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Yin GQ, Li J, Zhong B, Yang YF, Wang MR. New therapeutic options for persistent low-level viremia in patients with chronic hepatitis B virus infection: Increase of entecavir dosage. World J Gastroenterol 2021; 27:666-676. [PMID: 33716446 PMCID: PMC7934007 DOI: 10.3748/wjg.v27.i8.666] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/25/2020] [Accepted: 01/21/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection (CHB) is a public health concern worldwide. Current therapies utilizing nucleos(t)ide analogs (NA) have not resulted in a complete cure for CHB. Furthermore, patients on long-term NA treatment often develop low-level viremia (LLV). Persistent LLV, in addition to causing the progression of liver disease or hepatocellular carcinoma, may shed light on the current plight of NA therapy. Here, we review the literature on LLV, NA treatment, and various doses of entecavir to find a strategy for improving the efficacy of this antiviral agent. For LLV patients, three therapeutic options are available, switching to another antiviral monotherapy, interferon-α switching therapy, and continuing monotherapy. In real-world clinical practice, entecavir overdose has been used in antiviral therapy for CHB patients with NA refractory and persistent LLV, which encouraged us to conduct further in-depth literature survey on dosage and duration related entecavir studies. The studies of pharmacodynamics and pharmacokinetics show that entecavir has the maximal selected index for safety, and has great potential in inhibiting HBV replication, in all of the NAs. In the particular section of the drug approval package published by the United States Food and Drug Administration, entecavir doses 2.5-20 mg/d do not increase adverse events, and entecavir doses higher than 1.0 mg/d might improve the antiviral efficacy. The literature survey led us to two suggestions: (1) Increasing entecavir dose to 1.0 mg/d for the treatment of NA naïve patients with HBV DNA >2 × 106 IU/mL is feasible and would provide better prognosis; and (2) Further research is needed to assess the long-term toxic effects of higher entecavir doses (2.5 and 5.0 mg/d), which may prove beneficial in treating patients with prior NA treatment, partial virological response, or LLV state.
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Affiliation(s)
- Guo-Qing Yin
- Department of Infectious Diseases, Nanjing Zhong-Da Hospital, Southeast University School of Medicine, Nanjing 210009, Jiangsu Province, China
| | - Jun Li
- Department of Infectious Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Bei Zhong
- The Sixth Affiliated Hospital, Guangzhou Medical University/Qingyuan People’s Hospital, Qingyuan 511518, Guangdong Province, China
| | - Yong-Fong Yang
- Department of Liver Disease, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
| | - Mao-Rong Wang
- Department of Infectious Diseases and Liver Disease Center, The Affiliated Nanjing Jinling Hospital, Nanjing University, Nanjing 210002, Jiangsu Province, China
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Gerasi M, Frakolaki E, Papadakis G, Chalari A, Lougiakis N, Marakos P, Pouli N, Vassilaki N. Design, synthesis and anti-HBV activity evaluation of new substituted imidazo[4,5-b]pyridines. Bioorg Chem 2020; 98:103580. [DOI: 10.1016/j.bioorg.2020.103580] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 12/18/2019] [Accepted: 01/10/2020] [Indexed: 02/08/2023]
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Kang Y, Shao Z, Wang Q, Hu X, Yu D. Quantitation of polymorphic impurity in entecavir polymorphic mixtures using powder X-ray diffractometry and Raman spectroscopy. J Pharm Biomed Anal 2018; 158:28-37. [DOI: 10.1016/j.jpba.2018.05.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Revised: 05/15/2018] [Accepted: 05/16/2018] [Indexed: 10/16/2022]
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He S, Lin Q, Qu M, Wang L, Deng L, Xiao L, Zhang Z, Zhang L. Liver-Targeted Co-delivery of Entecavir and Glycyrrhetinic Acid Based on Albumin Nanoparticle To Enhance the Accumulation of Entecavir. Mol Pharm 2018; 15:3953-3961. [PMID: 30110554 DOI: 10.1021/acs.molpharmaceut.8b00408] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Hepatitis B, one of the most common contagious viral hepatitis with high infection rate, is challenging to treat. Although the treatment for hepatitis B has been improved over the years, many therapeutic drugs still have either severe adverse effects or insufficient effectiveness via systemic administration. In this study, we confirmed that glycyrrhetinic acid can enhance the accumulation of entecavir in HepaRG cell and liver. Then we constructed a novel albumin nanoparticle co-loading entecavir and glycyrrhetinic acid (ETV-GA-AN) to improve liver accumulation of entecavir and investigated its ability to deliver both drugs to liver. In vitro cellular uptake study and in vivo tissue distribution experiment showed that these negatively charged ETV-GA-AN (112 ± 2 nm in diameter) can increase the accumulation of entecavir in hepatic HepaRG cells and improve entecavir distribution in liver. We also revealed the mechanism that glycyrrhetinic acid enhances intracellular accumulation of entecavir by inhibiting the activity of specific efflux transporters. Our delivery system is the first liver-targeted albumin nanoparticle that utilizes the site-specific co-delivery strategy to delivery entecavir and glycyrrhetinic acid. As it combines high efficiency and low toxicity, it possess great potential for treating hepatitis B.
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Affiliation(s)
- Shanshan He
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu 610041 , China
| | - Qing Lin
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu 610041 , China
| | - Mengke Qu
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu 610041 , China
| | - Luyao Wang
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu 610041 , China
| | - Lang Deng
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu 610041 , China
| | - Linyu Xiao
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu 610041 , China
| | - Zhirong Zhang
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu 610041 , China
| | - Ling Zhang
- School of Pharmacy, College of Polymer Science and Engineering , Sichuan University , Chengdu 610041 , China
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Triantos C, Kalafateli M, Aggeletopoulou I, Mandellou M, Assimakopoulos S, Tselekouni P, Taprantzi D, Tsiaoussis G, Vourli G, Anastassiou ED, Gogos C, Labropoulou-Karatza C, Thomopoulos K. Lactate serum concentrations during treatment with nucleos(t)ide analogues in hepatitis B with or without cirrhosis. Eur J Gastroenterol Hepatol 2017; 29:998-1003. [PMID: 28746158 DOI: 10.1097/meg.0000000000000924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The aim of this study is to evaluate the clinical implications of lactate concentrations in patients with hepatitis B with or without cirrhosis during treatment with nucleos(t)ide analogues. PATIENTS AND METHODS One hundred and seven consecutive patients with chronic hepatitis B and median age 57 (24-85) years were prospectively included. Lactate concentrations were measured at baseline and at 12, 24, 36, 48, and 60 months following the baseline measurements. Eight (n=8, 7.5%) patients received lamivudine, 38 (n=38, 35.5%) patients received tenofovir, 34 (n=34, 31.8%) patients received entecavir, and 27 (n=27, 25.2%) patients received combined therapy. RESULTS None of the patients developed lactic acidosis during follow-up [median: 58 (6-155) months]. Overall, no trends of the lactic acid evolution were observed over time; however, there was a nonsignificant increasing trend in patients with cirrhosis up to 24 months of treatment. This increasing trend was significant in female patients with cirrhosis (P=0.016). The age of the patients, the presence of cirrhosis, and hepatocellular carcinoma were strongly associated with the survival of all patients. In the group of cirrhotic patients, the only independent prognostic factor that was associated with patients' survival was the Child-Pugh class. CONCLUSION None of the patients developed lactic acidosis. There is an indication of an increasing trend of lactic acid levels up to 24 months of therapy in female cirrhotic patients.
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Affiliation(s)
- Christos Triantos
- Departments of aGastroenterology bBiochemistry cInternal Medicine dMicrobiology, University Hospital of Patras, Patras eDepartment of Hygiene, Epidemiology and Medical Statistics, Medical School University of Athens, Athens, Greece
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Lee HW, Park JY, Ahn SH. An evaluation of entecavir for the treatment of chronic hepatitis B infection in adults. Expert Rev Gastroenterol Hepatol 2016; 10:177-86. [PMID: 26610256 DOI: 10.1586/17474124.2016.1125781] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Entecavir is a nucleoside analogue of 2'-deoxyguanosine whose intracellular triphosphate form inhibits replication of the hepatitis B virus. Entecavir is recommended as a first-line monotherapy option for nucleos(t)ide-naïve patients with HBeAg-positive or -negative chronic hepatitis B infection. Entecavir has a three-step mechanism of action: It maintains viral suppression with a greater than 90% chance of undetectable hepatitis B virus DNA during continuous therapy, improves liver histology, and reduces the risk of liver failure or hepatocellular carcinoma development. The safety profile of long-term entecavir therapy is favorable; however, its optimal treatment duration is unknown. Entecavir monotherapy is not a rescue option for patients with lamivudine/adefovir resistance or baseline lamivudine-resistant mutants; rather, combination treatment is recommended for patients with lamivudine/adefovir resistance.
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Affiliation(s)
- Hye Won Lee
- a Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Korea.,b Yonsei Liver Center , Severance hospital , Seoul , Korea
| | - Jun Yong Park
- a Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Korea.,b Yonsei Liver Center , Severance hospital , Seoul , Korea.,c Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Korea
| | - Sang Hoon Ahn
- a Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Korea.,b Yonsei Liver Center , Severance hospital , Seoul , Korea.,c Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Korea.,d Brain Korea 21 Project for Medical Science , Seoul , Korea
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7
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Ulbrich K, Holá K, Šubr V, Bakandritsos A, Tuček J, Zbořil R. Targeted Drug Delivery with Polymers and Magnetic Nanoparticles: Covalent and Noncovalent Approaches, Release Control, and Clinical Studies. Chem Rev 2016; 116:5338-431. [DOI: 10.1021/acs.chemrev.5b00589] [Citation(s) in RCA: 1086] [Impact Index Per Article: 120.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Karel Ulbrich
- Institute
of Macromolecular Chemistry, The Czech Academy of Sciences, v.v.i., Heyrovsky Square 2, 162 06 Prague 6, Czech Republic
| | - Kateřina Holá
- Regional
Centre of Advanced Technologies and Materials, Department of Physical
Chemistry, Faculty of Science, Palacky University, 17 Listopadu 1192/12, 771 46 Olomouc, Czech Republic
| | - Vladimir Šubr
- Institute
of Macromolecular Chemistry, The Czech Academy of Sciences, v.v.i., Heyrovsky Square 2, 162 06 Prague 6, Czech Republic
| | - Aristides Bakandritsos
- Regional
Centre of Advanced Technologies and Materials, Department of Physical
Chemistry, Faculty of Science, Palacky University, 17 Listopadu 1192/12, 771 46 Olomouc, Czech Republic
| | - Jiří Tuček
- Regional
Centre of Advanced Technologies and Materials, Department of Physical
Chemistry, Faculty of Science, Palacky University, 17 Listopadu 1192/12, 771 46 Olomouc, Czech Republic
| | - Radek Zbořil
- Regional
Centre of Advanced Technologies and Materials, Department of Physical
Chemistry, Faculty of Science, Palacky University, 17 Listopadu 1192/12, 771 46 Olomouc, Czech Republic
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8
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Morgnanesi D, Heinrichs EJ, Mele AR, Wilkinson S, Zhou S, Kulp JL. A computational chemistry perspective on the current status and future direction of hepatitis B antiviral drug discovery. Antiviral Res 2015; 123:204-15. [PMID: 26477294 DOI: 10.1016/j.antiviral.2015.10.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 10/02/2015] [Accepted: 10/11/2015] [Indexed: 12/11/2022]
Abstract
Computational chemical biology, applied to research on hepatitis B virus (HBV), has two major branches: bioinformatics (statistical models) and first-principle methods (molecular physics). While bioinformatics focuses on statistical tools and biological databases, molecular physics uses mathematics and chemical theory to study the interactions of biomolecules. Three computational techniques most commonly used in HBV research are homology modeling, molecular docking, and molecular dynamics. Homology modeling is a computational simulation to predict protein structure and has been used to construct conformers of the viral polymerase (reverse transcriptase domain and RNase H domain) and the HBV X protein. Molecular docking is used to predict the most likely orientation of a ligand when it is bound to a protein, as well as determining an energy score of the docked conformation. Molecular dynamics is a simulation that analyzes biomolecule motions and determines conformation and stability patterns. All of these modeling techniques have aided in the understanding of resistance mutations on HBV non-nucleos(t)ide reverse-transcriptase inhibitor binding. Finally, bioinformatics can be used to study the DNA and RNA protein sequences of viruses to both analyze drug resistance and to genotype the viral genomes. Overall, with these techniques, and others, computational chemical biology is becoming more and more necessary in hepatitis B research. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B."
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Affiliation(s)
- Dante Morgnanesi
- Department of Chemistry, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
| | - Eric J Heinrichs
- Department of Chemistry, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
| | - Anthony R Mele
- Department of Chemistry, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
| | - Sean Wilkinson
- Department of Chemistry, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
| | - Suzanne Zhou
- Department of Chemistry, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
| | - John L Kulp
- Department of Chemistry, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA.
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9
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The effect of cation size (H+, Li+, Na+, and K+) on McLafferty-type rearrangement of even-electron ions in mass spectrometry. Sci China Chem 2014. [DOI: 10.1007/s11426-014-5085-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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How to address the sample preparation of hydrophilic compounds: Determination of entecavir in plasma and plasma ultrafiltrate with novel extraction sorbents. J Pharm Biomed Anal 2014; 88:337-44. [DOI: 10.1016/j.jpba.2013.08.034] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Revised: 08/20/2013] [Accepted: 08/23/2013] [Indexed: 11/19/2022]
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Ramesh T, Rao PN, Rao RN. LC-MS/MS method for the characterization of the forced degradation products of Entecavir. J Sep Sci 2013; 37:368-75. [PMID: 24323372 DOI: 10.1002/jssc.201300959] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Revised: 10/28/2013] [Accepted: 12/02/2013] [Indexed: 11/10/2022]
Abstract
A rapid, specific, and reliable isocratic LC-MS/MS method has been developed and validated for the identification and characterization of the stressed degradation products of Entecavir (ETV). ETV, an antiviral drug, was subjected to hydrolysis (acidic, alkaline, and neutral), oxidation, photolysis and thermal stress, as per the international conference on harmonization specified conditions. The drug showed extensive degradation under oxidative and acid hydrolysis stress conditions. However, it was stable to thermal, acidic, neutral, and photolysis stress conditions. A total of five degradation products were observed and the chromatographic separation of the drug and its degradation products were achieved on a Waters Symmetry C18 (250 mm × 4.6 mm, id, 5 μm) column using 20 mM ammonium acetate (pH 3)/acetonitrile (50:50, v/v) as a mobile phase. The degradation products were characterized by LC-MS/MS and its fragmentation pathways were proposed. The LC-MS method was validated with respect to specificity, linearity, accuracy, and precision. No previous reports were found in the literature regarding the degradation behavior of ETV.
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Affiliation(s)
- Thippani Ramesh
- Department of Chemistry, National Institute of Technology, Warangal, Andhra Pradesh, India
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Lam YF, Yuen MF, Seto WK, Lai CL. Current Antiviral Therapy of Chronic Hepatitis B: Efficacy and Safety. CURRENT HEPATITIS REPORTS 2011; 10:235-243. [PMID: 22131901 PMCID: PMC3210946 DOI: 10.1007/s11901-011-0109-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The treatment of chronic hepatitis B is in constant evolution. Interferon, the first agent licensed for chronic hepatitis B treatment, has been superseded by the growing popularity of nucleoside/nucleotide analogues (NA). However, resistance to these agents is a major challenge. Newer NAs, such as entecavir and tenofovir dipivoxil fumarate, have very low resistance rates and favorable safety profiles. Long-term use of these agents can effectively suppress hepatitis B virus DNA, leading to decrease in incidence of hepatitic flares, as well as in the development of cirrhosis and hepatocellular carcinoma. The efficacy and safety of various antiviral agents is discussed in this review.
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Affiliation(s)
- Yuk-Fai Lam
- Department of Medicine, The University of Hong Kong Queen Mary Hospital, Pokfulam Road, Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong Queen Mary Hospital, Pokfulam Road, Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong Queen Mary Hospital, Pokfulam Road, Hong Kong, Hong Kong
| | - Ching-Lung Lai
- Department of Medicine, The University of Hong Kong Queen Mary Hospital, Pokfulam Road, Hong Kong, Hong Kong
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Challa BR, Awen BZ, Chandu BR, Rihanaparveen S. LC-ESI-MS/MS method for the quantification of entecavir in human plasma and its application to bioequivalence study. J Chromatogr B Analyt Technol Biomed Life Sci 2011; 879:769-76. [PMID: 21397572 DOI: 10.1016/j.jchromb.2011.02.023] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2010] [Revised: 02/09/2011] [Accepted: 02/11/2011] [Indexed: 10/18/2022]
Abstract
Liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) was used for a quantitative estimation of entecavir (EV) in human plasma using lamivudine (LM) as internal standard (IS). The method herein described is simple, sensitive, and specific. Chromatographic separation was performed on XBridge-C18, 4.6 mm × 50 mm, 5-μm column with an isocratic mobile phase composed of 10 mM ammonium hydrogen carbonate (pH 10.5):methanol (85:15 v/v), pumped at 0.3 ml/min. EV and LM were detected using proton adducts at m/z 278.1→152.1 and 230.2→112.0 in multiple reaction monitoring (MRM) positive mode. Solid phase extraction method was employed in the extraction of EV and LM from the biological matrix. This method was validated over a linear concentration range of 50.0-20000.0 pg/ml with a correlation coefficient (r) ≥0.9983. Intra and inter-day precision of EV was found within the range of 1.2-4.2 for EV and 4.4-4.5 for LM. EV was stable throughout three freeze/thaw cycles, bench top and postoperative studies. This method was successfully used in the analysis of plasma samples following oral administration of EV (0.5 mg) in 26 healthy human volunteers.
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Affiliation(s)
- Balasekhara Reddy Challa
- Siddharth Institute of Pharmacy, Nalanda Educational Society, Guntur, Andhrapradesh, India. baluchalla
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Liu J, Yang Y, Hu B, Ma ZY, Huang HP, Yu Y, Liu SP, Lu MJ, Yang DL. Development of HBsAg-binding aptamers that bind HepG2.2.15 cells via HBV surface antigen. Virol Sin 2010; 25:27-35. [PMID: 20960281 DOI: 10.1007/s12250-010-3091-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2009] [Accepted: 10/09/2009] [Indexed: 10/19/2022] Open
Abstract
Hepatitis B virus surface antigen (HBsAg), a specific antigen on the membrane of Hepatitis B virus (HBV)-infected cells, provides a perfect target for therapeutic drugs. The development of reagents with high affinity and specificity to the HBsAg is of great significance to the early-stage diagnosis and treatment of HBV infection. Herein, we report the selection of RNA aptamers that can specifically bind to HBsAg protein and HBsAg-positive hepatocytes. One high affinity aptamer, HBs-A22, was isolated from an initial 115 mer library of ~1.1 x 10¹⁵ random-sequence RNA molecules using the SELEX procedure. The selected aptamer HBs-A22 bound specifically to hepatoma cell line HepG2.2.15 that expresses HBsAg but did not bind to HBsAg-devoid HepG2 cells. This is the first reported RNA aptamer which could bind to a HBV specific antigen. This newly isolated aptamer could be modified to deliver imaging, diagnostic, and therapeutic agents targeted at HBV-infected cells.
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Affiliation(s)
- Jia Liu
- Division of Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Huang H, Cai Q, Lin T, Lin X, Liu Y, Gao Y, Peng R. Lamivudine for the prevention of hepatitis B virus reactivation after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for patients with advanced or relapsed non-Hodgkin's lymphoma single institution experience. Expert Opin Pharmacother 2009; 10:2399-406. [PMID: 19761353 DOI: 10.1517/14656560903251710] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVE Hepatitis B virus (HBV) reactivation is a well-known complication in cancer patients receiving cytotoxic chemotherapy, resulting in varying degrees of liver damage. The objective of this study was to investigate the efficacy of lamivudine for the prevention of HBV reactivation in non-Hodgkin's lymphoma (NHL) patients undergoing high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT). RESEARCH DESIGN AND METHODS Thirty-two patients with NHL who were HBV surface antigen (HBsAg)-positive were enrolled in this pilot study. They were divided into two groups: 20 patients received prophylactic oral lamivudine 100 mg/day before, and until at least 6 months after transplantation. The historical control group comprised 12 patients who received high-dose chemotherapy and AHSCT without lamivudine. The incidence and severity of hepatitis due to HBV reactivation, as well as other adverse clinical outcomes, were compared between the two groups. RESULTS Most baseline clinical characteristics were similar in the two groups, except for HBV e-antigen (HBeAg)-positive status (85% in the lamivudine group vs 33.3% in the control group, p = 0.006) and the type of AHSCT. There was a lower incidence of hepatitis due to HBV reactivation in the lamivudine group than in the control group (10 vs 50%, p = 0.030), less severe hepatitis (0 vs 25%, p = 0.009), and lower mortality (0 vs 25%, p = 0.236). An HBV variant with tyrosine methionine aspartate aspartate (YMDD) mutation was detected in one patient in the lamivudine group (5%) after administration of lamivudine for 9 months. No significant adverse events were associated with the use of prophylactic lamivudine, and hematopoietic reconstitution was not affected by the intervention. CONCLUSIONS Prophylactic lamivudine may reduce the incidence and severity of chemotherapy-related HBV reactivation and hepatitis-related mortality in HBsAg-positive NHL patients receiving high-dose chemotherapy and AHSCT. Additional randomized, multicenter trials are warranted.
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Affiliation(s)
- Huiqiang Huang
- Sun Yat-sen University, Cancer Center, Department of Medical Oncology, Guangzhou 510060, PR China.
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Antiviral activity, dose-response relationship, and safety of entecavir following 24-week oral dosing in nucleoside-naive Japanese adult patients with chronic hepatitis B: a randomized, double-blind, phase II clinical trial. Hepatol Int 2009; 3:445-52. [PMID: 19669249 DOI: 10.1007/s12072-009-9135-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2009] [Accepted: 05/07/2009] [Indexed: 01/04/2023]
Abstract
PURPOSE A randomized, double-blind, multicenter study (ETV-047) was conducted to evaluate the dose-response relationship of entecavir and compare its antiviral activity and safety with lamivudine in Japanese patients with chronic hepatitis B (CHB). METHODS One hundred thirty-seven nucleoside-naive adult patients with CHB were randomized to once-daily oral doses of entecavir 0.01, 0.1, or 0.5 mg or lamivudine 100 mg for 24 weeks. The primary efficacy end point used to evaluate the dose-response relationship was mean change from baseline in serum hepatitis B virus (HBV) DNA level at week 22, as determined by polymerase chain reaction assay. RESULTS Entecavir demonstrated a clear dose-response relationship, with mean change from baseline in serum HBV DNA level of -3.11, -4.77, and -5.16 log(10) copies/ml with entecavir 0.01, 0.1, and 0.5 mg, respectively. Entecavir 0.5 mg was superior to lamivudine 100 mg for the mean change in HBV DNA level (-5.16 vs. -4.29 log(10) copies/ml; P = 0.007). The overall incidence of adverse events was comparable between treatment groups. Two patients discontinued treatment because of adverse events (one with liver cirrhosis [entecavir 0.5 mg] and one with grade 4 serum alanine aminotransferase (ALT) elevation, nausea, and malaise [lamivudine 100 mg]). Serum ALT flares were observed in four patients; flares were associated with 2 log(10) reductions or more in HBV DNA level and resolved without dose interruption. CONCLUSION Entecavir 0.01-0.5 mg is well tolerated and produces a dose-dependent reduction in viral load in nucleoside-naive Japanese patients with CHB. Compared with lamivudine 100 mg, entecavir 0.1 mg demonstrated noninferiority and entecavir 0.5 mg was superior in this population.
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You J, Sriplung H, Geater A, Chongsuvivatwong V, Zhuang L, Li YL, Lei H, Liu J, Chen HY, Tang BZ, Huang JH. Impact of viral replication inhibition by entecavir on peripheral T lymphocyte subpopulations in chronic hepatitis B patients. BMC Infect Dis 2008; 8:123. [PMID: 18803883 PMCID: PMC2570678 DOI: 10.1186/1471-2334-8-123] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2007] [Accepted: 09/22/2008] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND To investigate dynamic fluctuations of serum viral load and peripheral T-lymphocyte subpopulations of chronic hepatitis B patients and their correlation during entecavir therapy. METHODS Fifty-five patients received entecavir 0.5 mg/d therapy. Serum HBV DNA load was measured by Real-Time-PCR, and the levels of peripheral T-lymphocyte subpopulations by flow cytometry biweekly, every four weeks and every eight weeks during weeks 1-12, 13-24 and 24-48, respectively. Multilevel modelling was used to analyse the relationship between these variables. RESULTS Of the 55 patients, all HBeAg positive and with detectable HBV DNA, the majority (81.8%) had serum levels of HBV DNA over 10(7) copies per milliliter. HBV viral load dropped sharply during the first two weeks. In 28 and 43 patients, the level became undetectable from week 24 and 48, respectively. Using pre-therapy level as the reference, a significant decrease in CD8+ T cells and increase in CD4+ T cells were found from week 12. Both parameters and CD4+/CD8+ ratio steadily improved throughout the 48 weeks. Multilevel analyses showed that the level of decrement of HBV DNA was associated with the increment of T-lymphocyte activities only in the later period (4-48 week). After 4 weeks of therapy, for each log10 scale decrement of HBV DNA, the percentage of CD4+ lymphocyte was increased by 0.49 and that of CD8+ decreased by 0.51. CONCLUSION T-lymphocyte subpopulations could be restored partially by entecavir treatment in patients with chronic hepatitis B concurrently with reduction of viremia.
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Affiliation(s)
- Jing You
- Epidemiology Unit, Faculty of Medicine, Prince of Songkla University, Thailand.
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Jakobsen M, Arildsen H, Krarup H, Tolstrup M, Østergaard L, Laursen A. Entecavir Therapy Induces de Novo HIV Reverse‐Transcriptase M184V Mutation in an Antiretroviral Therapy–Naive Patient. Clin Infect Dis 2008; 46:e88-91. [DOI: 10.1086/587174] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
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Wang XL, Xie SG, Zhang L, Yang WX, Wang X, Jin HZ. Comparison of ligase detection reaction and real-time PCR for detection of low abundant YMDD mutants in patients with chronic hepatitis B. World J Gastroenterol 2008; 14:120-4. [PMID: 18176973 PMCID: PMC2673375 DOI: 10.3748/wjg.14.120] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare the ligase detection reaction (LDR) and real-time PCR for detection of low abundant YMDD mutants in patients with chronic hepatitis B infection.
METHODS: Mixtures of plasmids and serum samples from 52 chronic hepatitis B patients with low abundant lamivudine-resistant mutations were tested with LDR and real-time PCR. Time required and reagent cost for both assays were evaluated.
RESULTS: Real-time PCR detected 100, 50, 10, 1 and 0.1% of YIDD plasmid, whereas LDR detected 100, 50, 10, 1, 0.1, and 0.01% of YIDD plasmid, in mixtures with YMDD plasmid of 106 copies/mL. Among the 52 clinical serum samples, completely concordant results were obtained for all samples by both assays, and 39 YIDD, 9 YVDD, and 4 YIDD/YVDD were detected. Cost and time required for LDR and real-time PCR are 60/80 CNY (8/10.7 US dollars) and 4.5/2.5 h, respectively.
CONCLUSION: LDR and real-time PCR are both sensitive and inexpensive methods for monitoring low abundant YMDD mutants during lamivudine therapy in patients with chronic hepatitis B. LDR is more sensitive and less expensive, while real-time PCR is more rapid.
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Shih YH, Yeh SH, Chen PJ, Chou WP, Wang HY, Liu CJ, Lu SF, Chen DS. Hepatitis B virus quantification and detection of YMDD mutants in a single reaction by real-time PCR and annealing curve analysis. Antivir Ther 2008; 13:469-480. [PMID: 18672526 DOI: 10.1177/135965350801300403] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
BACKGROUND Long-term antiviral therapy, although effective for treatment of hepatitis B, might select the emergence of drug-resistant hepatitis B virus (HBV) mutants. Detection of HBV mutants and determination of viral titre are two crucial parameters for monitoring treatment response and occurrence of mutants. In this study, we take lamivudine resistance as an example to develop a method that can determine both parameters in a single-tube PCR reaction. METHODS The method contained two consecutive steps: in the first step, real-time PCR was used for quantification; in the second step, a novel annealing curve analysis was used for detecting YMDD mutants. For accurate quantification, PCR primers and hybridization probes were chosen from highly conserved regions to ensure the equivalent amplification of all HBV genotypes. Within the sensor probe, there were signature nucleotide polymorphisms that could effectively differentiate YMDD mutants from wild type by distinct melting temperatures (Tm) values. The clinical applicability of the assay was tested in serial samples from 90 patients receiving lamivudine treatment. RESULTS This assay could readily differentiate YMDD, YIDD and YVDD mutants by their distinct Tm values. The quantification results showed great consistency in a linear range from 10(3) to 10(11) copies/ml. Moreover, this assay could detect YMDD mutants accounting for < or = 10% of the total viral population. Its clinical feasibility has been verified in primary specimens. CONCLUSIONS The newly designed YMDD detection method is simple, sensitive, cost-effective, time-saving and provides a useful tool for follow-up of patients treated with lamivudine or other antiviral drugs.
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Affiliation(s)
- Yi-Hsien Shih
- NTU Center for Genomic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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De Francesco R, Carfí A. Advances in the development of new therapeutic agents targeting the NS3-4A serine protease or the NS5B RNA-dependent RNA polymerase of the hepatitis C virus. Adv Drug Deliv Rev 2007; 59:1242-62. [PMID: 17869377 DOI: 10.1016/j.addr.2007.04.016] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2007] [Accepted: 04/13/2007] [Indexed: 01/28/2023]
Abstract
The HCV NS3 protease and NS5B polymerase play essential roles in the replication of the hepatitis C virus (HCV). Following the successful paradigm established for HIV protease and reverse transcriptase inhibitors, these enzymes have been elected as targets for the development of small molecule HCV inhibitors. By combining the power of high-throughput screening with rational, knowledge-based drug discovery, a number of competitive inhibitors of the NS3 protease as well as nucleoside and non-nucleoside inhibitors of the NS5B polymerase have been identified and some have now entered clinical trials. In this article we review recent progress in the discovery and development of small molecule inhibitors of these two essential viral enzymes as they are advancing in the clinic.
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Affiliation(s)
- Raffaele De Francesco
- Istituto di Ricerche di Biologia Molecolare, P. Angeletti, Via Pontina Km 30,600, 00040 Pomezia (Rome), Italy.
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Wen WH, Qin WJ, Gao H, Zhao J, Jia LT, Liao QH, Meng YL, Jin BQ, Yao LB, Chen SY, Yang AG. An hepatitis B virus surface antigen specific single chain of variable fragment derived from a natural immune antigen binding fragment phage display library is specifically internalized by HepG2.2.15 cells. J Viral Hepat 2007; 14:512-519. [PMID: 17576393 DOI: 10.1111/j.1365-2893.2007.00843.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatitis B virus surface antigen (HBsAg), a specific antigen on the membrane of hepatitis B virus (HBV)-infected cells, provides a perfect target for therapeutic drugs. In order to mediate successful targeted delivery of these therapies, it is essential to have antibodies that recognize HBsAg with high specificity and affinity. In this report, we constructed a natural immune antigen binding fragments (Fab) antibody phage display library against HBsAg and after three rounds of panning, five Fab fragments with significant HBsAg binding ability were selected and analysed. DNA sequencing revealed that all the light chains had the same sequence, while all the Fd genes exhibited different sequences. For further application, all of the Fab antibodies were reconstructed into single chain antibodies (scFvs) and expressed in Escherichia coli BL21 cells. Indirect enzyme-linked immunosorbent assay analysis demonstrated that all five scFvs maintained a high affinity for HBsAg and could bind HBsAg on the membrane of HBV-infected cells. Indirect fluorescent staining analysis revealed that one of the scFvs (scFv15) could be internalized into HBsAg-positive HepG2.2.15 cells through clathrin-mediated endocytosis pathway. The internalizing scFv15 antibody would have great potential for the targeted delivery of therapeutics to HBV-infected cells.
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Affiliation(s)
- W-H Wen
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, China
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Abstract
Infections in patients with end-stage liver disease (ESLD) are an important cause of morbidity and mortality in these patients. Abnormalities in their natural defense mechanisms, alterations in the enteric flora and the growing utilization of invasive procedures increase the risk of infections in these patients. Common bacterial infections in ESLD patients include spontaneous bacterial peritonitis, urinary tract infections, community-acquired pneumonia, dermatologic infections, and bacteremia. Viral infections such as influenza can have a devastating course in ESLD patients. Hepatitis B and C are now among the most common causes of ESLD. They also present an important therapeutic challenge. As patients with human immunodeficiency virus are surviving longer, ESLD due to hepatitis C is now emerging as a leading cause of morbidity in these patients. Prompt detection of infections, use of appropriate antibiotics for treatment and prophylactic measures such as vaccinations can help improve survival in these patients.
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Affiliation(s)
- Rekha Cheruvattath
- Division of Transplant Medicine, Mayo Clinic Hospital, 5777 E Mayo Boulevard, 5th Floor, Phoenix, AR 85054, USA
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Yang ZJ, Tu MZ, Liu J, Wang XL, Jin HZ. Comparison of amplicon-sequencing, pyrosequencing and real-time PCR for detection of YMDD mutants in patients with chronic hepatitis B. World J Gastroenterol 2006; 12:7192-6. [PMID: 17131486 PMCID: PMC4087785 DOI: 10.3748/wjg.v12.i44.7192] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [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
AIM: To compare the sequencing of PCR products, pyrosequencing, and real-time PCR for detection of Tyrosine-methionine-aspartate-aspartate (YMDD) mutants in patients with chronic hepatitis B.
METHODS: Mixtures of plasmids and serum samples from 69 chronic hepatitis B patients treated with lamivudine were tested for YMDD mutations by sequencing of PCR products, pyrosequencing, and real-time PCR, respectively. Time required and reagent costs of the three assays were evaluated.
RESULTS: Real-time PCR detected 100%, 50%, 10%, 1% and 0.1% of YVDD plasmid in mixtures with 106 copies/mL of YMDD plasmid, whereas sequencing and pyrosequencing only detected 100% and 50% of YVDD plasmid in aliquots of the corresponding mixtures. Completely concordant results were obtained from 60 (87%) out of the 69 clinical serum samples by the three assays. Mutants were detected by real-time PCR in less than 20% of the total virus population, but no mutant was detected by sequencing and pyrosequencing. In addition, real-time PCR required less time and was more cost-effective than the other two assays. However, throughput of pyrosequencing was the highest.
CONCLUSION: Among the three assays compared, real-time PCR is the most sensitive, cost-effective, and time saving for monitoring YMDD mutants in patients with chronic hepatitis B on lamivudine therapy.
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Affiliation(s)
- Zhi-Jun Yang
- Management School, Shanghai Jiaotong University, No. 1289 Yishan Road, Shanghai 200233, China.
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Villet S, Pichoud C, Villeneuve JP, Trépo C, Zoulim F. Selection of a multiple drug-resistant hepatitis B virus strain in a liver-transplanted patient. Gastroenterology 2006; 131:1253-61. [PMID: 17030194 DOI: 10.1053/j.gastro.2006.08.013] [Citation(s) in RCA: 131] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2006] [Accepted: 06/02/2006] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Sequential anti-hepatitis B virus (HBV) therapy may lead to the selection of complex mutants. We analyzed the genetic and phenotypic evolution of the viral quasispecies of a patient who received successively lamivudine, add-on adefovir+lamivudine, followed by lamivudine+adefovir+hepatitis B immunoglobulins (HBIg) after orthotopic liver transplantation. METHODS For genotypic analysis, a 1310-bp region of the polymerase gene was amplified, cloned, and sequenced. Huh-7 cells were transfected to compare the replication fitness of HBV mutants and their susceptibility to drugs. RESULTS At baseline, all HBV genomes carried a wild-type (wt) RT gene but 22% harbored the sP120S and 55% the sC107stop mutations within the surface (S) gene associated with vaccine escape. Following viral breakthrough to lamivudine monotherapy, a complex mixture of lamivudine-resistant HBV strains prevailed. Interestingly, among these mutants emerged a population harboring only the rtL180M+A181V mutations, conferring lamivudine-resistance in vitro. After addition of adefovir to the ongoing treatment, viral load dropped, and the patient underwent an orthotopic liver transplantation and received HBIg. As viral load rose again, a single viral population was progressively selected, harboring the rtV173L+L180M+A181V+N236T and sP120S mutations. In vitro, this last mutant showed a level of replication reduced by only 30% compared to wt HBV and a strong resistance to both lamivudine (>1000-fold) and adefovir (>10-fold). It remained sensitive to tenofovir both in vitro and in vivo. CONCLUSIONS We report the selection of a complex HBV mutant that escaped the antiviral pressure of lamivudine, adefovir, and HBIg, and provide insight on the process of selection via genotypic and phenotypic analysis.
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Affiliation(s)
- Stéphanie Villet
- INSERM U271, Laboratoire des Virus Hépatiques et Pathologies Associées, 151 cours Albert Thomas, 69424 Lyon cedex 03, France
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