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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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Boora S, Sharma V, Kaushik S, Bhupatiraju AV, Singh S, Kaushik S. Hepatitis B virus-induced hepatocellular carcinoma: a persistent global problem. Braz J Microbiol 2023; 54:679-689. [PMID: 37059940 PMCID: PMC10235410 DOI: 10.1007/s42770-023-00970-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 04/05/2023] [Indexed: 04/16/2023] Open
Abstract
Hepatitis B virus (HBV) infections are highly prevalent globally, representing a serious public health problem. The diverse modes of transmission and the burden of the chronic carrier population pose challenges to the effective management of HBV. Vaccination is the most effective preventive measure available in the current scenario. Still, HBV is one of the significant health issues in various parts of the globe due to non-response to vaccines, the high number of concealed carriers, and the lack of access and awareness. Universal vaccination programs must be scaled up in neonates, especially in the developing parts of the world, to prevent new HBV infections. Novel treatments like combinational therapy, gene silencing, and new antivirals must be available for effective management. The prolonged infection of HBV, direct and indirect, can promote the growth of hepatocellular carcinoma (HCC). The present review emphasizes the problems and probable solutions for better managing HBV infections, causal risk factors of HCC, and mechanisms of HCC.
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Affiliation(s)
- Sanjit Boora
- Centre for Biotechnology, Maharshi Dayanand University, 124001, Haryana, Rohtak, India
| | - Vikrant Sharma
- Centre for Biotechnology, Maharshi Dayanand University, 124001, Haryana, Rohtak, India
| | | | | | - Sandeep Singh
- Department of Biochemistry, Maharshi Dayanand University, Rohtak, India
| | - Samander Kaushik
- Centre for Biotechnology, Maharshi Dayanand University, 124001, Haryana, Rohtak, India.
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3
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Chen D, Tan X, Chen W, Liu Y, Li C, Wu J, Zheng J, Shen HC, Zhang M, Wu W, Wang L, Xiong J, Dai J, Sun K, Zhang JD, Xiang K, Li B, Ni X, Zhu Q, Gao L, Wang L, Feng S. Discovery of Novel cccDNA Reducers toward the Cure of Hepatitis B Virus Infection. J Med Chem 2022; 65:10938-10955. [PMID: 35973101 DOI: 10.1021/acs.jmedchem.1c02215] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is a worldwide disease that causes thousands of deaths per year. Currently, there is no therapeutic that can completely cure already infected HBV patients due to the inability of humans to eliminate covalently closed circular DNA (cccDNA), which serves as the template to (re)initiate an infection even after prolonged viral suppression. Through phenotypic screening, we discovered xanthone series hits as novel HBV cccDNA reducers, and subsequent structure optimization led to the identification of a lead compound with improved antiviral activity and pharmacokinetic profiles. A representative compound 59 demonstrated good potency and oral bioavailability with no cellular toxicity. In an HBVcircle mouse model, compound 59 showed excellent efficacy in significantly reducing HBV antigens, DNA, and intrahepatic cccDNA levels.
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Affiliation(s)
- Dongdong Chen
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Xuefei Tan
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Wenming Chen
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Yongfu Liu
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Chao Li
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Jun Wu
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Jiamin Zheng
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Hong C Shen
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Meifang Zhang
- Lead Discovery, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Waikwong Wu
- Lead Discovery, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Lin Wang
- pCMC, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Jing Xiong
- pCMC, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Jieyu Dai
- Pharmaceutical Sciences, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Kai Sun
- Pharmaceutical Sciences, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Jitao David Zhang
- Pharmaceutical Science, Roche Innovation Center Basel, Roche Pharma Research & Early Development, Grenzacherstrasse 124, Basel CH-4070, Switzerland
| | - Kunlun Xiang
- Discovery Virology, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Baocun Li
- Discovery Virology, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - XiaoJu Ni
- Discovery Virology, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Qihui Zhu
- Discovery Virology, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Lu Gao
- Discovery Virology, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Li Wang
- Discovery Virology, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Song Feng
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
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Fujimoto K, Fukai M, Urano R, Shinoda W, Ishikawa T, Omagari K, Tanaka Y, Nakagawa A, Okazaki S. Free energy profile of permeation of Entecavir through Hepatitis B virus capsid studied by molecular dynamics calculation. PURE APPL CHEM 2020; 92:1585-1594. [DOI: 10.1515/pac-2020-0109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Abstract
Entecavir, triphosphorylated in liver cells, is an antiviral reagent against Hepatitis B virus (HBV). The reagent inhibits reverse transcription of RNA inside the virus capsid. In the present study, free energy profile of an Entecavir triphosphate (ETVTP) molecule has been calculated when it passes through pores of the capsid along two- and three-fold rotational symmetry axes in order to investigate permeation pathway of the reagent to the inside of the capsid. The calculations have been done based on thermodynamic integration (TI) method combined with all-atomistic molecular dynamic (MD) calculations. A free energy minimum of −19 kJ/mol was found at the entrance of the pore from the outside along the three-fold symmetry axis. This stabilization is from the interaction of negatively charged ETVTP with positively charged capsid methionine residues. This excess free energy concentrates of the reagent at the entrance of the pore by a factor of about 2000. A free energy barrier of approximately 13 kJ/mol was also found near the exit of the pore to the inside of the capsid due to narrow space of the pore surrounded by hydrophobic wall made by proline residues and negatively charged wall by aspartic acid residues. There, ETVTP is partially dehydrated in order to pass through the narrow space, which causes the great free energy loss. Further, the negatively charged residues produce repulsive forces on the ETVTP molecule. In contrast, in the case of the pore along the two-fold symmetry axis, the calculated free energy profile showed shallower free energy minimum, −4 kJ/mol at the entrance in spite of the similarly high barrier, 7 kJ/mol, near the exit of the pore.
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Affiliation(s)
- Kazushi Fujimoto
- Department of Materials Chemistry , Nagoya University , Nagoya , Japan
| | - Motohiro Fukai
- Department of Materials Chemistry , Nagoya University , Nagoya , Japan
| | - Ryo Urano
- Department of Materials Chemistry , Nagoya University , Nagoya , Japan
| | - Wataru Shinoda
- Department of Materials Chemistry , Nagoya University , Nagoya , Japan
| | - Tetsuya Ishikawa
- Department of Radiological and Medical Laboratory Sciences , Nagoya University , Nagoya , Japan
| | - Katsumi Omagari
- Department of Virology and Liver Unit , Nagoya City University , Nagoya , Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit , Nagoya City University , Nagoya , Japan
| | - Atsushi Nakagawa
- Institute for Protein Research , Osaka University , Suita , Japan
| | - Susumu Okazaki
- Department of Materials Chemistry , Nagoya University , Nagoya , Japan
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Abstract
Recent advances in RNA engineering during the last two decades have supported the development of RNA-based therapeutics targeting a variety of human diseases. The broad scope of these emerging drugs clearly demonstrates the versatility of RNA. Ribozymes have been seen as promising candidates in this area. However, efficient intracellular application of ribozymes remains challenging, and other strategies appear to have outperformed ribozymes as molecular drugs. Nevertheless, trans-cleaving ribozymes have been applied for specific cleavage of target mRNAs in order to inhibit undesired gene expression. Furthermore, ribozymes have been engineered to allow site-directed RNA sequence alterations, enabling the correction of genetic misinformation at the RNA level. This chapter provides an overview of ribozyme-based strategies, highlighting the promises and pitfalls for potential therapeutic applications.
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Affiliation(s)
- Darko Balke
- University of Greifswald, Institute of Biochemistry Felix-Hausdorff-Str. 4 17487 Greifswald Germany
| | - Sabine Müller
- University of Greifswald, Institute of Biochemistry Felix-Hausdorff-Str. 4 17487 Greifswald Germany
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Feng S, Gao L, Han X, Hu T, Hu Y, Liu H, Thomas AW, Yan Z, Yang S, Young JAT, Yun H, Zhu W, Shen HC. Discovery of Small Molecule Therapeutics for Treatment of Chronic HBV Infection. ACS Infect Dis 2018; 4:257-277. [PMID: 29369612 DOI: 10.1021/acsinfecdis.7b00144] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The chronic infection of hepatitis B virus (HBV) inflicts 250 million people worldwide representing a major public health threat. A significant subpopulation of patients eventually develop cirrhosis and hepatocellular carcinoma (HCC). Unfortunately, none of the current standard therapies for chronic hepatitis B (CHB) result in a satisfactory clinical cure rate. Driven by a highly unmet medical need, multiple pharmaceutical companies and research institutions have been engaged in drug discovery and development to improve the CHB functional cure rate, defined by sustainable viral suppression and HBsAg clearance after a finite treatment. This Review summarizes the recent advances in the discovery and development of novel anti-HBV small molecules. It is believed that an improved CHB functional cure rate may be accomplished via the combination of molecules with distinct MoAs. Thus, certain molecules may evolve into key components of a suitable combination therapy leading to superior outcome of clinical efficacy in the future.
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Affiliation(s)
- Song Feng
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Lu Gao
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Xingchun Han
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Taishan Hu
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Yimin Hu
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Haixia Liu
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Andrew W. Thomas
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Zhipeng Yan
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Song Yang
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - John A. T. Young
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Hongying Yun
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Wei Zhu
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Hong C. Shen
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
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Straus SE. Unanticipated Risk in Clinical Research ∗ ∗The editors have included Dr. Stephen Straus'original unedited contribution, penned for the book's 2002 edition and published with minor modification in the second edition in 2007, to honor his memory. This is a classic and compelling chapter with a story that remains relevant today. References to regulation and guidelines may not be current. The editors have added current references as of the time of publication to the end of the chapter. PRINCIPLES AND PRACTICE OF CLINICAL RESEARCH 2018:141-159. [DOI: 10.1016/b978-0-12-849905-4.00011-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Abstract
Persistent hepatitis B virus (HBV) infection of hepatocytes is associated with a covalently closed circular DNA (cccDNA) episome. Although serologic hepatitis B surface antigen tests are negative, the presence of cccDNA is obviously increased in HBeAg-positive patients compared with that in HBeAg-negative patients, inactive carriers and patients. Moreover, trace cccDNA levels can also be found in the liver cells of patients with resolved hepatitis B infections. Therefore, clearance of cccDNA in hepatocytes could be an effective cure for HBV. In this review, we summarize the strategies that have been employed to eliminate cccDNA in recent years and discuss the future development of treatments for chronic hepatitis B.
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Karayiannis P. Hepatitis B virus: virology, molecular biology, life cycle and intrahepatic spread. Hepatol Int 2017; 11:500-508. [PMID: 29098564 DOI: 10.1007/s12072-017-9829-7] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 10/05/2017] [Indexed: 12/18/2022]
Abstract
Hepatitis B virus is a member of the Hepadnaviridae family and responsible for causing acute and chronic hepatitis in humans. The current estimates of people chronically infected with the virus are put at 250 million worldwide. Immune-mediated liver damage in these individuals may lead to the development of cirrhosis and hepatocellular carcinoma later in life. This review deals with our current understanding of the virology, molecular biology, life cycle and cell-to-cell spread of this very important pathogen, all of which are considered essential for current and future approaches to antiviral treatment.
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Affiliation(s)
- P Karayiannis
- Medical School, University of Nicosia, 21 Ilia Papakyriakou, 2414 Engomi, P.O. Box 24005, CY-1700, Nicosia, Cyprus.
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Striki A, Manolakopoulos S, Deutsch M, Kourikou A, Kontos G, Kranidioti H, Hadziyannis E, Papatheodoridis G. Hepatitis B s antigen kinetics during treatment with nucleos(t)ides analogues in patients with hepatitis B e antigen-negative chronic hepatitis B. Liver Int 2017; 37:1642-1650. [PMID: 28345181 DOI: 10.1111/liv.13432] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 03/17/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND/AIMS Serum hepatitis B s antigen (HBsAg) levels might be used as a predictor of virological breakthrough or of sustained off-treatment virological response in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients. We evaluated the changes of HBsAg in those patients under nucleos(t)ide analogue(s) [NA(s)] therapy for ≥12 months. METHODS We included 99 HBeAg-negative CHB patients treated with low-genetic barrier NA(s) for a mean of 66 months (lamivudine: 66, adefovir: 6, lamivudine plus adefovir: 11 and telbivudine: 16) and 86 HBeAg-negative CHB patients treated under entecavir or tenofovir for a mean of 30 months as the comparison group. RESULTS Compared to baseline, HBsAg levels decreased by a median of 162, 1525, 943, 1545, 2163 and 3859 IU/mL at 6, 12, 24, 36, 48 and 60 months of therapy with low-genetic barrier NA(s) respectively. The 6-, 12-, 24-, 36-, 48- and 60-month cumulative rates of HBsAg<100 IU/mL were 2%, 3%, 3%, 5%, 5% and 5%, and <1000 IU/mL 6%, 9%, 15%, 19%, 24% and 61% respectively. Baseline HBsAg levels were the only significant variable associated with the time to HBsAg drop <1000 IU/mL. HBsAg loss occurred in 3.0% of patients. The high-genetic barrier NAs were not found to offer a greater or faster HBsAg decline. CONCLUSIONS In HBeAg-negative CHB patients, long-term therapy with low-genetic barrier NA(s) decreases serum HBsAg levels, but the rate of decline is slow. Lower baseline HBsAg levels are significantly associated with on-therapy HBsAg drop <1000 IU/mL. Serum HBsAg decline is similar during therapy with low- or high-genetic barrier NAs.
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Affiliation(s)
- Athanasia Striki
- 2nd Department of Internal Medicine, Hippokration General Hospital of Athens, Medical School of National & Kapodistrian University of Athens, Athens, Greece
| | - Spilios Manolakopoulos
- 2nd Department of Internal Medicine, Hippokration General Hospital of Athens, Medical School of National & Kapodistrian University of Athens, Athens, Greece
| | - Melanie Deutsch
- 2nd Department of Internal Medicine, Hippokration General Hospital of Athens, Medical School of National & Kapodistrian University of Athens, Athens, Greece
| | - Anastasia Kourikou
- 2nd Department of Internal Medicine, Hippokration General Hospital of Athens, Medical School of National & Kapodistrian University of Athens, Athens, Greece
| | - George Kontos
- 2nd Department of Internal Medicine, Hippokration General Hospital of Athens, Medical School of National & Kapodistrian University of Athens, Athens, Greece
| | - Hariklia Kranidioti
- 2nd Department of Internal Medicine, Hippokration General Hospital of Athens, Medical School of National & Kapodistrian University of Athens, Athens, Greece
| | - Emilia Hadziyannis
- 2nd Department of Internal Medicine, Hippokration General Hospital of Athens, Medical School of National & Kapodistrian University of Athens, Athens, Greece
| | - George Papatheodoridis
- Department of Gastroenterology, Laiko General Hospital of Athens, Medical School of National & Kapodistrian University of Athens, Athens, Greece
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Lu D, Liu F, Xing W, Tong X, Wang L, Wang Y, Zeng L, Feng C, Yang L, Zuo J, Hu Y. Optimization and Synthesis of Pyridazinone Derivatives as Novel Inhibitors of Hepatitis B Virus by Inducing Genome-free Capsid Formation. ACS Infect Dis 2017; 3:199-205. [PMID: 27989113 DOI: 10.1021/acsinfecdis.6b00159] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The capsid of hepatitis B virus (HBV) plays a vital role in virus DNA replication. Targeting nucleocapsid function has been demonstrated as an effective approach for anti-HBV drug development. A high-throughput screening and mechanism study revealed the hit compound 4a as an HBV assembly effector (AEf), which could inhibit HBV replication by inducing the formation of HBV DNA-free capsids. The subsequent SAR study and drug-like optimization resulted in the discovery of the lead candidate 4r, with potent antiviral activity (IC50 = 0.087 ± 0.002 μM), low cytotoxicity (CC50 = 90.6 ± 2.06 μM), sensitivity to nucleoside analogue-resistant HBV mutants, and synergistic effect with nucleoside analogues in HepG2.2.15 cells.
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Affiliation(s)
- Dong Lu
- State
Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Feifei Liu
- Laboratory
of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Weiqiang Xing
- State
Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China
| | - Xiankun Tong
- Laboratory
of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China
| | - Lang Wang
- State
Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China
| | - Yajuan Wang
- Laboratory
of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Limin Zeng
- State
Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China
| | - Chunlan Feng
- Laboratory
of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China
| | - Li Yang
- Laboratory
of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China
| | - Jianping Zuo
- Laboratory
of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China
| | - Youhong Hu
- State
Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China
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Papatheodoridis G, Triantos C, Hadziyannis E, Zisimopoulos K, Georgiou A, Voulgaris T, Vlachogiannakos I, Nikolopoulou V, Manolakopoulos S. Serum HBsAg kinetics and usefulness of interferon-inducible protein 10 serum in HBeAg-negative chronic hepatitis B patients treated with tenofovir disoproxil fumarate. J Viral Hepat 2015; 22:1079-87. [PMID: 26146764 DOI: 10.1111/jvh.12434] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2015] [Accepted: 06/04/2015] [Indexed: 01/27/2023]
Abstract
The kinetics of serum HBsAg and interferon-inducible protein 10 (IP10) levels in patients with chronic hepatitis B infection treated with tenofovir are unclear. We evaluated the changes of HBsAg levels and the predictability of IP10 for HBsAg decline in 160 HBeAg-negative patients receiving tenofovir for ≥12 months. Serum samples taken before and at 6, 12, 24, 36 and 48 months after tenofovir were tested for HBsAg levels. In 104 patients, serum samples before tenofovir were tested for IP10 levels. Compared to before tenofovir, HBsAg levels decreased by a median of 0.08, 0.11, 0.24, 0.33 and 0.38 log10 IU/mL at 6, 12, 24, 36 and 48 months, respectively (P < 0.001). HBsAg kinetics did not differ between nucleos(t)ide analogue(s) naive and experienced patients. The 12-, 24-, 36- and 48-month cumulative rates of ≥0.5 log10 HBsAg decline were 8%, 16%, 24% and 41% and of HBsAg ≤100 IU/mL were 9%, 12%, 14% and 18%, respectively. The only factor associated with HBsAg ≤100 IU/mL was lower HBsAg levels before tenofovir (P < 0.001), while HBsAg decline ≥0.5 log10 was associated with higher IP10 levels (P = 0.002) and particularly with IP10 > 350 pg/mL (P < 0.001). In conclusion, tenofovir decreases serum HBsAg levels in both nucleos(t)ide analogue(s) naive and experienced patients with HBeAg-negative chronic hepatitis B infection. After 4 years of therapy, HBsAg ≤100 IU/mL can be achieved in approximately 20% of patients, particularly in those with low baseline HBsAg levels. HBsAg decline is slow (≥0.5 log10 in 40% of patients after 4 years) and is associated only with higher baseline serum IP10 levels.
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Affiliation(s)
- G Papatheodoridis
- Department of Gastroenterology, Athens University Medical School, Laiko Hospital of Athens, Athens, Greece
| | - C Triantos
- Department of Gastroenterology, University Hospital of Patras, Patras, Greece
| | - E Hadziyannis
- 2nd Department of Internal Medicine, Athens University Medical School, Hippokratio Hospital of Athens, Athens, Greece
| | - K Zisimopoulos
- Department of Gastroenterology, University Hospital of Patras, Patras, Greece
| | - A Georgiou
- Department of Gastroenterology, Athens University Medical School, Laiko Hospital of Athens, Athens, Greece
| | - T Voulgaris
- Department of Gastroenterology, Athens University Medical School, Laiko Hospital of Athens, Athens, Greece
| | - I Vlachogiannakos
- Department of Gastroenterology, Athens University Medical School, Laiko Hospital of Athens, Athens, Greece
| | - V Nikolopoulou
- Department of Gastroenterology, University Hospital of Patras, Patras, Greece
| | - S Manolakopoulos
- 2nd Department of Internal Medicine, Athens University Medical School, Hippokratio Hospital of Athens, Athens, Greece
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Poortahmasebi V, Malekzadeh R, Montazeri G, Fakhari E, Norouzi M, Khamseh A, Mahmoodi Karkhaneh M, Tavakoli A, Jazayeri SM. Lamivudine Resistance and Precore Variants in Iranian Patients With Chronic Hepatitis B: Correlation With Virological and Clinical Features. Jundishapur J Microbiol 2015; 8:e20262. [PMID: 26487918 PMCID: PMC4609034 DOI: 10.5812/jjm.20262] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 09/22/2014] [Accepted: 12/28/2014] [Indexed: 01/10/2023] Open
Abstract
Background: Long-term lamivudine therapy, despite its initial effectiveness against hepatitis B virus (HBV), is associated with the emergence of drug resistance mutations in polymerase protein. Objectives: The aim of the present study was to determine the prevalence of precore and lamivudine drug resistance mutations in lamivudine treated patients with chronic B hepatitis. Patients and Methods: Sequential sera were obtained from 88 chronic HBV carriers who received lamivudine for more than 24 months. Polymerase and precore regions were directly sequenced for these groups: I (before treatment), II, and III (12 and 24 months after treatment, respectively). Results: All patients (100%) were contained genotype D, subtype ayw2. One (1.1%), 12 (13.6%), and 22 (25%) members of groups I, II, and III had the replacement of either isoleucine or valine instead of methionine in tyrosine-methionine-aspartate-aspartate (YMDD) motif, respectively. The frequency of mutations from 0 time point to 12 and 24 months showed that there was an increasing trend between sequential samples (P < 0.001). In group I, 31 (35.2%); II, 36 (41.0%) and III, 41 (46.6%) members had the precore stop codon mutations. The frequency of mutations from 0 time point to 12 and 24 months showed that there was an ascending trend between sequential samples. Indeed, frequency of precore stop codon was significantly increased with the passage of time (P < 0.001). Conclusions: Presence of drug resistance mutations among the patients was significant. Precore mutations were common amongst Iranian HBV chronic carriers under lamivudine therapy and these mutations were accompanied by clinical relapse.
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Affiliation(s)
- Vahdat Poortahmasebi
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Reza Malekzadeh
- Digestive Disease Research Center, Shariati Hospital, Tehran, IR Iran
| | | | - Ehsan Fakhari
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Mehdi Norouzi
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Azam Khamseh
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Masoud Mahmoodi Karkhaneh
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Ahmad Tavakoli
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Seyed Mohammad Jazayeri
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran
- Corresponding author: Seyed Mohammad Jazayeri, Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran. Tel: +98-2188950187, Fax: +98-2188954913, E-mail:
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14
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Progress and Prospects of Anti-HBV Gene Therapy Development. Int J Mol Sci 2015; 16:17589-610. [PMID: 26263978 PMCID: PMC4581210 DOI: 10.3390/ijms160817589] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Revised: 07/20/2015] [Accepted: 07/22/2015] [Indexed: 12/11/2022] Open
Abstract
Despite the availability of an effective vaccine against hepatitis B virus (HBV), chronic infection with the virus remains a major global health concern. Current drugs against HBV infection are limited by emergence of resistance and rarely achieve complete viral clearance. This has prompted vigorous research on developing better drugs against chronic HBV infection. Advances in understanding the life cycle of HBV and improvements in gene-disabling technologies have been impressive. This has led to development of better HBV infection models and discovery of new drug candidates. Ideally, a regimen against chronic HBV infection should completely eliminate all viral replicative intermediates, especially covalently closed circular DNA (cccDNA). For the past few decades, nucleic acid-based therapy has emerged as an attractive alternative that may result in complete clearance of HBV in infected patients. Several genetic anti-HBV strategies have been developed. The most studied approaches include the use of antisense oligonucleotides, ribozymes, RNA interference effectors and gene editing tools. This review will summarize recent developments and progress made in the use of gene therapy against HBV.
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15
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Jeffrey Mphahlele M. Impact of HIV co-infection on hepatitis B prevention and control: a view from sub-Saharan Africa. ACTA ACUST UNITED AC 2015. [DOI: 10.1080/10158782.2008.11441294] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- M Jeffrey Mphahlele
- HIV and Hepatitis Research Unit, Department of Virology, University of Limpopo, Medunsa Campus, Pretoria, Gauteng, South Africa
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16
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Zhang F, Wang G. A review of non-nucleoside anti-hepatitis B virus agents. Eur J Med Chem 2014; 75:267-81. [PMID: 24549242 DOI: 10.1016/j.ejmech.2014.01.046] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 01/12/2014] [Accepted: 01/17/2014] [Indexed: 12/14/2022]
Abstract
Hepatitis B Virus is the most common cause of chronic liver disease worldwide. Currently approved agents of chronic HBV infection treatment include interferon and nucleoside analogues. However, the side effects of interferon and the viral resistance of nucleoside analogues make the current treatment far from satisfactory. Therefore, new drugs with novel structures and mechanisms are needed. Recently, a number of non-nucleoside HBV inhibitors have been obtained from natural sources or prepared by synthesis/semi-synthesis. Some of them exhibited potent anti-HBV activity with novel mechanisms. These compounds provide useful information for the medicinal chemist to develop novel non-nucleoside compounds as anti-HBV agents.
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Affiliation(s)
- Fan Zhang
- School of Pharmacy, Liaoning Medical University, No. 40, Section 3, Songpo Road, Linghe District, Jinzhou 121001, PR China.
| | - Gang Wang
- School of Pharmacy, Liaoning Medical University, No. 40, Section 3, Songpo Road, Linghe District, Jinzhou 121001, PR China
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Hadziyannis SJ, Papatheodoridis GV. Adefovir dipivoxil in the treatment of chronic hepatitis B virus infection. Expert Rev Anti Infect Ther 2014; 2:475-83. [PMID: 15482214 DOI: 10.1586/14787210.2.4.475] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Adefovir dipivoxil (Hepsera, Gilead Sciences) is a prodrug of adefovir, with potent antiviral activity against hepatitis B virus. Adefovir dipivoxil therapy, 10 mg daily for 48 weeks, is effective in hepatitis B e antigen-positive and -negative chronic hepatitis B. In hepatitis B e antigen-negative chronic hepatitis B, adefovir dipivoxil was recently found to maintain its efficacy even after 3 years of therapy. Adefovir dipivoxil is effective in patients with compensated or decompensated chronic viral B liver disease, and in pre- and post-transplant hepatitis B virus patients who develop resistance to lamivudine (Epivir, GlaxoSmithKline). It is well-tolerated and safe even after the third year of long-term therapy, and is associated with low rates of viral resistance. All these characteristics make adefovir dipivoxil an important drug for the treatment of hepatitis B virus infection and an excellent candidate for long-term maintenance therapy in chronic viral B liver disease.
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Affiliation(s)
- Stephanos J Hadziyannis
- Department of Medicine and Hepatology, Henry Dunant Hospital, 107 Messogion Avenue, 11526 Athens, Greece.
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18
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Changes of HBsAg and interferon-inducible protein 10 serum levels in naive HBeAg-negative chronic hepatitis B patients under 4-year entecavir therapy. J Hepatol 2014; 60:62-8. [PMID: 24012614 DOI: 10.1016/j.jhep.2013.08.023] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2013] [Revised: 08/26/2013] [Accepted: 08/28/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Serum HBsAg levels might represent an important predictor of sustained off-treatment response in HBeAg-negative chronic hepatitis B (CHB). We evaluated the changes of HBsAg and interferon-inducible protein 10 (IP10) serum levels in HBeAg-negative CHB patients treated with entecavir. METHODS 114 patients received entecavir for a median of 4.3 years. HBsAg levels were determined at baseline, 6 and 12 months and every year thereafter until year-4. IP10 levels were measured at baseline and annually until year-4 in 76 patients. RESULTS Virological remission rates were high (year-1: 94%, after year-2: 97-98%). Compared to baseline, HBsAg levels decreased by a median of 0.03, 0.13, 0.17, 0.22, and 0.32 log₁₀ IU/ml at 6 months and 1, 2, 3, and 4 years, respectively (p≤0.001 for all comparisons). The proportions of patients with HBsAg decline of ≥0.5 or ≥1 log₁₀ IU/ml were 9% or 6% at year-1 and 21% or 10% at the last visit. Median IP10 levels (pg/ml) did not change from baseline to year-1 or -2 (245 vs. 229 or 251), but increased at year-3 and -4 (275 and 323, p<0.030). HBsAg drop ≥0.5 log₁₀ was associated with baseline IP10 or IP10 >350 pg/ml (p≤0.002). HBsAg loss occurred in 4/114 (3.5%) patients or in 1/2, 3/21, and 0/91 patients with baseline HBsAg <100, 100-1000 and >1000 IU/ml, respectively (p<0.001). CONCLUSIONS In HBeAg-negative CHB patients, 4-year entecavir therapy decreases serum HBsAg levels, but the rate of decline is rather slow. Serum IP10 levels represent a promising predictor of HBsAg decline in this setting.
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Kimkong I, Tangkijvanich P, Hirankarn N. Association of interferon-alpha gene polymorphisms with chronic hepatitis B virus infection. Int J Immunogenet 2013; 40:476-81. [PMID: 23566196 DOI: 10.1111/iji.12055] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Revised: 01/30/2013] [Accepted: 03/10/2013] [Indexed: 12/15/2022]
Abstract
In this study, the association between the risk of chronic hepatitis B virus infection and the polymorphisms within promoter regions of IFN-α1 and five genes was explored. This association study was performed on 180 Thai patients with chronic HBV infection [hepatocellular carcinoma (HCC) = 65 and non-HCC = 115], 173 individuals with self-limited HBV infection and 140 healthy controls. Our results showed that the A allele of -1823G/A SNP within IFNA1 gene was significantly associated with an increased risk of chronic HBV infection as compared to healthy individuals and self-limited HBV group [OR (95% CI) = 2.20 (1.51-3.19), P = 0.000014 and OR (95% CI) = 1.61 (1.12-2.33), P = 0.0073, respectively]. The effect of A allele was similar to autosomal recessive in which the presence of AA genotype when compared to GG and GA conferred the OR of 2.79 (95% CI = 1.72-4.52, P = 0.0000085). By multifactor dimensionality reduction analysis, we found the interaction between IFNA5 (-2529) and IFNA1 (-1823) genes that gave the risk to chronic HBV infection, with the OR (95% CI) of the high-risk to low-risk group was 2.79 (1.77-4.40), P < 0.0001. However, further study in functional significance is required.
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Affiliation(s)
- I Kimkong
- Department of Microbiology, Faculty of Science, Kasetsart University, Bangkok, Thailand; Center for Advanced Studies in Tropical Natural Resources, National Research University-Kasetsart University, Kasetsart University, Bangkok, Thailand
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20
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Hu Y, Zhu W, Tang G, Mayweg AV, Yang G, Wu JZ, Shen HC. Novel Therapeutics in Discovery and Development for Treatment of Chronic HBV Infection. ANNUAL REPORTS IN MEDICINAL CHEMISTRY 2013. [DOI: 10.1016/b978-0-12-417150-3.00017-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Karayiannis P. Serum hepatitis B surface antigen levels and their utility as a predictor of sustained virological response after antiviral treatment. HEPATITIS MONTHLY 2012; 12:420-2. [PMID: 23008721 PMCID: PMC3437451 DOI: 10.5812/hepatmon.6201] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/27/2011] [Revised: 04/01/2012] [Accepted: 04/08/2012] [Indexed: 12/11/2022]
Affiliation(s)
- Peter Karayiannis
- Hepatology and Gastroenterology Section Department of Medicine, Imperial College London, London, England
- Corresponding author: Peter Karayiannis, Hepatology and Gastroenterology Section Department of Medicine, Imperial College London, Variety Wing Floor D, St. Mary’s Campus, Norfolk Place, W2 1PG, London, England. Tel.: +44-2075949048, Fax: +44-2077249369, E-mail:
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Li SY, Qin L, Zhang L, Song XB, Zhou Y, Zhou J, Lu XJ, Cao J, Wang LL, Wang J, Ying BW. Molecular epidemical characteristics of Lamivudine resistance mutations of HBV in southern China. Med Sci Monit 2012; 17:PH75-80. [PMID: 21959623 PMCID: PMC3539467 DOI: 10.12659/msm.881965] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Lamivudine (LMV), as the preferred oral drug for use in treatment of HBV, always results in development of resistance mutations after long-term treatment. In this study we investigated chronic hepatitis B (CHB) patients in southern China to determine whether different HBV genotypes affect the incidence of LMV resistance mutations. MATERIAL/METHODS The study recruited 185 CHB patients living in southern China. Enzyme-linked immunosorbent assay was used to test for HBV serological markers, and HBV DNA was quantified by real-time PCR. Sequencing was performed to detect HBV genotypes and mutations. RESULTS There were 49.19% (91/185) CHB patients with HBV resistant to LMV. Only 2 genotypes were found: B and C; 62.16% (115/185) of patients were infected with genotype B HBV and 37.84% (70/185) of patients were infected with genotype C HBV. The incidence rate of LMV resistance was not significantly different between genotype B and C (49.57% vs. 48.57%, P>0.05). For the mean age and sex ratio, no significant difference was found. The pattern of rtM204I alone was predominantly observed (36.26%, 33/91), followed by rtM204V+rtL180M (23.08%, 21/91). The overall incidence rate of rtM204I mutation in genotype B (45.61%, 26/57) was more frequent than that in genotype C (20.59%, 7/34) (45.61% vs. 20.59%, P<0.05), but the incidence rate of other mutation patterns was not significantly different between genotypes B and C. CONCLUSIONS Our results emphasize that a LMV resistance test before treatment is of great importance in rational and optimal CHB therapy.
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Affiliation(s)
- Si-Yue Li
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Sichuan Province, China
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Straus SE. Unanticipated Risk in Clinical Research. PRINCIPLES AND PRACTICE OF CLINICAL RESEARCH 2012:109-126. [DOI: 10.1016/b978-0-12-382167-6.00010-2] [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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Lin CL, Chien RN, Hu CC, Lai MW, Yeh CT. Identification of hepatitis B virus rtS117F substitution as a compensatory mutation for rtM204I during lamivudine therapy. J Antimicrob Chemother 2011; 67:39-48. [PMID: 22001270 DOI: 10.1093/jac/dkr416] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES The replication defect of hepatitis B virus (HBV) lamivudine-resistant mutants can be restored by the development of compensatory mutations. Such mutations have long been recognized for the rtM204V mutant, while little is known about any compensatory mutation specific to the rtM204I mutant. The aim of this study was to search for previously unrecognized compensatory mutations following development of lamivudine-resistant mutants. METHODS Of 83 lamivudine-resistant patients, 49 and 34 patients harboured the rtM204I and rtM204V mutations, respectively. Serial serum samples obtained during the therapeutic course were submitted to sequence analysis. Site-directed mutagenesis experiments were performed to examine the functions of the identified associated mutations. RESULTS Of the 49 patients carrying the rtM204I mutation, 5 subsequently developed an rtS117F substitution during the follow-up, whereas 4 harboured an rtN124D substitution prior to the development of the rtM204I mutation. Emergence of the rtS117F mutation was associated with an increase in hepatitis activity, whereas prior existence of the rtN124D mutation was associated with decompensated liver function upon development of the rtM204I mutation. Site-directed mutagenesis experiments showed that the rtS117F mutation by itself did not confer lamivudine resistance but it compensated for replication deficiency of the rtM204I mutant in HepG2 and Mahlavu cells. Additionally, virion and hepatitis B surface antigen secretion of the rtS117F mutant was significantly impaired. CONCLUSIONS The rtS117F substitution served as a compensatory mutation for rtM204I. Emergence of the rtS117F mutation in lamivudine-resistant patients carrying rtM204I was associated with increased hepatitis activities. Prior existence of the rtN124D substitution was associated with liver decompensation upon development of the rtM204I mutation.
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Affiliation(s)
- Chih-Lang Lin
- Liver Research Unit, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Keelung, Taiwan
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Chen D, Zhai X, Yuan QH, Luo J, Xie SC, Gong P. Synthesis and in vitro anti-hepatitis B virus activity of 1H-benzimidazol-5-ol derivatives. CHINESE CHEM LETT 2010. [DOI: 10.1016/j.cclet.2010.05.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Al-Mahtab M. Immune Interventional Strategies against
Chronic Infection Diseases and Cancers:
Present Challenges and Road Map
to Solution. Euroasian J Hepatogastroenterol 2010. [DOI: 10.5005/jp-journals-10018-1002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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Lucifora J, Vincent IE, Berthillon P, Dupinay T, Michelet M, Protzer U, Zoulim F, Durantel D, Trepo C, Chemin I. Hepatitis B virus replication in primary macaque hepatocytes: crossing the species barrier toward a new small primate model. Hepatology 2010; 51:1954-60. [PMID: 20301206 DOI: 10.1002/hep.23602] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
UNLABELLED The development of new anti-hepatitis B virus (HBV) therapies, especially immunotherapeutic approaches, has been limited by the lack of a primate model more accessible than chimpanzees. We have previously demonstrated that sylvanus and cynomolgus macaques are susceptible to in vivo HBV infection after intrahepatic HBV DNA inoculation. In this study, we evaluated the susceptibility of primary macaque hepatocytes (PMHs) to HBV infection with a highly efficient HBV genome-mediated transfer system via a recombinant baculovirus (Bac-HBV). Freshly prepared PMHs, isolated from macaque liver tissue by collagenase perfusion, were transduced with Bac-HBV, and intermediates of replication were followed for 9 days post-transduction. Evidence of HBV replication (hepatitis B surface antigen secretion, viral DNA, RNA, and covalently closed circular DNA) was detected from day 1 to day 9 post-transduction. HBV markers were dose-dependent and still detectable at a multiplicity of infection of 10. Importantly, transduced PMHs secreted all typical forms of HBV particles, as evidenced by a cesium chloride gradient as well as transmission electron microscopy. Furthermore, the Toll-like receptor 9 (TLR9) ligand was used to stimulate freshly prepared macaque peripheral blood mononuclear cells to generate TLR9-induced cytokines. We then demonstrated the antiviral effects of both TLR9-induced cytokines and nucleoside analogue (lamivudine) on HBV replication in transduced PMHs. CONCLUSION Baculovirus-mediated genome transfer initiated a full HBV replication cycle in PMHs; thus highlighted both the baculovirus efficiency in crossing the species barrier and macaque susceptibility to HBV infection. Moreover, our results demonstrate the relevance of thus system for antiviral compound evaluations with either nucleoside analogues or inhibitory cytokines. Cynomolgus macaques are readily available, are immunologically closely related to humans, and may therefore represent a promising model for the development of new immunotherapeutic strategies.
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Affiliation(s)
- Julie Lucifora
- INSERM Unité 871, Institut National de la Santé et de la Recherche Médicale, Lyon, France
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Arora PK, Patil VM, Gupta SP. A QSAR study on some series of anti-hepatitis B virus (HBV) agents. Bioinformation 2010; 4:417-20. [PMID: 20975892 PMCID: PMC2951641 DOI: 10.6026/97320630004417] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2010] [Accepted: 03/02/2010] [Indexed: 12/21/2022] Open
Abstract
A quantitative structureactivity relationship (QSAR) study has been made on some series of antihepatitis B virus (HBV) agents, namely, a
series of novel bis(Lamino acid) ester prodrugs of 9[2(phosphonomethoxy)ethyl]adenine, a similar series of compounds comprising of 2
amino6arylthio9[2(phosphonoethoxy)ethyl] purine bis(2,2,2 trifluoroethyl) esters, and a series of 1isopropylsulfonyl2amine
benzimidazoles. In each case significant correlations are found between the antiHBV potencies and some physicochemical and steric
properties of the compounds, indicating that for the first two series the activity is controlled by the hydrophobic and the bulk properties of
the molecules and, for the third series, the steric and hydrogen bonding properties of compounds are crucial for their antiHBV potency.
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Affiliation(s)
- Preet K Arora
- Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut 250005, India
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Beyond oncology--application of HPMA copolymers in non-cancerous diseases. Adv Drug Deliv Rev 2010; 62:258-71. [PMID: 19909776 DOI: 10.1016/j.addr.2009.10.006] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2009] [Revised: 10/27/2009] [Accepted: 10/29/2009] [Indexed: 11/22/2022]
Abstract
Macromolecular drug conjugates have been developed to improve the efficacy and safety profile of various therapeutic agents for many years. Among them, N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates are the most extensively studied delivery platforms for the effective treatment of cancer. In recent years, the applications of HPMA copolymers for the treatment of a broader range of non-cancerous diseases have also been explored. This review highlights the recent developments in the rational design, synthesis, and evaluation of novel HPMA copolymer-drug conjugates for non-cancerous diseases, such as musculoskeletal diseases, infectious diseases and spinal cord injury. The translation potential of these applications is also briefly discussed.
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Akbar SMF, Hiasa Y, Mishiro S, Onji M. Treatment of hepatitis B virus-infected patients: utility of therapeutic recommendations in developing countries. Expert Opin Pharmacother 2009; 10:1605-14. [PMID: 19496738 DOI: 10.1517/14656560903005579] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND The treatment of individuals infected with hepatitis B virus (HBV) is a complex issue in practical settings, despite the explosion of new and effective antiviral agents. OBJECTIVE To assess the scope and limitations of ongoing treatment guidelines against HBV from a global perspective. METHODS Present therapeutic guidelines against HBV have been discussed with emphasis on their value in developing countries that harbor about 90% of the total number of global patients who are infected with HBV. RESULTS/CONCLUSION Treatment of HBV-infected patients should be appropriately followed up and healthcare delivery systems should be able to combat treatment-induced adverse side effects. Current therapeutic guidelines should be optimized based on the socio-economic conditions of developing countries.
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Affiliation(s)
- Sheikh Mohammad Fazle Akbar
- Department of Medical Sciences, Toshiba General Hospital, 6-3-22 Higashi Oi, Shinagawa, Tokyo 140-8522, Japan.
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32
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Sun Y, Li LJ, Li J, Li Z. Inhibition of hepatitis B virus replication by Rheum palmatum L. ethanol extract in a stable HBV-producing cell line. Virol Sin 2009. [DOI: 10.1007/s12250-007-0056-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
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33
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Suh HJ, Park MK, Lee HI, Gwak GY, Koh KC, Paik SW, Yoo BC, Lee JH. [Antiviral efficacy of lamivudine/adefovir combination therapy in chronic hepatitis b patients with resistance to lamivudine and adefovir consecutively]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2009; 53:305-10. [PMID: 19458467 DOI: 10.4166/kjg.2009.53.5.305] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND/AIMS The aim of this study was to elucidate the antiviral efficacy of lamivudine (LMV)-adefovir (ADV) combination therapy in chronic hepatitis B patients who showed resistance to LMV and ADV consecutively. METHODS A retrospective review was performed in eighteen patients with chronic hepatitis B who developed virologic breakthroughs during LMV-ADV sequential mono-therapy and treated with LMV-ADV combination therapy. RESULTS The median duration of follow up was 17 months (range, 6-27) after the start of LMV-ADV combination therapy. Mean HBV DNA level in log10 IU/mL was 6.08+/-0.95, 4.05+/-1.66, 3.17+/-1.58, 3.18+/-2.16, and 2.35+/-1.52 at 0, 3, 6, 12, and 24 months, respectively. Sixteen patients (88.9%) showed HBV DNA reduction below detection limit (<20,000 IU/mL). HBeAg seroconversion was observed in one patient (7.1%) after 8 months of combination therapy. Virologic breakthrough occurred in only one patient after 21 months of combination therapy. Viral rebound occurred in two patients at 12 months and 14 months of combination therapy. Normalization of serum ALT was achieved in twelve patients (66.7%). Primary non-response was observed in two cases (11.1%). CONCLUSIONS LMV-ADV combination treatment was effective in 88.9% of patients with resistance to LMV and ADV in a short-term follow up. It may be applied as a bridge therapy until another effective antiviral regimen becomes available.
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Affiliation(s)
- Hyun Joo Suh
- Department of Internal Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Gangnam-gu, Seoul, Korea
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34
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Serruys B, Van Houtte F, Verbrugghe P, Leroux-Roels G, Vanlandschoot P. Llama-derived single-domain intrabodies inhibit secretion of hepatitis B virions in mice. Hepatology 2009; 49:39-49. [PMID: 19085971 DOI: 10.1002/hep.22609] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
UNLABELLED Hepatitis B virus (HBV) infections cause 500,000 to 700,000 deaths per year as a consequence of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Efficient and safe antivirals to treat chronically infected patients and consequently to prevent development of hepatocellular carcinoma are still awaited. We isolated five single-domain antibodies (VHHs) that recognize the most abundant envelope protein (S) of HBV. VHHs, when expressed and retained in the endoplasmic reticulum as intrabodies, reduced levels of secreted hepatitis B surface antigen (HBsAg) particles in a cellular HBV model. In a hydrodynamics-based HBV mouse model, these intrabodies caused a marked reduction in HBsAg concentrations and a 10- to >100-fold reduction in the concentration of HBV virions in plasma. CONCLUSION VHHs potently inhibited secretion of HBV virions in vivo, showing that this approach might be useful in the treatment of HBV. To our knowledge, this is the first report of intrabody-mediated inhibition of viral secretion in mammals.
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Affiliation(s)
- Benedikte Serruys
- Center for Vaccinology, Ghent University and Hospital, Ghent, Belgium
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35
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Zhang Q, Wang Y, Wei L, Jiang D, Wang JH, Rao HY, Zhu L, Chen H, Fei R, Cong X. Role of ISGF3 in modulating the anti-hepatitis B virus activity of interferon-alpha in vitro. J Gastroenterol Hepatol 2008; 23:1747-61. [PMID: 17559358 DOI: 10.1111/j.1440-1746.2007.04985.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIM Although interferon-alpha (IFN-alpha) is an effective treatment for hepatitis B virus (HBV) infection, its precise mechanism of action has not been identified. In this study, we investigated the role of signal transduction pathways in the activation of anti-HBV responses mediated by IFN-alpha. METHODS Using an oligo microarray, we found that four genes in the IFN-alpha signal pathway were markedly upregulated by IFN-alpha in human hepatoma cells regardless of whether they had been transfected with a plasmid containing the HBV genome: signal transducers and activators of transcription 1 (STAT1), interferon regulatory factor-9 (IRF-9, also called ISGF3gamma or P48), IFN-alpha-inducible protein 15 (IFI-15) and IFN-alpha-inducible protein 6-16 (IFI-6-16). We also investigated the role of IFN-stimulated gene factor3 (ISGF3) complex in IFN-alpha-mediated anti-HBV responses in human hepatoma cells by measuring the mRNA of the three genes within ISGF3 (STAT1, STAT2 and IRF-9) using semiquantitative reverse-transcription PCR (RT-PCR), and expression of the three proteins by western blot, and the mRNA and protein of dsRNA-dependent protein kinase (PKR). RESULTS STAT1, STAT2, IRF-9 and PKR mRNA as well as protein levels were upregulated by IFN-alpha treatment. When cells were pretreated with genistein, STAT1, STAT2 and IRF-9 mRNA levels remained unchanged after IFN-alpha stimulation, but PKR mRNA levels decreased, and the expression of the STAT1, P-STAT2, IRF-9 and PKR proteins decreased. Levels of HBV DNA decreased in the supernatants of cells treated with IFN-alpha, while ISGF3 levels increased. The quantity of HBV DNA remained unchanged by pretreating with genistein. CONCLUSIONS These observations suggested that the Janus tyrosine kinase-STAT (JAK-STAT) pathway may play a major role in mediating the effects of IFN-alpha against HBV, and that ISGF3 might be a key factor.
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Affiliation(s)
- Quan Zhang
- Hepatology Institute, Peking University People's Hospital, Beijing, China
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36
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Li Z, Yao H, Ma Y, Dong Q, Chen Y, Peng Y, Zheng BJ, Huang JD, Chan CY, Lin MC, Sung JJ, Yuen KY, Kung HF, He ML. Inhibition of HBV gene expression and replication by stably expressed interferon-alpha1 via adeno-associated viral vectors. J Gene Med 2008; 10:619-27. [PMID: 18383553 PMCID: PMC7166674 DOI: 10.1002/jgm.1174] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background Interferon‐α2 (IFNα2) is routinely used for anti‐hepatitis B virus (HBV) treatment. However, the therapeutic efficiency is unsatisfactory, particularly in East Asia. Such inefficiency might be a result of the short half‐life, relatively low local concentration and strong side‐effects of interferons. Frequent and repeated injection is also a big burden for patients. In the present study, a single dose of vector‐delivered IFNα1 was tested for its anti‐HBV effects. Methods Adeno‐associated viral vector (AAV‐IFNα1) was generated to deliver the IFNα1 gene into hepatocytes. IFNα1, hepatitis B surface (HBsAg) and e (HBeAg) antigens were measured by enzyme‐linked immunosorbent assay and/or western blotting. The level of viral DNA was measured by quantitative real‐time polymerase chain reaction. Results AAV‐IFNα1 effectively transduced HBV‐producing cells (HepAD38) and mouse hepatocytes, where IFNα1 was expressed in a stable manner. Both intracellular and extracellular HBsAg and HBeAg were significantly reduced in vitro. In the HBV‐producing mice, the concentration of IFNα1 in the liver was eight‐fold higher than that in plasma. Compared with control groups, HBeAg/HBsAg antigen levels were reduced by more than ten‐fold from day 1–5, and dropped to an undetectable level on day 9 in the AAV‐IFNα1 group. Concurrently, the level of viral DNA decreased over 30‐fold for several weeks. Conclusions A single dose administration of AAV‐IFNα1 viral vector displayed prolonged transgene expression and superior antiviral effects both in vitro and in vivo. Therefore, the use of AAV‐IFNα1 might be a potential alternative strategy for anti‐HBV therapy. Copyright © 2008 John Wiley & Sons, Ltd.
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Affiliation(s)
- Zhi Li
- Department of Microbiology, The University of Hong Kong, Hong Kong, China
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37
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Lucifora J, Durantel D, Belloni L, Barraud L, Villet S, Vincent IE, Margeridon-Thermet S, Hantz O, Kay A, Levrero M, Zoulim F. Initiation of hepatitis B virus genome replication and production of infectious virus following delivery in HepG2 cells by novel recombinant baculovirus vector. J Gen Virol 2008; 89:1819-1828. [PMID: 18632952 DOI: 10.1099/vir.0.83659-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
One of the major problems in gaining further insight into hepatitis B virus (HBV)/host-cell interactions is to improve the existing cellular models for the study of HBV replication. The first objective of this study was to improve the system based on transduction of HepG2 cells with a recombinant baculovirus to study HBV replication. A new HBV recombinant baculovirus, Bac-HBV-1.1, in which the synthesis of pre-genomic RNA is driven by a strong mammalian promoter, was generated. Transduction with this new recombinant baculovirus led to higher levels of HBV replication in HepG2 cells compared with levels obtained with previously described baculovirus vectors. The initiation of a complete HBV DNA replication cycle in Bac-HBV-1.1-transduced HepG2 cells was shown by the presence of HBV replicative intermediates, including covalently closed circular DNA (cccDNA). Only low levels of cccDNA were detected in the nucleus of infected cells. Data showed that cccDNA resulted from the recycling of newly synthesized nucleocapsids and was bound to acetylated histones in a chromatin-like structure. HBV particles released into the supernatant of transduced HepG2 cells were infectious in differentiated HepaRG cells. Several Bac-HBV-1.1 baculoviruses containing HBV strains carrying mutations conferring resistance to lamivudine and/or adefovir were constructed. Phenotypic analysis of these mutants confirmed the results obtained with the transfection procedures. In conclusion, an improved cell-culture system was established for the transduction of replication-competent HBV genomes. This will be useful for future studies of the fitness of HBV mutants.
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Affiliation(s)
- J Lucifora
- Université Lyon 1, IFR62 Lyon Est, 69008 Lyon, France.,INSERM, U871, 151 Cours Albert Thomas, 69003 Lyon, France
| | - D Durantel
- Hospices Civils de Lyon, Hôtel Dieu Hospital, 69002 Lyon, France.,Université Lyon 1, IFR62 Lyon Est, 69008 Lyon, France.,INSERM, U871, 151 Cours Albert Thomas, 69003 Lyon, France
| | - L Belloni
- Laboratoire Associé INSERM, U785, Villejuif, France.,Department of Internal Medicine and Laboratory of Gene Expression, Fondazione A. Cesalpino, University of Rome La Sapienza, Rome, Italy
| | - L Barraud
- Department of Internal Medicine and Laboratory of Gene Expression, Fondazione A. Cesalpino, University of Rome La Sapienza, Rome, Italy
| | - S Villet
- Université Lyon 1, IFR62 Lyon Est, 69008 Lyon, France.,INSERM, U871, 151 Cours Albert Thomas, 69003 Lyon, France
| | - I E Vincent
- Université Lyon 1, IFR62 Lyon Est, 69008 Lyon, France.,INSERM, U871, 151 Cours Albert Thomas, 69003 Lyon, France
| | - S Margeridon-Thermet
- Université Lyon 1, IFR62 Lyon Est, 69008 Lyon, France.,INSERM, U871, 151 Cours Albert Thomas, 69003 Lyon, France
| | - O Hantz
- Université Lyon 1, IFR62 Lyon Est, 69008 Lyon, France.,INSERM, U871, 151 Cours Albert Thomas, 69003 Lyon, France
| | - A Kay
- Université Lyon 1, IFR62 Lyon Est, 69008 Lyon, France.,INSERM, U871, 151 Cours Albert Thomas, 69003 Lyon, France
| | - M Levrero
- Eurofins-Viralliance, BioAlliance Pharma SA, Paris, France.,Laboratoire Associé INSERM, U785, Villejuif, France
| | - F Zoulim
- Hospices Civils de Lyon, Hôtel Dieu Hospital, 69002 Lyon, France.,Université Lyon 1, IFR62 Lyon Est, 69008 Lyon, France.,INSERM, U871, 151 Cours Albert Thomas, 69003 Lyon, France
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38
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Wang GF, Shi LP, Zuo JP. Anti-hepatitis B virus drugs in clinical and preclinical development. Virol Sin 2008. [DOI: 10.1007/s12250-008-2945-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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39
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Zhao YL, Cai GM, Hong X, Shan LM, Xiao XH. Anti-hepatitis B virus activities of triterpenoid saponin compound from Potentilla anserine L. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2008; 15:253-8. [PMID: 18337074 DOI: 10.1016/j.phymed.2008.01.005] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
The Tibetan herb Potentilla anserina L. has been widely used in China for many thousands of years to treat hepatitis-B. Bioassay-guided fractionation of the ethanol extract of the rhizomes led to the isolation of a triterpenoid saponin (TS) that was determined to be 2alpha,3beta,19alpha-trihydroxyurs-12-en-28-oic acid beta-D-glucopyranosyl ester. Using models of HBV infection, this compound was evaluated for its effect on HBV antigene expression in the 2.2.15 cell line in vitro and anti-hepatitis B virus (HBV) activities in Peking ducklings in vivo. Results showed that it could decrease the expression levels of HBsAg, HBeAg and HBVDNA in the 2.2.15 cell culture and the inhibitory effect was not due to the cytotoxity of the triterpenoid saponin. The antiviral study in vivo on Peking ducklings also demonstrated that this compound inhibits duck hepatitis B virus (DHBV) DNA replication.
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Affiliation(s)
- Y-L Zhao
- Institute of Traditional Chinese Material Medica, People's Liberation Army, Beijing 100039, PR China.
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40
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Hadziyannis SJ, Vassilopoulos D. Telbivudine in the treatment of chronic hepatitis B. Expert Rev Gastroenterol Hepatol 2008; 2:13-22. [PMID: 19072366 DOI: 10.1586/17474124.2.1.13] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Treatment of chronic hepatitis B with oral nucleos(t)ide analogs is evolving rapidly with newer compounds gaining approval. Recently, the US FDA and European Medicines Agency (EMEA) have approved telbivudine, a potent anti-hepatitis B virus (HBV)-specific agent with a hitherto excellent safety profile. This review focuses on the efficacy of this agent in chronic hepatitis B compared with lamivudine, evaluated clinically in Phase II and a large Phase III study. Monitoring of the virologic response under treatment with sensitive HBV-DNA assays has been applied, aiming at increasing efficacy and reducing HBV resistance. The results are critically presented and the evolving concept of effective long-term telbivudine and other nucleos(t)ide analog therapy, predicted by the extent of suppression of HBV replication at week 24, are analyzed and discussed.
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Affiliation(s)
- Stephanos J Hadziyannis
- Department of Medicine and Hepatology, Henry Dunant Hospital, 107 Messogion Avenue, 115 26 Athens, Greece.
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41
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Wu M, Xu Y, Lin S, Zhang X, Xiang L, Yuan Z. Hepatitis B virus polymerase inhibits the interferon-inducible MyD88 promoter by blocking nuclear translocation of Stat1. J Gen Virol 2008; 88:3260-3269. [PMID: 18024894 DOI: 10.1099/vir.0.82959-0] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Previous studies have suggested that hepatitis B virus (HBV) blocks expression of the alpha interferon (IFN-alpha)-inducible myeloid differential primary response protein (MyD88) gene. To study the molecular mechanism(s) of the inhibition of MyD88 expression by HBV, MyD88 promoter reporter plasmids and vectors expressing different HBV viral proteins were constructed. Co-transfection experiments showed that IFN-induced MyD88 promoter activity was inhibited by HBV polymerase expression in a dose-dependent manner and that the terminal protein (TP) domain of HBV polymerase was responsible for this antagonistic activity. Analysis of site mutants showed that the region targeted by the polymerase protein contained the signal transducer and activator of transcription (Stat) binding site. Chromatin immunoprecipitation analysis showed that the IFN-induced DNA-binding activity of Stat1 was affected. Further study demonstrated that the HBV polymerase protein inhibited the Stat1 nuclear translocation induced by IFN-alpha, but did not induce Stat1 degradation nor interfere with its phosphorylation. In addition, HBV polymerase could inhibit the transcriptional activity of other IFN-stimulated response element-driven promoters and the expression of interferon-stimulated genes (ISGs), such as Stat1 and ISG15. In summary, these results indicate that HBV polymerase is a general inhibitor of IFN signalling and can inhibit IFN-inducible MyD88 expression by inhibiting the activity of the MyD88 promoter through blocking the nuclear translocation of Stat1.
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Affiliation(s)
- Min Wu
- Department of Research, Shanghai Public Health Clinic Center, Fudan University, Shanghai 201508, China.,Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yang Xu
- Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Shanshan Lin
- Institutes of Medical Microbiology and Biomedical Sciences, Fudan University, Shanghai 200032, China.,Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xiaonan Zhang
- Department of Research, Shanghai Public Health Clinic Center, Fudan University, Shanghai 201508, China
| | - Li Xiang
- Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Zhenghong Yuan
- Institutes of Medical Microbiology and Biomedical Sciences, Fudan University, Shanghai 200032, China.,Department of Research, Shanghai Public Health Clinic Center, Fudan University, Shanghai 201508, China.,Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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42
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Knight A. The poor contribution of chimpanzee experiments to biomedical progress. J APPL ANIM WELF SCI 2007; 10:281-308. [PMID: 17970631 DOI: 10.1080/10888700701555501] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Biomedical research on captive chimpanzees incurs substantial nonhuman animal welfare, ethical, and financial costs that advocates claim resultin substantial advancements in biomedical knowledge. However, demonstrating minimal contribution toward the advancement of biomedical knowledge generally, subsequent papers did not cite 49.5% (47/95), of 95 experiments randomly selected from a population of 749 published worldwide between 1995 and 2004. Only 14.7% (14/95) were cited by 27 papers that abstracts indicated described well-developed methods for combating human diseases. However, detailed examination of these medical papers revealed that in vitrostudies, human clinical and epidemiological studies, molecular assays and methods, and genomic studies contributed most to their development. No chimpanzee study made an essential contribution, or, in most cases, a significant contribution of any kind, to the development of the medical method described. The approval of these experiments indicates a failure of the ethics committee system. The demonstrable lack of benefit of most chimpanzee experimentation and its profound animal welfare and bioethical costs indicate that a ban is warranted in those remaining countries - notably the United States - that continue to conduct it.
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Affiliation(s)
- Andrew Knight
- Animal Consultants International, London, United Kingdom
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43
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Identification of natural compounds with anti-hepatitis B virus activity from Rheum palmatum L. ethanol extract. Chemotherapy 2007; 53:320-6. [PMID: 17785969 DOI: 10.1159/000107690] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2005] [Accepted: 07/24/2006] [Indexed: 12/22/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a severe health problem in the world; however, there is still no satisfactory therapeutic strategy for the HBV infection. In search for new anti-HBV agents with higher efficiency and less side effects, the anti-HBV activities of traditional Chinese medicine Rheum palmatum L. ethanol extract (RPE) and isolated anthraquinones were evaluated. METHODS The anti-HBV activities of RPE and isolated anthraquinones were demonstrated in a stable HBV-producing cell line HepG2 2.2.15 by using real-time polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA) and Southern blot analysis. RESULTS RPE could inhibit HBV-DNA production and HBsAg expression in a dose-dependent manner. The concentration of 50% HBV-DNA inhibition (IC(50)) of RPE was calculated at 212.36 +/- 11 microg/ml. Six anthraquinones were isolated from RPE by using RP-HPLC. Five free anthraquinones showed weakly or slightly inhibitory activities against HBV. The only combined anthraquinone chrysophanol 8-O-beta-D-glucoside exhibited significant activity against HBV DNA production and antigens expression with an IC(50) value of 36.98 +/- 2.28 microg/ml on HBV DNA inhibition. Endogenous HBV DNA polymerase activity assay indicated that chrysophanol 8-O-beta-D-glucoside might be a potential inhibitor of the HBV DNA polymerase. CONCLUSIONS The results suggested that RPE could effectively inhibit HBV. The combined anthraquinone chrysophanol 8-O-beta-D-glucoside is the major active compound in RPE and could be a promising candidate for the development of new anti-HBV drugs in the treatment of HBV infection.
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44
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McMahon MA, Jilek BL, Brennan TP, Shen L, Zhou Y, Wind-Rotolo M, Xing S, Bhat S, Hale B, Hegarty R, Chong CR, Liu JO, Siliciano RF, Thio CL. The HBV drug entecavir - effects on HIV-1 replication and resistance. N Engl J Med 2007; 356:2614-21. [PMID: 17582071 PMCID: PMC3069686 DOI: 10.1056/nejmoa067710] [Citation(s) in RCA: 231] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Entecavir, a drug approved by the Food and Drug Administration for the treatment of chronic hepatitis B virus (HBV) infection, is not believed to inhibit replication of human immunodeficiency virus type 1 (HIV-1) at clinically relevant doses. We observed that entecavir led to a consistent 1-log(10) decrease in HIV-1 RNA in three persons with HIV-1 and HBV coinfection, and we obtained supportive in vitro evidence that entecavir is a potent partial inhibitor of HIV-1 replication. Detailed analysis showed that in one of these patients, entecavir monotherapy led to an accumulation of HIV-1 variants with the lamivudine-resistant mutation, M184V. In vitro experiments showed that M184V confers resistance to entecavir. Until more is known about HIV-1-resistance patterns and their selection by entecavir, caution is needed with the use of entecavir in persons with HIV-1 and HBV coinfection who are not receiving fully suppressive antiretroviral regimens.
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Affiliation(s)
- Moira A McMahon
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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45
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Li YF, Wang GF, Luo Y, Huang WG, Tang W, Feng CL, Shi LP, Ren YD, Zuo JP, Lu W. Identification of 1-isopropylsulfonyl-2-amine benzimidazoles as a new class of inhibitors of hepatitis B virus. Eur J Med Chem 2007; 42:1358-64. [PMID: 17499889 DOI: 10.1016/j.ejmech.2007.03.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2006] [Revised: 01/24/2007] [Accepted: 03/12/2007] [Indexed: 11/23/2022]
Abstract
A series of 1-isopropylsulfonyl-2-amine benzimidazole derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity in the HepG2.2.15 cell line. In general, these derivatives are potent HBV inhibitors (IC(50)<4 microM) with high selectivity indices (SIs>40). Compounds 5b-e, g, j, and 9a were among the most prominent compounds, with IC(50)s of 0.70-2.0 microM and SIs of 41-274. The potent anti-HBV activity and safety profiles of the most promising compounds 5d and j (IC(50)s=0.70 microM, SIs>120) demonstrate the potential of this series of benzimidazoles for the development of new anti-HBV drugs.
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Affiliation(s)
- Yun-Fei Li
- Institute of Medicinal Chemistry, Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry, East China Normal University, 3663 North Zhongshan Road, Shanghai, Shanghai 200062, China
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46
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STRAUS STEPHENE. Unanticipated Risk in Clinical Research. PRINCIPLES AND PRACTICE OF CLINICAL RESEARCH 2007:77-95. [DOI: 10.1016/b978-012369440-9/50010-4] [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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47
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Lodato F, Mazzella G, Festi D, Azzaroli F, Colecchia A, Roda E. Hepatocellular carcinoma prevention: A worldwide emergence between the opulence of developed countries and the economic constraints of developing nations. World J Gastroenterol 2006; 12:7239-49. [PMID: 17143937 PMCID: PMC4087479 DOI: 10.3748/wjg.v12.i45.7239] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common neoplasm, the major cause of death in patients with liver cirrhosis, and the third most common cause of cancer-related death in the world. The geographic distribution of HCC varies significantly and 80% of cases occur in developing countries (Far East and South Asia) where the prevalence of viral hepatitis is higher. The treatment of HCC is difficult because most patients are diagnosed when the tumour is in an advanced stage and is not amenable to potential curative therapy, thus prevention is the key to reducing HCC and its related morbidity and mortality. HCC is unique among cancers, occurring mostly in patients with a known risk factor. Ninety percent of HCCs develop in the context of chronic liver diseases and mainly in patients with cirrhosis. Viral hepatitis is the most common cause of HCC worldwide, followed by alcoholic liver disease (ALD) and other causes such as non-alcoholic fatty liver disease (NAFLD), genetic haemocromatosis (GH) and primary biliary cirrhosis in an advanced stage (III-V). In certain areas of the People’s Republic of China, exposure to aflatoxin and HBV infection are thought to be responsible for the extraordinary high risk of HCC. Substantial progresses in the prevention of virusl-related hepatitis (screening of blood units, use of disposable sanitary tools, HBV vaccination) have been achieved in developed countries, but in the same areas, alcohol- and dysmetabolism-related HCCs are emerging problems which require specific interventions in terms of public health measures. In developing countries, economic constraints limit the development of any program for the prevention of viral hepatitis transmission (including health education campaigns, healthcare politics, primary prevention and the improvement of hygienic and sanitary conditions). When viral liver disease is established, only a minority of patients are treated worldwide and benefit a possible preventive effect of medical treatment on HCC development. Thus the real contribution of medical treatment to HCC prevention in patients with chronic viral hepatitis is small. Great efforts are needed to identify more effective medical measures for primary and secondary prevention of HCC.
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Affiliation(s)
- Francesca Lodato
- Dipartimento di Medicina Interna e Gastroenterologia, UO di Gastroenterologia, Via Massarenti 9, Bologna 40138, Italy.
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Zampino R, Marrone A, Adinolfi LE, Ruggiero G. Treatment of chronic hepatitis B: efficacy of current drugs and prospects for the future. Expert Rev Clin Immunol 2006; 2:915-29. [PMID: 20476979 DOI: 10.1586/1744666x.2.6.915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Chronic hepatitis B is an important clinical problem often leading to severe complications. In this review, the results obtained in the last few years with the use of current drugs, such as interferon and nucleo(t)side analogues, are summarized and the problems of obtaining a sustained remission, which is only achieved in a small number of patients, are discussed. The new approaches, such as the use of combinations of drugs, to optimize long-term tolerable treatment are also considered.
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Affiliation(s)
- Rosa Zampino
- Second University Naples, Internal Medicine and Hepatology C/O Ospedale Gesù e Maria, Via Cotugno, 1 80135 Napoli, Italy.
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Sun D, Nassal M. Stable HepG2- and Huh7-based human hepatoma cell lines for efficient regulated expression of infectious hepatitis B virus. J Hepatol 2006; 45:636-45. [PMID: 16935386 DOI: 10.1016/j.jhep.2006.05.019] [Citation(s) in RCA: 100] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2006] [Revised: 05/29/2006] [Accepted: 05/31/2006] [Indexed: 12/19/2022]
Abstract
BACKGROUND/AIMS Hepatitis B virus (HBV) cannot be propagated in cultured cells but two human hepatoma cell lines, HepG2 and Huh7, support virus replication when transfected with HBV DNA. If standardization is required stably transfected cell lines provide distinct advantages. One such line, HepG2.2.15, is widely used in antiviral research but HBV production is limited and difficult to control. Our aim was to establish stable, inducibly HBV producing HepG2 and Huh7 cell lines that overcome these limitations. METHODS Based on the tetracycline (Tet)-regulated TetOFF system, a Tet-responsive promoter-controlled HBV genome was introduced into separately established, well-regulatable HepG2 and Huh7 lines expressing Tet-responsive trans-activators (tTAs). Stable clones were analyzed for regulatability and levels of HBV expression, quality of the virus produced, and responsiveness towards antivirals. RESULTS HepG2- and Huh7-based cell lines were established which, Tet-controllably, produce more HBV than HepG2.2.15 cells. The secreted virions were infectious for primary tupaia hepatocytes, and the cell lines responded as well as HepG2.215 cells to different antivirals. CONCLUSIONS The new HBV cell lines should be valuable tools for academic and pharmaceutical HBV research. The parental tTA-cells will facilitate the generation of additional lines, producing HBV variants, or other genes, in an identical host cell background.
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Affiliation(s)
- Dianxing Sun
- University Hospital Freiburg, Internal Medicine II/Molecular Biology, Hugstetter Strasse 55, D-79106 Freiburg, Germany
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Song LH, Toan NL, Xuan NT, Uhlemann AC, Boldt ABW, Duy DN, Binh VQ, Kremsner PG, Kun JFJ. A promoter polymorphism in the interferon alpha-2 gene is associated with the clinical presentation of hepatitis B. Mutat Res 2006; 601:137-43. [PMID: 16920161 DOI: 10.1016/j.mrfmmm.2006.06.011] [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: 03/09/2006] [Revised: 06/03/2006] [Accepted: 06/15/2006] [Indexed: 05/11/2023]
Abstract
Cytokine gene polymorphisms influence the severity of infectious diseases of viral and parasitic origin. Interferon alpha (IFN-alpha) is known to be involved in the defence against hepatitis B. The promoter of the IFN-alpha-2 gene was investigated for mutations in 344 hepatitis B virus (HBV)-infected Vietnamese patients and 293 uninfected Vietnamese. We found a deletion in the promoter, which was present significantly more frequently in HBV-infected patients than in control individuals; 20% of the healthy, whereas 35% of the HBV-infected cohort carries this deletion (P<0.001). Reporter gene assays showed that a construct with the deletion had a lower level of transcription in comparison to the wild type (P=0.011). These findings indicate that the deletion in the promoter of the IFN-alpha-2 gene reduces the transcription of this gene in vitro. This reduction could explain the individually different interferon levels in humans and could also be one cause of susceptibility to hepatitis B.
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Affiliation(s)
- Le H Song
- Department of Parasitology, Institute of Tropical Medicine, University of Tübingen, Wilhelmstrasse 27, Tübingen, Germany
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