-S.S.); (C.-N.C.); (S.-W.C.); (T.-S.C.)
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Hsin-Yi Lin
- Institute of Chemical Engineering, National Taipei University of Technology, Taipei 106, Taiwan
- Institute of Biochemical and Biomedical Engineering, National Taipei University of Technology, Taipei 106, Taiwan
| | - Ming-Shun Wu
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan; (S.-J.S.); (C.-L.C.); (H.-S.S.); (C.-N.C.); (S.-W.C.); (T.-S.C.)
- Integrative Therapy Center for Gastroenterologic Cancers, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
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Zhu L, Li J, Xu J, Chen F, Wu X, Zhu C. Significance of T-Cell Subsets for Clinical Response to Peginterferon Alfa-2a Therapy in HBeAg-Positive Chronic Hepatitis B Patients. Int J Gen Med 2022; 15:4441-4451. [PMID: 35509606 PMCID: PMC9058244 DOI: 10.2147/ijgm.s356696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 04/14/2022] [Indexed: 11/23/2022] Open
Abstract
Introduction The adaptive immune response may reflect the immunomodulatory efficacy during peginterferon alfa-2a (PEG-IFN α-2a) treatment in chronic hepatitis B (CHB) patients. We evaluated the predictive efficiency of T-cell subsets on patient's response to PEG-IFN α-2a treatment. Methods The proportions of CD8+PD-1+, CD8+Tim-3+ and CD4+CD25high T-cells were measured at baseline and week 52 in CHB patients who underwent PEG-IFN α-2a treatment. The proportions of T-cell subsets were compared among different responders and non-responders (determined by biochemical, serological, and virological responses). Results The baseline proportions of the three T-cell subsets were significantly higher in CHB patients (65 cases) than in healthy controls (28 cases), while the proportions declined significantly after 52 weeks of PEG-IFN treatment. Responders (ALT < 40 IU/L, 89.2% [58/65]; HBV DNA < 2.7 log10 IU/ml, 66.2% [43/65]; and HBeAg seroconversion [SR], 53.9% [35/65]) experienced more pronounced declines in the proportion of T-cell subsets compared to non-responders. In particular, the baseline proportions of CD4+CD25high T-cells displayed significant difference between SR and non-SR groups. The stepwise logistic regression analysis identified that CD4+CD25high T-cells combined with baseline HBV DNA and ALT can predict SR and CR (ALT < 40 IU/L, HBV DNA < 2.7 log10 IU/mL and HBeAg seroconversion) after 52 weeks of PEG-IFN treatment with high accuracy. Conclusion PEG-IFN therapy induces significant declines in the proportion of some key T-cell subsets in HBeAg-positive patients. The model constructed with CD4+CD25high T-cells combined with ATL and HBV DNA may help to predict the efficacy of PEG-IFN α-2a therapy.
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Affiliation(s)
- Li Zhu
- Department of Infectious Diseases, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Department of Hepatology, the Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Department of Hepatology, the Fifth People’s Hospital of Suzhou, Suzhou, Jiangsu, People’s Republic of China
| | - Jin Li
- Central Laboratory, the Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Central Laboratory, the Fifth People’s Hospital of Suzhou, Suzhou, Jiangsu, People’s Republic of China
| | - Junchi Xu
- Central Laboratory, the Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Central Laboratory, the Fifth People’s Hospital of Suzhou, Suzhou, Jiangsu, People’s Republic of China
| | - Fan Chen
- Department of Hepatology, the Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Department of Hepatology, the Fifth People’s Hospital of Suzhou, Suzhou, Jiangsu, People’s Republic of China
| | - Xunxun Wu
- Department of Hepatology, the Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Department of Hepatology, the Fifth People’s Hospital of Suzhou, Suzhou, Jiangsu, People’s Republic of China
| | - Chuanwu Zhu
- Department of Infectious Diseases, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Department of Hepatology, the Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Department of Hepatology, the Fifth People’s Hospital of Suzhou, Suzhou, Jiangsu, People’s Republic of China
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Khan IW, Dad Ullah MU, Choudhry M, Ali MJ, Ali MA, Lam SLK, Shah PA, Kaur SP, Lau DTY. Novel Therapies of Hepatitis B and D. Microorganisms 2021; 9:2607. [PMID: 34946209 PMCID: PMC8707465 DOI: 10.3390/microorganisms9122607] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/03/2021] [Accepted: 12/07/2021] [Indexed: 02/05/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global public health issue and is a major cause of cirrhosis and hepatocellular carcinoma (HCC). Hepatitis D virus (HDV) requires the hepatitis B surface antigen (HBsAg) to replicate. The eradication of HBV, therefore, can also cure HDV. The current therapies for chronic hepatitis B and D are suboptimal and cannot definitely cure the viruses. In order to achieve functional or complete cure of these infections, novel therapeutic agents that target the various sites of the viral replicative cycle are necessary. Furthermore, novel immunomodulatory agents are also essential to achieve viral clearance. Many of these new promising compounds such as entry inhibitors, covalently closed circular DNA (cccDNA) inhibitors, small interfering RNAs (siRNAs), capsid assembly modulators and nucleic acid polymers are in various stages of clinical developments. In this review article, we provided a comprehensive overview of the structure and lifecycle of HBV, the limitations of the current therapies and a summary of the novel therapeutic agents for both HDV and HBV infection.
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Affiliation(s)
- Iman Waheed Khan
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Mati Ullah Dad Ullah
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Mina Choudhry
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Mukarram Jamat Ali
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Muhammad Ashar Ali
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Sam L. K. Lam
- Liver Center, Department of Medicine, Department of Pharmacy, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA;
| | - Pir Ahmad Shah
- Department of Internal Medicine, University of Texas, San Antonio, TX 78229, USA;
| | - Satinder Pal Kaur
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Daryl T. Y. Lau
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
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6
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Goh ZY, Ren EC, Ko HL. Intracellular interferon signalling pathways as potential regulators of covalently closed circular DNA in the treatment of chronic hepatitis B. World J Gastroenterol 2021; 27:1369-1391. [PMID: 33911462 PMCID: PMC8047536 DOI: 10.3748/wjg.v27.i14.1369] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/23/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
Infection with the hepatitis B virus (HBV) is still a major global health threat as 250 million people worldwide continue to be chronically infected with the virus. While patients may be treated with nucleoside/nucleotide analogues, this only suppresses HBV titre to sub-detection levels without eliminating the persistent HBV covalently closed circular DNA (cccDNA) genome. As a result, HBV infection cannot be cured, and the virus reactivates when conditions are favorable. Interferons (IFNs) are cytokines known to induce powerful antiviral mechanisms that clear viruses from infected cells. They have been shown to induce cccDNA clearance, but their use in the treatment of HBV infection is limited as HBV-targeting immune cells are exhausted and HBV has evolved multiple mechanisms to evade and suppress IFN signalling. Thus, to fully utilize IFN-mediated intracellular mechanisms to effectively eliminate HBV, instead of direct IFN administration, novel strategies to sustain IFN-mediated anti-cccDNA and antiviral mechanisms need to be developed. This review will consolidate what is known about how IFNs act to achieve its intracellular antiviral effects and highlight the critical interferon-stimulated gene targets and effector mechanisms with potent anti-cccDNA functions. These include cccDNA degradation by APOBECs and cccDNA silencing and transcription repression by epigenetic modifications. In addition, the mechanisms that HBV employs to disrupt IFN signalling will be discussed. Drugs that have been developed or are in the pipeline for components of the IFN signalling pathway and HBV targets that detract IFN signalling mechanisms will also be identified and discussed for utility in the treatment of HBV infections. Together, these will provide useful insights into design strategies that specifically target cccDNA for the eradication of HBV.
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Affiliation(s)
- Zhi Yi Goh
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
- Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore 119077, Singapore
| | - Ee Chee Ren
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Singapore
| | - Hui Ling Ko
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
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Lee YH, Cha HM, Hwang JY, Park SY, Vishakantegowda AG, Imran A, Lee JY, Yi YS, Jun S, Kim GH, Kang HJ, Chung SJ, Kim M, Kim H, Han SB. Sulfamoylbenzamide-based Capsid Assembly Modulators for Selective Inhibition of Hepatitis B Viral Replication. ACS Med Chem Lett 2021; 12:242-248. [PMID: 33603970 PMCID: PMC7883466 DOI: 10.1021/acsmedchemlett.0c00606] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 12/29/2020] [Indexed: 02/08/2023] Open
Abstract
As the spread of infections caused by hepatitis B virus (HBV) threatens public health worldwide, investigations from multiple perspectives and of various mechanisms of action are urgently required to increase the HBV cure rate. Targeting the encapsidation of the nuclear capsid protein (core protein, HBc) has emerged as an attractive strategy for inhibiting the viral assembly process; however, a drug targeting this mechanism has not yet been approved. We synthesized novel sulfamoylbenzamides (SBAs) as capsid assembly modulators of HBV and found that the effects and safety profiles of compounds 3 and 8 have potential therapeutic applicability against HBV. The formation of tubular particles was time-dependent in the presence of 3, indicating a new mode of protein assembly by SBA compounds. Our findings provide a new entity for developing safe and efficient treatments for HBV infection.
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Affiliation(s)
- Yeon Hee Lee
- Therapeutics
& Biotechnology Division, Korea Research
Institute of Chemical Technology, Daejeon 34114, Republic of Korea
- Department
of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea
| | - Hyeon-Min Cha
- Therapeutics
& Biotechnology Division, Korea Research
Institute of Chemical Technology, Daejeon 34114, Republic of Korea
- Graduate
School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic
of Korea
| | - Jun Yeon Hwang
- Therapeutics
& Biotechnology Division, Korea Research
Institute of Chemical Technology, Daejeon 34114, Republic of Korea
| | - So Yeong Park
- Therapeutics
& Biotechnology Division, Korea Research
Institute of Chemical Technology, Daejeon 34114, Republic of Korea
- Department
of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea
| | - Avinash G. Vishakantegowda
- Therapeutics
& Biotechnology Division, Korea Research
Institute of Chemical Technology, Daejeon 34114, Republic of Korea
- Department
of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea
| | - Ali Imran
- Therapeutics
& Biotechnology Division, Korea Research
Institute of Chemical Technology, Daejeon 34114, Republic of Korea
| | - Joo-Youn Lee
- Therapeutics
& Biotechnology Division, Korea Research
Institute of Chemical Technology, Daejeon 34114, Republic of Korea
| | - Yoon-Sun Yi
- Center
for Research Equipment, Korea Basic Science
Institute, Cheongju 28119, Republic of Korea
| | - Sangmi Jun
- Center
for Research Equipment, Korea Basic Science
Institute, Cheongju 28119, Republic of Korea
| | - Ga Hyeon Kim
- School
of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
- AbTis Co.
Ltd. Suwon Venture Valley II, 142-10, Saneop-ro 156, Gwonseon-gu, Suwon 16648, Republic of Korea
| | - Hyo Jin Kang
- AbTis Co.
Ltd. Suwon Venture Valley II, 142-10, Saneop-ro 156, Gwonseon-gu, Suwon 16648, Republic of Korea
| | - Sang J. Chung
- School
of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
- AbTis Co.
Ltd. Suwon Venture Valley II, 142-10, Saneop-ro 156, Gwonseon-gu, Suwon 16648, Republic of Korea
| | - Meehyein Kim
- Therapeutics
& Biotechnology Division, Korea Research
Institute of Chemical Technology, Daejeon 34114, Republic of Korea
- Graduate
School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic
of Korea
| | - Hyejin Kim
- Therapeutics
& Biotechnology Division, Korea Research
Institute of Chemical Technology, Daejeon 34114, Republic of Korea
| | - Soo Bong Han
- Therapeutics
& Biotechnology Division, Korea Research
Institute of Chemical Technology, Daejeon 34114, Republic of Korea
- Department
of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea
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8
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Gill US, Kennedy PTF. The impact of currently licensed therapies on viral and immune responses in chronic hepatitis B: Considerations for future novel therapeutics. J Viral Hepat 2019; 26:4-15. [PMID: 30415490 DOI: 10.1111/jvh.13040] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 10/25/2018] [Indexed: 12/14/2022]
Abstract
Despite the availability of a preventative vaccine, chronic hepatitis B (CHB) remains a global healthcare challenge with the risk of disease progression due to cirrhosis and hepatocellular carcinoma. Although current treatment strategies, interferon and nucleos(t)ide analogues have contributed to reducing morbidity and mortality related to CHB, these therapies are limited in providing functional cure. The treatment paradigm in CHB is rapidly evolving with a number of new agents in the developmental pipeline. However, until novel agents with functional cure capability are available in the clinical setting, there is a pressing need to optimize currently licensed therapies. Here, we discuss current agents used alone and/or in combination strategies along with the impact of these therapies on viral and immune responses. Novel treatment strategies are outlined, and the potential role of current therapies in the employment of pipeline agents is discussed.
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Affiliation(s)
- Upkar S Gill
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Patrick T F Kennedy
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
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9
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Subramaniam R, Hillberry Z, Chen H, Feng Y, Fletcher K, Neuenschwander P, Shams H. Delivery of GM-CSF to Protect against Influenza Pneumonia. PLoS One 2015; 10:e0124593. [PMID: 25923215 PMCID: PMC4414562 DOI: 10.1371/journal.pone.0124593] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 03/16/2015] [Indexed: 01/10/2023] Open
Abstract
Background Since adaptive immunity is thought to be central to immunity against influenza A virus (IAV) pneumonias, preventive strategies have focused primarily on vaccines. However, vaccine efficacy has been variable, in part because of antigenic shift and drift in circulating influenza viruses. Recent studies have highlighted the importance of innate immunity in protecting against influenza. Methods Granulocyte-macrophage colony stimulating factor (GM-CSF) contributes to maturation of mononuclear phagocytes, enhancing their capacity for phagocytosis and cytokine production. Results Overexpression of granulocyte macrophage-colony stimulating factor (GM-CSF) in the lung of transgenic mice provides remarkable protection against IAV, which depends on alveolar macrophages (AM). In this study, we report that pulmonary delivery of GM-CSF to wild type young and aged mice abrogated mortality from IAV. Conclusion We also demonstrate that protection is species specific and human GM-CSF do not protect the mice nor stimulates mouse immunity. We also show that IAV-induced lung injury is the culprit for side-effects of GM-CSF in treating mice after IAV infection, and introduce a novel strategy to deliver the GM-CSF to and retain it in the alveolar space even after IAV infection.
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Affiliation(s)
- Renuka Subramaniam
- Center for Pulmonary and Infectious Diseases Control (CPIDC), The University of Texas Health Science Center at Tyler, 11937 U.S. Highway 271, Tyler, TX, United States of America
| | - Zachary Hillberry
- Center for Pulmonary and Infectious Diseases Control (CPIDC), The University of Texas Health Science Center at Tyler, 11937 U.S. Highway 271, Tyler, TX, United States of America
| | - Han Chen
- Center for Pulmonary and Infectious Diseases Control (CPIDC), The University of Texas Health Science Center at Tyler, 11937 U.S. Highway 271, Tyler, TX, United States of America
| | - Yan Feng
- Center for Pulmonary and Infectious Diseases Control (CPIDC), The University of Texas Health Science Center at Tyler, 11937 U.S. Highway 271, Tyler, TX, United States of America
| | - Kalyn Fletcher
- Center for Pulmonary and Infectious Diseases Control (CPIDC), The University of Texas Health Science Center at Tyler, 11937 U.S. Highway 271, Tyler, TX, United States of America
| | - Pierre Neuenschwander
- Biomedical Research, The University of Texas Health Science Center at Tyler, U.S. Highway 271, Tyler, TX, USA
| | - Homayoun Shams
- Center for Pulmonary and Infectious Diseases Control (CPIDC), The University of Texas Health Science Center at Tyler, 11937 U.S. Highway 271, Tyler, TX, United States of America
- * E-mail:
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10
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Chen M, Hu P, Ling N, Peng H, Lei Y, Hu H, Zhang D, Ren H. Enhanced functions of peripheral γδ T cells in chronic hepatitis B infection during interferon α treatment in vivo and in vitro. PLoS One 2015; 10:e0120086. [PMID: 25774808 PMCID: PMC4361562 DOI: 10.1371/journal.pone.0120086] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 01/19/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND γδ T cells play an important role in infectious, autoimmune, or neoplastic diseases. Here, a study was conducted to investigate the dynamic changes in phenotype and function of peripheral γδ T cells in patients with chronic hepatitis B (CHB) during pegylated-interferon (pegIFN)-α treatment, and to explore their roles in IFN-α therapy. METHODS Total 15 CHB patients with pegIFN-α therapy and 6 healthy controls (HC) were enrolled in this study. Flow cytometry was used for the study of frequency of peripheral γδ T cells, subtypes, effector or memory γδ T cells, and also the IFN-γ+, TNF-α+, CD107a+ or Granzyme B+ γδ T cells in 10 patients at week 0, 4, 8, 12, 24, 36 and 48 of treatment. Another 5 CHB patients and 6 HC were recruited for the γδ T cell isolation, and gene expression in γδ T cells was evaluated before or after IFN-α treatment in vitro. RESULTS Although γδT cells decreased in CHB patients during pegIFN-α therapy, their capacities to produce TNF-α and to express CD107a were enhanced. More effector γδT cells (CD27-CD45RA+) were found in the response group than in non-response group. Furthermore, IFN-α boosted the expression of Mx2 and cytokine genes in γδT cells from CHB patients in vitro. CONCLUSION IFN-α could enhance the cytokine production or cytotoxicity potential of γδT cells in vivo and in vitro. The enhanced function of γδT cells might contribute to the effect of IFN-α treatment.
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Affiliation(s)
- Min Chen
- Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- * E-mail: (MC); (HR)
| | - Peng Hu
- Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ning Ling
- Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Hui Peng
- Department of laboratory medicine, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yu Lei
- Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Huaidong Hu
- Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Dazhi Zhang
- Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Hong Ren
- Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- * E-mail: (MC); (HR)
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11
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Kao JH. HBeAg-positive chronic hepatitis B: why do I treat my patients with pegylated interferon? Liver Int 2014; 34 Suppl 1:112-9. [PMID: 24373087 DOI: 10.1111/liv.12400] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Accepted: 10/18/2013] [Indexed: 02/06/2023]
Abstract
Although chronic hepatitis B (CHB) is a global health threat, it is now a preventable and treatable disease. Seven agents have been approved for the treatment of CHB. Although many patients prefer potent long-term nucleos(t)ide analogues (NAs) as the first-line therapy because they are convenient to use and well-tolerated, a finite duration of pegylated interferon (PEG-IFN) is still an attractive strategy because it provides higher rates of off-therapy host immune control over hepatitis B virus (HBV) compared with NAs. In addition, the rates of HBeAg/HBsAg loss or seroconversion increase over time in patients who respond to PEG-IFN therapy. Nevertheless, these benefits are limited to 30% of all patients, and significant adverse effects are still a concern. Therefore, patients who can benefit most from PEG-IFN therapy should be more carefully selected according to baseline host and viral predictors, such as age, ALT level, viral load, HBV genotype and HBV mutants. In addition, on-treatment predictors including HBV DNA, HBeAg and HBsAg kinetics, can help decide who should continue or discontinue PEG-IFN and shift to NA. Understanding these factors can help determine personalized PEG-IFN therapy for CHB patients. In the near future, the treatment paradigm of CHB should be tailored on the basis of viral (HBV DNA level, HBV genotype and HBV mutants) and host (age, gender, ALT level and host genetic polymorphisms) factors, disease status (stage of fibrosis and comorbidities) and the selection of antiviral agents (immunomodulatory effect, antiviral potency, adverse effects and rate of drug resistance).
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Affiliation(s)
- Jia-Horng Kao
- Department of Internal Medicine, Department of Medical Research, Graduate Institute of Clinical Medicine, and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
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12
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The comparison of the efficacy of pegylated interferon α-2a and α-2b in chronic hepatitis B patients. Eur J Gastroenterol Hepatol 2013; 25:1312-6. [PMID: 23652913 DOI: 10.1097/meg.0b013e328362389a] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND/AIM Although 48-week therapy with pegylated-interferons has been shown to be effective for the treatment of chronic hepatitis B (CHB), comparison of the efficacy of pegylated-interferon α-2a (Peg-IFNα-2a) and Peg-IFNα-2b in the therapy is not obvious. We aimed to compare the efficacy of Peg-IFNα-2a versus Peg-IFNα-2b in the treatment of CHB. PATIENTS AND METHODS Fifty-one CHB patients treated with 48 weeks of Peg-IFNα-2a (n=24) and Peg-IFNα-2b (n=27) who had been followed up between 2009 and 2011 at the Liver Clinic of Adana Numune Training and Research Hospital, Turkey, were investigated retrospectively. Six (25%) patients in the Peg-IFNα-2a group and nine (33%) in the Peg-IFNα-2b group were HBeAg-positive. Serum HBV-DNA, HBeAg, and HBsAg values were assessed at baseline. Biochemical and virological responses were evaluated every 12 weeks during the course of the treatment, at the end of the treatment, and follow-up week 24. Sustained virological response (SVR) was defined as sustained inhibition of viral replication (HBV-DNA<10 000 copies/ml) and a normal alanine aminotransaminase level until 24 weeks after treatment. Undetectable HBV-DNA was considered as less than 400 copies/ml. RESULTS Six of the 24 (25%) patients treated with Peg-IFNα-2a versus eight of the 27 (29.6%) patients treated with Peg-IFNα-2b achieved an SVR (P=0.75). HBeAg seroconversion occurred in three patients only in the Peg-IFNα-2b group. Rates of patients with undetectable HBV-DNA at 24 weeks after a 48-week course of therapy were 20.8% for Peg-IFNα-2a and 22.2% for Peg-IFNα-2b (P=0.82). CONCLUSION In CHB, there were no significant differences between Peg-IFNα-2a and Peg-IFNα-2b treatment groups in achieving an SVR and undetectable HBV-DNA levels.
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Sonneveld MJ, Zoutendijk R, Hansen BE, Janssen HLA. Pegylated interferon results in higher serological, but not virological, response rates when compared to continuous entecavir. Antivir Ther 2012; 17:1605-8. [PMID: 22898565 DOI: 10.3851/imp2319] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2012] [Indexed: 10/28/2022]
Abstract
BACKGROUND Hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) clearance are associated with an improved prognosis in chronic hepatitis B (CHB) patients. These end points are more often achieved with a one-year course of pegylated interferon (PEG-IFN) compared with one year of nucleoside/nucleotide analogue therapy. However, prolonged nucleoside/nucleotide analogue therapy may result in comparable serological response rates as with PEG-IFN. METHODS We compared serological and virological response rates among HBeAg-positive CHB patients treated with long-term continuous entecavir (ETV; n=91) for a median of 92 (IQR 50-132) weeks or one year of PEG-IFN (n=266) with comparable follow-up. RESULTS Median follow-up was 92 weeks (IQR 78-198) for patients treated with PEG-IFN and 92 weeks (IQR 50-132) for patients treated with ETV. Finite PEG-IFN therapy resulted in significantly higher rates of HBeAg seroconversion (adjusted hazard ratio [HR] 3.16; P<0.001) and HBsAg clearance (HR 5.66; P=0.027) when compared to prolonged ETV treatment, whereas, ETV resulted in higher rates of HBV DNA undetectability (OR 31.14; P<0.001) also after adjustment for HBV genotype and other relevant baseline factors. CONCLUSIONS Our study shows that finite PEG-IFN is associated with a higher probability of serological, but not virological, response for HBeAg-positive CHB patients when compared to prolonged ETV, even after correction for baseline differences.
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Affiliation(s)
- Milan J Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
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14
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Abstract
Hepatitis B may cause a varying spectrum of diseases ranging from an asymptomatic or mild anicteric acute illness, to severe or fulminant hepatitis. Similarly, the outcome of chronic hepatitis B is variable. Viral factors associated with outcome of chronic hepatitis B virus (HBV) infection include hepatitis B e antigen status, HBV DNA, genotype, and HBV variants. HBV genotypes and subgenotypes have been associated with differences in clinical and virological characteristics, indicating that they may play a role in the virus-host relationship. A total of ten hepatitis B virus genotypes have been defined with a distinct geographical distribution. Hitherto, genotypes A, B, C and D have been studied most extensively. The HBV genotype appears to influence not only the natural history of HBV related liver disease but also the response to HBV treatment. HBV genotypes are also linked with both core promoter and BCP mutations. Progression to chronic infection appears to occur more frequently following acute infection with genotypes A and D than with the other studied genotypes. Genotypes A and B appear to have higher rates of spontaneous HBeAg seroconversion. More advanced liver disease and progression to HCC is more often seen in chronic infection with genotypes C and D in contrast to genotypes A and B. More specifically, genotypes A1, C, B2-B5 and H appear to be associated with more serious complications than genotypes A2, B1 and B6. These observations suggest important pathogenic differences between HBV genotypes. Genotypes A and B have higher response rates to interferon based therapy than genotypes C and D. Knowledge of HBV genotype enables clinicians to identify those patients at increased risk of disease progression whilst aiding the selection of appropriate antiviral therapy. Genotyping and monoclonal subtyping can provide useful information for epidemiological studies. In conclusion, genotyping of chronic HBV infections can help practicing physicians identify those at risk of disease progression and determine optimal anti-viral therapy.
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Affiliation(s)
- Sudeep Tanwar
- Centre for Hepatology, University College London Royal Free Campus, Rowland Hill Street Hampstead, London, NW3 2PF, UK.
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15
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Rijckborst V, Sonneveld MJ, Janssen HLA. Review article: chronic hepatitis B - anti-viral or immunomodulatory therapy? Aliment Pharmacol Ther 2011; 33:501-13. [PMID: 21198707 DOI: 10.1111/j.1365-2036.2010.04555.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND First-line treatment options for chronic hepatitis B (CHB) consist of nucleos(t)ide analogues with a high barrier to resistance (entecavir and tenofovir) or the immunomodulatory agent peginterferon (PEG-IFN). The optimal choice for individual patients remains controversial. AIM To review treatment options for CHB, with a focus on deciding between prolonged nucleos(t)ide analogue therapy or a finite course of PEG-IFN. METHODS A comprehensive literature search was undertaken. RESULTS Long-lasting, treatment-maintained suppression of hepatitis B virus (HBV) DNA without resistance is achievable in most patients by entecavir or tenofovir. A sustained off-treatment response is, however, unlikely and long-term therapy must be anticipated. PEG-IFN offers a higher rate of sustained response in a subgroup of patients, but is frequently complicated by side effects. Pre-treatment predictors of response, including HBV genotype, alanine aminotransferase and HBV DNA levels, aid in selecting patients for PEG-IFN therapy. Furthermore, on-treatment markers such as quantitative hepatitis B surface antigen may be applied to identify nonresponders early during the PEG-IFN treatment course, thereby preventing unnecessary treatment. CONCLUSIONS Both nucleos(t)ide analogues and PEG-IFN can be prescribed as first-line treatment options for CHB. However, PEG-IFN should only be considered for patients with a high chance of response based on pre-treatment and on-treatment factors.
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Affiliation(s)
- V Rijckborst
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
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16
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Ali L, Idrees M, Ali M, Rehman IU, Hussain A, Afzal S, Butt S, Saleem S, Munir S, Badar S. An overview of treatment response rates to various anti-viral drugs in Pakistani hepatitis B virus infected patients. Virol J 2011; 8:20. [PMID: 21235813 PMCID: PMC3027132 DOI: 10.1186/1743-422x-8-20] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2010] [Accepted: 01/15/2011] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) is one of the leading health problem with up to 350 million affected people worldwide including 4.5 million only in Pakistan. It has mortality rate of 0.5 to 1.2 million per year worldwide. Pakistan lies in the endemic region with 3-5% HBV carrier rate in the country. The present article reviews the literature on the treatment response of HBV prevalent in Pakistani population. The average treatment response of Lamivudine and interferon-α is 25.81% and 47.95%, respectively. Peg-Interferon was shown to be not effective against the HBV/HCV (hepatitis C virus)/HDV (hepatitis Delta virus) co-infection. The present study reveals that interferon-α is the most effective therapy available for HBV infection prevalent in Pakistani population. Genotype C & D are the most common HBV genotypes in Pakistan and are associated with increased severity and less response to interferon therapy. This poses a great challenge for physicians and researchers and further studies are needed to describe the outcome of the current therapies recommended against HBV infection in Pakistani population.
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Affiliation(s)
- Liaqat Ali
- Division of Molecular Virology, National Centre of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Thoker Niaz Baig, Lahore 53700, Pakistan.
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17
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Abstract
Pegylated interferon-α (PEG-IFN) is still an important treatment option for both HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB) patients even with the availability of potent nucleos(t)ide analogues (NUCs) with a low risk of resistance. The major advantages of PEG-IFN-based treatment include the limited duration of treatment and the good probability of achieving a sustained off-treatment response. Responders to PEG-IFN have an increased probability of HBsAg loss and survival. However, the limited number of patients who achieve a response and the high costs and side-effects associated with PEG-IFN limit its clinical use. The potent NUCs entecavir and tenofovir are therefore often used as a first-line treatment option. Unfortunately, the off-treatment durability of response to NUCs is generally low, requiring long-term continuous therapy. Recent progress making it possible to select patients with a high probability of achieving a response to PEG-IFN, and to adapt therapy early on in probable non-responders, should help further optimize the utilization of PEG-IFN in CHB.
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Affiliation(s)
- Milan J Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
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18
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Abstract
Despite the introduction of new nucleos(t)ide analogues in recent years, peginterferon is still recommended as a potential first-line treatment option by current practice guidelines for the management of chronic hepatitis B. Peginterferon offers the advantage of higher sustained off-treatment response rates compared to nucleos(t)ide analogues because of its immunomodulatory effects. Sustained transition to the inactive hepatitis B surface antigen (HBsAg) carrier state can be achieved in about 30% of hepatitis B e antigen (HBeAg)-positive patients and 20% of HBeAg-negative patients. Recent studies have focused on identification of pretreatment and on-treatment factors that allow the selection of patients who are likely to achieve a sustained response to peginterferon therapy in order to avoid the side-effects and costs associated with unnecessary treatment. Future studies need to address whether specific virologic benchmarks can guide individualized decisions concerning therapy continuation and whether peginterferon combined with new potent nucleos(t)ide analogues improves treatment outcomes.
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Affiliation(s)
- Vincent Rijckborst
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, ’s Gravendijkwal 230, Room Ca 415, 3015 CE Rotterdam, The Netherlands
| | - Harry L. A. Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, ’s Gravendijkwal 230, Room Ha 204, 3015 CE Rotterdam, The Netherlands
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19
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Sonneveld MJ, Rijckborst V, Boucher CAB, Hansen BE, Janssen HLA. Prediction of sustained response to peginterferon alfa-2b for hepatitis B e antigen-positive chronic hepatitis B using on-treatment hepatitis B surface antigen decline. Hepatology 2010; 52:1251-7. [PMID: 20830787 DOI: 10.1002/hep.23844] [Citation(s) in RCA: 226] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
UNLABELLED Serum hepatitis B surface antigen (HBsAg) levels may reflect the immunomodulatory efficacy of pegylated interferon (PEG-IFN). We investigated within a large randomized trial whether quantitative HBsAg levels predict response to PEG-IFN in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. Serum HBsAg was measured in samples taken at baseline and weeks 4, 8, 12, 24, 52, and 78 of 221 patients treated with PEG-IFN alfa-2b with or without lamivudine for 52 weeks. HBsAg decline was compared between treatment arms and between responders and nonresponders. Response was defined as HBeAg loss with HBV DNA < 10,000 copies/mL at 26 weeks after treatment (week 78); 43 of 221 (19%) patients achieved a response. One year of PEG-IFN with or without lamivudine resulted in a significant decline in serum HBsAg, which was sustained after treatment (decline 0.9 log IU/mL at week 78, P < 0.001). Patients treated with combination therapy experienced a more pronounced on-treatment decline, but relapsed subsequently. Responders experienced a significantly more pronounced decline in serum HBsAg compared to nonresponders (decline at week 52: 3.3 versus 0.7 log IU/mL, P < 0.001). Patients who achieved no decline at week 12 had a 97% probability of nonresponse through posttreatment follow-up and no chance of HBsAg loss. In a representative subset of 149 patients similar results were found for prediction through long-term (mean 3.0 years) follow-up. CONCLUSION PEG-IFN induces a significant decline in serum HBsAg in HBeAg-positive patients. Patients who experience no decline from baseline at week 12 have little chance of achieving a sustained response and no chance of HBsAg loss and should be advised to discontinue therapy with PEG-IFN.
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Affiliation(s)
- Milan J Sonneveld
- Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
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20
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Yang JF, Kao YH, Dai CY, Huang JF, Hsieh MY, Lin ZY, Chen SC, Hsieh MY, Wang LY, Chuang WL, Yu ML. Comparison of adverse effects related to pegylated interferon-based therapy for patients with chronic hepatitis B and chronic hepatitis C in Taiwan. Hepatol Int 2010; 4:732-740. [PMID: 21286344 PMCID: PMC2994613 DOI: 10.1007/s12072-010-9208-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2009] [Accepted: 07/21/2010] [Indexed: 02/07/2023]
Abstract
PURPOSE Pegylated interferon (Peg-IFN)-based therapy is effective in treating chronic hepatitis B (CHB) and C (CHC) but frequently induces adverse events (AEs). This study was conducted to compare the incidence of Peg-IFN-based therapy-associated AEs in Taiwanese patients with CHB and CHC. METHODS Fifty-six patients with CHB and 103 age-, sex- and treatment duration-matched patients with CHC were enrolled. Patients with CHB were treated with Peg-IFN-α-2a 180 μg/week for 24 weeks (HBeAg(+), n = 31) or 48 weeks (HBeAg(-), n = 25); patients with CHC were treated with Peg-IFN-α-2a 180 μg/week plus ribavirin 1,000-1,200 mg/day for 24 weeks (genotype 2/3, n = 57) or 48 weeks (genotype 1, n = 46). RESULTS Significantly higher incidences of Peg-IFN-related AEs, especially neuropsychiatric symptoms, and ribavirin-associated skin manifestations were observed in patients with CHC compared with those with CHB, with either the 24- or 48-week regimen. Frequencies of laboratory abnormalities, except for anemia, were comparable in both groups. Neither group showed overt hepatic decompensation. Frequency of dose reduction was similar between the groups. Substantially higher rates of early termination and severe AEs were observed in patients with CHC. CONCLUSIONS Patients with CHB treated with Peg-IFN had fewer AEs than patients with CHC treated with Peg-IFN/ribavirin. All patients were treated safely.
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Affiliation(s)
- Jeng-Fu Yang
- Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yi-Hui Kao
- School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan
| | - Ming-Yen Hsieh
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Yuh Hsieh
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Liang-Yen Wang
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
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Sonneveld MJ, Janssen HLA. Pros and Cons of Peginterferon Versus Nucleos(t)ide Analogues for Treatment of Chronic Hepatitis B. CURRENT HEPATITIS REPORTS 2010; 9:91-98. [PMID: 20461129 PMCID: PMC2861769 DOI: 10.1007/s11901-010-0041-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The emergence of new and more potent treatment options has markedly changed the treatment landscape of chronic hepatitis B. Both peginterferon and nucleos(t)ide analogues have considerable advantages and limitations, and current treatment guidelines refrain from clearly suggesting a first-line treatment option. Peginterferon offers the advantage of higher sustained response rates in both hepatitis B early antigen (HBeAg)-positive and HBeAg-negative patients, at the price of considerable side effects and high costs. Nucleos(t)ide analogues offer easy daily oral dosing, and newly registered agents can maintain viral suppression for prolonged treatment duration. However, relapse is common after therapy discontinuation and extended therapy therefore often necessary. Prolonged treatment with nucleos(t)ide analogues may enhance chances of virologic and serologic response at the potential cost of the emergence of viral resistance and side effects. Baseline and on-treatment prediction of response may help select patients for peginterferon therapy and can aid individualized treatment decisions concerning therapy continuation or discontinuation.
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Affiliation(s)
- Milan J. Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, ‘s Gravendijkwal 230, Room Ca4.19 3015 CE, Rotterdam, The Netherlands
| | - Harry L. A. Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, ‘s Gravendijkwal 230, Room Ha206 3015 CE, Rotterdam, The Netherlands
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22
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Yang J, Zhao LS. Clinical significance of 4 patients with chronic hepatitis B achieving HBsAg clearance by treated with pegylated interferon alpha-2a for less than 1 year: a short report. Virol J 2009; 6:97. [PMID: 19583877 PMCID: PMC2714489 DOI: 10.1186/1743-422x-6-97] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2009] [Accepted: 07/08/2009] [Indexed: 02/05/2023] Open
Abstract
We report 4 chinese patients with hepatitis B e antigen-positive chronic hepatitis B achieving clearance of HBsAg by using pegylated interferon alpha-2a for less than 1 year, to provide one clinical clue for the treatment of chronic hepatitis B.
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Affiliation(s)
- Jin Yang
- Center of Infectious Diseases, National Key Laboratory of Biotherapy for Human Diseases, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
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23
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QIE J, MA J, WANG L, XU X, ZHOU W, QI C, ZHAO X, ZHANG Y, LIU K. Site-directed PEGylations of Thymosin α1 Analogs and Evaluation of Their Immunoactivity. CHINESE J CHEM 2009. [DOI: 10.1002/cjoc.200990134] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Buster EHCJ, Schalm SW, Janssen HLA. Peginterferon for the treatment of chronic hepatitis B in the era of nucleos(t)ide analogues. Best Pract Res Clin Gastroenterol 2008; 22:1093-108. [PMID: 19187869 DOI: 10.1016/j.bpg.2008.11.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The practising clinician is currently faced with a number of effective treatment options for chronic hepatitis B, including two formulations of interferon (standard IFN and pegylated IFN) and five nucleos(t)ide analogues (lamivudine, adefovir, entecavir, telbivudine and tenofovir). Treatment strategies can be divided into those aiming for sustained response after discontinuation of therapy and those that need to be maintained by prolonged antiviral therapy. Sustained response is particularly achieved with interferon-based therapy, while treatment-maintained response can be achieved with long-term nucleos(t)ide analogue therapy in the majority of patients. Of currently available drugs for the treatment of chronic hepatitis B, PEG-IFN seems to result in the highest rate of off-treatment sustained response after a 1-year course of therapy. Sustained transition to the immune-control phase (inactive HBsAg carrier state) can be achieved in 30-35% of HBeAg-positive patients and 20-25% of HBeAg-negative patients. Loss of HBsAg has been observed in 11% of both HBeAg-positive and HBeAg-negative patients after 3-4 years. Since hepatitis B virus (HBV) genotype is an important predictor of response to PEG-IFN, determination of HBV genotype is essential in patients in whom sustained off-treatment response is pursued. Aiming for sustained response is of particular interest because many HBV-infected patients are in need of antiviral therapy at a young age and may otherwise require indefinite antiviral therapy.
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Affiliation(s)
- Erik H C J Buster
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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25
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Abstract
Interferons, IFNs, are among the most widely studied and clinically used biopharmaceuticals. Despite their invaluable therapeutic roles, the widespread use of IFNs suffers from some inherent limitations, mainly their relatively short circulation lifespan and their unwanted effects on some non-target tissues. Therefore, both these constraints have become the central focus points for the research efforts on the development of a variety of novel delivery systems for these therapeutic agents with the ultimate goal of improving their therapeutic end-points. Generally, the delivery systems currently under investigation for IFNs can be classified as particulate delivery systems, including micro- and nano-particles, liposomes, minipellets, cellular carriers, and non-particulate delivery systems, including PEGylated IFNs, other chemically conjugated IFNs, immunoconjugated IFNs, and genetically conjugated IFNs. All these strategies and techniques have their own possibilities and limitations, which should be taken into account when considering their clinical application. In this article, currently studied delivery systems/techniques for IFN delivery have been reviewed extensively, with the main focus on the pharmacokinetic consequences of each procedure.
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Affiliation(s)
- Mehrdad Hamidi
- Department of Pharmaceutics, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
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26
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Carosi G, Rizzetto M. Treatment of chronic hepatitis B: recommendations from an Italian workshop. Dig Liver Dis 2008; 40:603-617. [PMID: 18499540 DOI: 10.1016/j.dld.2008.03.011] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2008] [Revised: 03/03/2008] [Accepted: 03/04/2008] [Indexed: 12/11/2022]
Abstract
The changing scenario of hepatitis B virus therapy has encouraged the organisation of a workshop, endorsed by three Italian scientific societies, aimed at defining the current recommendations for hepatitis B virus treatment. Liver histology and stage of disease remain fundamental for treatment decisions; interferon and nucleoside/nucleotide analogues-based therapy represent different strategies for different phases of the hepatitis B virus disease. The recommendations defined: new and lower cut-off of hepatitis B virus-DNA for eligibility to therapy according to disease stage, how to optimise the use of nucleoside/nucleotide analogues and to individualise the monitoring of response and what to do with treatment failures. Specific recommendations have also been given for cirrhosis patients, those immune suppressed and co-infected with HIV and other hepatitis viruses.
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Affiliation(s)
- G Carosi
- Department of Infectious and Tropical Diseases, University of Brescia, AO Spedali Civili, Brescia, Italy.
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27
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Bell SJ, Fam CM, Chlipala EA, Carlson SJ, Lee JI, Rosendahl MS, Doherty DH, Cox GN. Enhanced Circulating Half-Life and Antitumor Activity of a Site-Specific Pegylated Interferon-α Protein Therapeutic. Bioconjug Chem 2007; 19:299-305. [DOI: 10.1021/bc070131q] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Stacie J. Bell
- Bolder BioTechnology, Inc., 2945 Wilderness Place, Boulder, Colorado 80301, and BolderPATH, Inc., Campus Box 347, University of Colorado, Boulder, Colorado 80309
| | - Christine M. Fam
- Bolder BioTechnology, Inc., 2945 Wilderness Place, Boulder, Colorado 80301, and BolderPATH, Inc., Campus Box 347, University of Colorado, Boulder, Colorado 80309
| | - Elizabeth A. Chlipala
- Bolder BioTechnology, Inc., 2945 Wilderness Place, Boulder, Colorado 80301, and BolderPATH, Inc., Campus Box 347, University of Colorado, Boulder, Colorado 80309
| | - Sharon J. Carlson
- Bolder BioTechnology, Inc., 2945 Wilderness Place, Boulder, Colorado 80301, and BolderPATH, Inc., Campus Box 347, University of Colorado, Boulder, Colorado 80309
| | - Ji I. Lee
- Bolder BioTechnology, Inc., 2945 Wilderness Place, Boulder, Colorado 80301, and BolderPATH, Inc., Campus Box 347, University of Colorado, Boulder, Colorado 80309
| | - Mary S. Rosendahl
- Bolder BioTechnology, Inc., 2945 Wilderness Place, Boulder, Colorado 80301, and BolderPATH, Inc., Campus Box 347, University of Colorado, Boulder, Colorado 80309
| | - Daniel H. Doherty
- Bolder BioTechnology, Inc., 2945 Wilderness Place, Boulder, Colorado 80301, and BolderPATH, Inc., Campus Box 347, University of Colorado, Boulder, Colorado 80309
| | - George N. Cox
- Bolder BioTechnology, Inc., 2945 Wilderness Place, Boulder, Colorado 80301, and BolderPATH, Inc., Campus Box 347, University of Colorado, Boulder, Colorado 80309
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29
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Rudin D, Shah SM, Kiss A, Wetz RV, Sottile VM. Interferon and lamivudine vs. interferon for hepatitis B e antigen-positive hepatitis B treatment: meta-analysis of randomized controlled trials. Liver Int 2007; 27:1185-93. [PMID: 17919229 PMCID: PMC2156150 DOI: 10.1111/j.1478-3231.2007.01580.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
AIMS To compare interferon monotherapy with its combination with lamivudine for hepatitis B e antigen (HBeAg)-positive hepatitis B treatment. METHODS Two independent researchers identified pertinent randomized controlled trials. The trials were evaluated for methodological quality and heterogeneity. Rates of sustained virological and biochemical responses, and HBeAg clearance and seroconversion were used as primary efficacy measures. Quantitative meta-analyses were conducted to assess differences between groups for conventional and pegylated interferon, and overall. RESULTS Greater sustained virological, biochemical and seroconversion rates were observed with addition of lamivudine to conventional [odds ratio (OR)=3.1, 95% confidence intervals (CI) (1.7-5.5), P<0.0001, OR=1.8, 95% CI (1.2-2.7), P=0.007 and OR=1.8, 95% CI (1.1-2.8), P=0.01 respectively], although not pegylated [OR=1.1, 95% CI (0.5-2.3), P=0.8, OR=1.0, 95% CI (0.7-1.3), P=0.94, and OR=0.9, 95% CI (0.6-1.2), P=0.34 respectively] interferon-alpha, with no significant affect on HBeAg clearance rates [OR=1.6, 95% CI (0.9-2.7), P=0.09, and OR=0.8, 95% CI (0.6-1.1), P=0.26 respectively]. Excluding virological response (P<0.001), pegylated interferon monotherapy and conventional interferon and lamivudine combination therapy were similarly efficacious (P>0.05), with the former studied in harder to treat patients, as evidenced by the superior virological response observed with conventional as compared with pegylated interferon monotherapy (P<0.0001). CONCLUSION In comparable populations, pegylated interferon monotherapy is likely to be equally or more efficacious than conventional interferon and lamivudine combination therapy, thus constituting the treatment of choice, with no added benefit with lamivudine addition. However, when conventional interferon is used, its combination with lamivudine should be considered.
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Affiliation(s)
- Dan Rudin
- Department of Internal Medicine, Staten Island University Hospital, Staten Island, NY 10305, USA.
| | - Sooraj M Shah
- Department of Internal Medicine, Staten Island University HospitalStaten Island, NY, USA
| | - Alexander Kiss
- Department of Research Design and Biostatistics, Sunnybrook Health Sciences CenterToronto, ON, Canada,Institute for Clinical Evaluative SciencesToronto, ON, Canada
| | - Robert V Wetz
- Department of Internal Medicine, Staten Island University HospitalStaten Island, NY, USA
| | - Vincent M Sottile
- Department of Gastroenterology, Staten Island University HospitalStaten Island, NY, USA
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30
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Vassiliadis T, Tziomalos K, Patsiaoura K, Zagris T, Giouleme O, Soufleris K, Grammatikos N, Theodoropoulos K, Mpoumponaris A, Dona K, Zezos P, Nikolaidis N, Orfanou-Koumerkeridou E, Balaska A, Eugenidis N. Lamivudine/pegylated interferon alfa-2b sequential combination therapy compared with lamivudine monotherapy in HBeAg-negative chronic hepatitis B. J Gastroenterol Hepatol 2007; 22:1582-1588. [PMID: 17683500 DOI: 10.1111/j.1440-1746.2007.05103.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND AND AIM Monotherapy has been proven insufficient in achieving sustained control of chronic hepatitis B. We aimed to assess the efficacy of combined sequential administration of lamivudine and pegylated interferon alfa-2b in patients with hepatitis Be antigen (HBeAg)-negative chronic hepatitis B. METHODS Eighteen patients were given sequential combination treatment starting with 3 months of lamivudine monotherapy followed by 9 months of pegylated interferon alfa-2b (after a 3-month period of concomitant administration of the two drugs) and 24 patients received lamivudine monotherapy. RESULTS At the end of treatment, 88.9% of the patients who received sequential combination treatment and 70.8% of those who received lamivudine monotherapy had hepatitis B virus (HBV) DNA levels below 400 copies/mL (P = not significant). At the end of treatment, 72.2% of the patients who received sequential combination treatment and 70.8% of those who received lamivudine monotherapy achieved alanine aminotransferase normalization (P = not significant). After 12 months of follow up, 33.3% of the patients who received sequential combination treatment and 16.7% of those who received lamivudine monotherapy had HBV-DNA levels below 400 copies/mL (P = 0.4). After 12 months of follow up, 72.2% of the patients who received sequential combination treatment and 25.0% of those who received lamivudine monotherapy had normal alanine aminotransferase levels (P < 0.01). Twenty-five percent of the patients in the lamivudine monotherapy group had virological breakthrough compared to none in the sequential combination treatment group (P = 0.06). CONCLUSIONS Sequential combination treatment is able to improve sustained biochemical response rates and prevent the emergence of lamivudine-resistant mutants in patients with HBeAg-negative chronic hepatitis B.
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Affiliation(s)
- Themistoklis Vassiliadis
- 2nd Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
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31
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Lian M, Zhou X, Wei L, Qiu S, Zhou T, Li L, Gu X, Luo M, Zheng X. Serum levels of preS antigen (HBpreSAg) in chronic hepatitis B virus infected patients. Virol J 2007; 4:93. [PMID: 17892580 PMCID: PMC2082030 DOI: 10.1186/1743-422x-4-93] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2007] [Accepted: 09/24/2007] [Indexed: 12/24/2022] Open
Abstract
Background Hepatitis B virus (HBV) infection is a serious health problem worldwide. Treatment recommendation and response are mainly indicated by viral load, e antigen (HBeAg) seroconversion, and ALT levels. The S antigen (HBsAg) seroconversion is much less frequent. Since HBeAg can be negative in the presence of high viral replication, preS antigen (HBpreSAg) might be a useful indicator in management of chronic HBV infection. Results A new assay of double antibody sandwich ELISA was established to detect preS antigens. Sera of 104 HBeAg-negative and 50 HBeAg-positive chronic hepatitis B patients have been studied and 23 HBeAg-positive patients were enrolled in a treatment follow-up study. 70% of the HBeAg-positive patients and 47% of the HBeAg-negative patients showed HBpreSAg positive. Particularly, in the HBeAg-negative patients, 30 out of 47 HBpreSAg positive patients showed no evidence of viral replication based on HBV DNA copies. A comparison with HBV DNA copies demonstrated that the overall accuracy of the HBpreSAg test could reach 72% for active HBV replication. HBpreSAg changes were well correlated with changes of HBsAg, HBV DNA and ALT levels during the course of IFN-α treatment and follow-up. HBeAg positive patients responded well to treatment when reduction of HBpreSAg levels was more pronounced. Conclusion Our results suggested that HBpreSAg could be detected effectively, and well correlated with HBsAg and HBV DNA copies. The reduction of HBpreSAg levels in conjunction with the HBV DNA copies appears to be an improved predictor of treatment outcome.
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Affiliation(s)
- Min Lian
- National Laboratory of Protein Engineering and Plant Genetic Engineering, Peking University, Beijing, 100871, China
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Peking University, Beijing, 100871, China
| | - Xu Zhou
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Peking University, Beijing, 100871, China
| | - Lai Wei
- Peking University People's Hospital, Beijing, 100014, China
| | - Shihong Qiu
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA
| | - Tong Zhou
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA
| | - Lanfen Li
- National Laboratory of Protein Engineering and Plant Genetic Engineering, Peking University, Beijing, 100871, China
| | - Xiaocheng Gu
- National Laboratory of Protein Engineering and Plant Genetic Engineering, Peking University, Beijing, 100871, China
| | - Ming Luo
- National Laboratory of Protein Engineering and Plant Genetic Engineering, Peking University, Beijing, 100871, China
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA
| | - Xiaofeng Zheng
- National Laboratory of Protein Engineering and Plant Genetic Engineering, Peking University, Beijing, 100871, China
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Peking University, Beijing, 100871, China
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32
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Berraondo P, Ochoa L, Crettaz J, Rotellar F, Vales A, Martínez-Ansó E, Zaratiegui M, Ruiz J, González-Aseguinolaza G, Prieto J. IFN-alpha gene therapy for woodchuck hepatitis with adeno-associated virus: differences in duration of gene expression and antiviral activity using intraportal or intramuscular routes. Mol Ther 2006; 12:68-76. [PMID: 15963922 DOI: 10.1016/j.ymthe.2005.02.017] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2004] [Revised: 02/21/2005] [Accepted: 02/23/2005] [Indexed: 12/09/2022] Open
Abstract
Gene delivery of IFN-alpha to the liver may represent an interesting strategy to maximize its antiviral efficacy and reduce side effects. We used a recombinant adeno-associated virus (AAV) encoding woodchuck IFN-alpha (AAV-IFN) to treat animals with chronic woodchuck hepatitis virus infection. The vector was given by intraportal or intramuscular route. Long-term transgene expression was detected after intraportal administration of an AAV encoding luciferase. In contrast, in the majority of the animals that received AAV-IFN through the portal vein, the expression of IFN-alpha was transient (30-40 days) and was associated with a significant but transient decrease in viral load. One animal, in which hepatic production of IFN-alpha persisted at high levels, died because of bone marrow toxicity. The disappearance of IFN-alpha expression correlated with the disappearance of AAV genomes from the liver. Intramuscular administration of AAV-IFN resulted in prolonged but fluctuating expression of the cytokine with no significant antiviral effect. In summary, this report shows that long-term expression of IFN-alpha in muscle is feasible but higher interferon levels might be needed to control viral replication. On the other hand, IFN-alpha gene delivery to the liver using an AAV vector induces a significant but transient antiviral effect in the woodchuck model.
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Affiliation(s)
- Pedro Berraondo
- Laboratory of Gene Therapy of Viral Hepatitis, Division of Hepatology and Gene Therapy, Clínica Universitaria/School of Medicine, Center for Applied Medical Research, University of Navarra, 31080 Pamplona, Navarra, Spain
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33
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Vassiliadis T, Patsiaoura K, Tziomalos K, Gkiourtzis T, Giouleme O, Grammatikos N, Rizopoulou D, Nikolaidis N, Katsinelos P, Orfanou-Koumerkeridou E, Eugenidis N. Pegylated IFN-alpha 2b added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B. World J Gastroenterol 2006; 12:2417-2422. [PMID: 16688836 PMCID: PMC4088081 DOI: 10.3748/wjg.v12.i15.2417] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2005] [Revised: 12/22/2005] [Accepted: 01/14/2006] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the role of pegylated-interferon (IFN) alpha-2b in the management of patients with lamivudine-resistant chronic hepatitis B. METHODS Twenty consecutive anti-HBe positive patients were treated with pegylated IFN alpha-2b (100 mug sc once weekly) for 12 mo. There was no interruption in lamivudine therapy. Hematology, liver biochemistry, serum HBV DNA levels were detected by PCR, and vital signs were also assessed. Liver histology was assessed in some patients at entry and at wk 52 for comparison. RESULTS Nine patients (45%) had a partial virological end-treatment response; seven patients (35%) showed complete virological end-treatment response. Eight patients (40%) showed biochemical end-treatment response. There was a trend for higher virological response rates in patients who had previously responded to IFN and relapsed compared to IFN non-responders (four out of seven patients vs none out of six patients, respectively; P=0.1). Patients without virological end-treatment response showed significant worsening of fibrosis [median score 2 (range, 1 to 3) vs median score 3 (range, 1 to 4)], in the first and second biopsy respectively (P=0.014), whereas necroinflammatory activity was not significantly affected. Patients with complete or partial virological end-treatment response did not show any significant changes in histological findings, possibly due to the small number of patients with paired biopsies (n=5). Nevertheless, after 12 mo of follow-up, only one patient (5%) showed sustained virological response and only 2 patients (10%) showed sustained biochemical response. Two patients (10%) discontinued pegylated IFN both after 6 mo of treatment due to flu-like symptoms. CONCLUSION Pegylated IFNalpha-2b, when added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B, induces sustained responses only in a small minority of cases.
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Affiliation(s)
- Themistoklis Vassiliadis
- 2 ndPropaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki, Greece
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Abstract
The last 40 years have seen the development of several antiviral drugs with therapeutic value in treating life-threatening or debilitating diseases such as those caused by HIV, hepatitis B virus, herpesviruses (such as herpes simplex virus and varicella zoster virus) and influenza virus. These relatively recent advances have been due to technical breakthroughs in the cultivation of viruses in the laboratory, identification of viral enzymes and, more recently, their molecular biology. We describe here the antecedence of several of the existing antivirals and their strengths and weaknesses. We indicate where the major challenges lie for future improvements of current therapies and possible new indications, such as hepatitis C virus and papillomavirus. We also describe how current antiviral therapies are restricted to a rather limited number of viral diseases of sufficient interest to the pharmaceutical industry. Finally we describe the potential threat of emerging viruses and bio-weapons and the challenges that they present to therapy.
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35
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Current Management: Viral Hepatitis. APOLLO MEDICINE 2005. [DOI: 10.1016/s0976-0016(11)60516-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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36
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Gish RG. Current treatment and future directions in the management of chronic hepatitis B viral infection. Clin Liver Dis 2005; 9:541-65, v. [PMID: 16207563 DOI: 10.1016/j.cld.2005.08.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The World Health Organization places hepatitis B virus (HBV) in the top 10 causes of death worldwide. It is estimated that there are over 400 million carriers of HBV as well. At least 20% to 30% of hepatitis B surface antigen (HBsAg) carriers will die of complications of chronic liver disease, including cirrhosis and liver cancer. The serious consequences of end-stage liver disease and liver cancer occur in 30% of chronic carriers and confront patients and physicians throughout the world. Vaccination is the major form of treatment (prevention) that may eventually eliminate HBV worldwide. This article discusses the currently available treatments as well as evolving treatments for chronic HBV infection.
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Affiliation(s)
- Robert G Gish
- Department of Medicine, Division of Hepatology and Complex GI, Physicians Foundation, California Pacific Medical Center, 2340 Clay Street, Room 232, San Francisco, CA 94115, USA.
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37
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Pawlotsky J. Application of Molecular Biology to the Diagnosis of Viral Hepatitis. VIRAL HEPATITIS 2005:755-768. [DOI: 10.1002/9780470987131.ch49] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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38
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Asmuth DM, Nguyen HH, Melcher GP, Cohen SH, Pollard RB. Treatments for hepatitis B. Clin Infect Dis 2004; 39:1353-62. [PMID: 15494913 DOI: 10.1086/425010] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2004] [Accepted: 06/29/2004] [Indexed: 12/13/2022] Open
Abstract
New optimism surrounds treatments for chronic hepatitis B (CHB). Interferon- alpha , lamivudine, and adefovir dipivoxil are currently approved by the United States Food and Drug Administration for the treatment of CHB. All 3 treatments possess unique characteristics with respect to their side effect profiles, potencies, and treatment niches within the spectrum of CHB. New agents, which are in various stages of clinical development, represent potential improvements within existing, as well as novel, classes of antiviral therapy, and they offer significant promise of a cure for the many patients with chronic and progressive hepatitis B. However, there remain many challenges in understanding the implications of drug resistance, the role of combination therapy, and how to define the response to therapy within subsets of patients with hepatitis B.
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Affiliation(s)
- David M Asmuth
- Division of Infectious Diseases, Dept. of Internal Medicine, UC Davis Medical Center, 4150 V St., PSSB G500, Sacramento, CA 95817 , USA.
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Vallet-Pichard A, Pol S. Hepatitis viruses and human immunodeficiency virus co-infection: pathogenesis and treatment. J Hepatol 2004; 41:156-66. [PMID: 15246224 DOI: 10.1016/j.jhep.2004.05.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Anaïs Vallet-Pichard
- Unité d'Hépatologie et Inserm U-370, Hôpital Necker, 149 Rue de S èvres, 75015 Paris, France
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