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Sedohara A, Takahashi K, Arai K, Arizono K, Tuvshinjargal K, Saito M, Nakahara F, Tsutsumi T, Ikeuchi K, Adachi E, Yotsuyanagi H. Characterization of mutations in hepatitis B virus DNA isolated from Japanese HBsAg-positive blood donors in 2021 and 2022. Arch Virol 2024; 169:103. [PMID: 38632180 PMCID: PMC11023964 DOI: 10.1007/s00705-024-06016-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 02/04/2024] [Indexed: 04/19/2024]
Abstract
Missense mutations in certain small envelope proteins diminish the efficacy of antibodies. Consequently, tracking the incidence and types of vaccine-escape mutations (VEMs) was crucial both before and after the introduction of universal hepatitis B vaccination in Japan in 2016. In this study, we isolated hepatitis B virus (HBV) DNA from 58 of 169 hepatitis B surface antigen (HBsAg)-positive blood samples from Japanese blood donors and determined the nucleotide sequence encoding the small envelope protein. DNA from six (10%) of the samples had VEMs, but no missense mutations, such as G145R, were detected. Complete HBV genome sequences were obtained from 29 of the 58 samples; the viral genotype was A1 in one (3%), A2 in three (10%), B1 in nine (31%), B2 in five (17%), B4 in one (3%), and C2 in 10 (34%) samples. Tenofovir-resistance mutations were detected in two (7%) samples. In addition, several core promoter mutations, such as 1762A>T and 1764G>A, and a precore nonsense mutation, 1986G>A, which are risk factors for HBV-related chronic liver disease, were detected. These findings provide a baseline for future research and highlight the importance of ongoing monitoring of VEMs and drug resistance mutations in HBV DNA from HBsAg-positive blood donors without HBV antibodies.
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Affiliation(s)
- Ayako Sedohara
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
| | - Kazuaki Takahashi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Keiko Arai
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Kotaro Arizono
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Khulan Tuvshinjargal
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Makoto Saito
- Department of Infectious Disease and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Fumio Nakahara
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
| | - Takeya Tsutsumi
- Department of Infectious Disease and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Department of Infectious Diseases, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Ikeuchi
- Department of Infectious Disease and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Eisuke Adachi
- Department of Infectious Disease and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
- Department of Infectious Disease and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
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Li J, Zhang D, Zhang X. The Occurrence of rtA194T Mutant After Long-Term Lamivudine Monotherapy Remains Sensitive to Tenofovir Disoproxil Fumarate: A Case Report. Infect Drug Resist 2021; 14:1013-1017. [PMID: 33758517 PMCID: PMC7979339 DOI: 10.2147/idr.s295060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 03/03/2021] [Indexed: 01/11/2023] Open
Abstract
Tenofovir disoproxil fumarate (TDF) is recommended as first-line agents in chronic hepatitis B (CHB) patients for its high antiviral effects and high barrier to resistance. It is controversial whether the rtA194T mutation truly confers resistance against TDF. We present here a 62-year-old CHB patient who occurred rtL180M, rtM204V and rtA194T mutants after lamivudine (LAM) monotherapy for 9 years. TDF was introduced in replacement of LAM and led to Hepatitis B Virus (HBV) DNA undetectable in 1 month, maintained in the follow up of 52 weeks. These observations suggest that rtA194T mutation emerges under LAM monotherapy and remains sensitive to TDF.
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Affiliation(s)
- Jing Li
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Donghua Zhang
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Xinxin Zhang
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.,Sino-French Research Centre for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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Clinical Manifestations and Laboratory Tests of AECHB and Severe Hepatitis (Liver Failure). ACUTE EXACERBATION OF CHRONIC HEPATITIS B 2019. [PMCID: PMC7418529 DOI: 10.1007/978-94-024-1603-9_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This chapter describes the clinical symptoms and signs of AECHB and HBV ACLF, classification, grading of HBV ACLF and their features, diagnostic principles and standards in liver pathology, biochemistry, and virology of HBV ACLF.
Liver failure is defined as serious damage to the liver cause by a variety of etiologies, leading to liver function disorder or even decompensation, and clinical syndromes with coagulopathy, jaundice, hepatic encephalopathy, and ascites. Severe hepatitis B can be indicated pathologically by apparent hepatocellular necrosis, including extensive multifocal, confluent, bridging, sub-massive or massive necrosis. Laboratory tests during the course of severe exacerbation of chronic hepatitis B can reflect pathological changes and liver function in a timely manner, providing objective and informative reference data for evaluation of disease severity and treatment efficacy. Among the most important laboratory tests are those for prothrombin activity, international normalized ratio, and increases in total bilirubin concentration. Severe hepatitis B is associated with interactions between the virus and host factors. Detection of HBV DNA, HBV genotype, quasispecies and HBV mutation can provide important theoretical bases for the prevention, control or mitigation of the progress of severe hepatitis B. Noninvasive imaging modalities can be used to visualize the entire liver and parts of it. Measuring liver volume to evaluate liver size and liver reserve capacity is regarded as important in diagnosis, surgical approach and prognostic evaluation of patients with severe exacerbation of chronic hepatitis B and liver failure. Model for End-Stage Liver Disease (MELD) is the first quantitative method developed to assess whether a patient with liver failure requires a liver transplant. The predictive value of the MELD model has been improved by the MELD-Na, iMELD, and MESO models. Several other valuable prognostic models have been developed. For example, for patients with HBV-ACLF, the established TPPM scoring system was found to be more predictive than MELD score.
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Evaluation of drug resistance mutations in patients with chronic hepatitis B. Folia Microbiol (Praha) 2018; 64:237-243. [PMID: 30259350 DOI: 10.1007/s12223-018-0650-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 09/16/2018] [Indexed: 01/17/2023]
Abstract
Mutations occurring in viral polymerase gene of hepatitis B virus (HBV) due to the use of nucleos(t)id analogs reduce the activity of the drugs by causing antiviral resistance. In this study, it was aimed to evaluate mutations responsible for drug resistance and drug resistance mutation rates in patients followed up by the diagnosis of chronic hepatitis B (CHB). A total of 318 CHB patients were included in the study. HBV mutations were detected using the INNO-LiPA commercial kit based on the reverse hybridization principle. Drug resistance mutation was detected in 46.86% (149/318) of the patients. The rates of drug resistance were found 36.79% (117/318) for lamivudine resistance, 12.58% (40/318) for entecavir (ETV), and 7.86% (25/318) for adefovir. In 10 patients, the possible tenofovir (TDF) resistance (3.14%) was found. Single-drug and double-drug resistances were detected in 34.59% and in 11.01% of the patients, respectively. Triple drug resistance was detected in only 1.26% of the patients. Unlike various studies in Turkey and in other countries, remarkable resistance to ETV and TDF were found in this study. The high rate of the probable TDF resistance was striking, with 3.14%.
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Yamani LN, Yano Y, Utsumi T, Wasityastuti W, Rinonce HT, Widasari DI, Juniastuti, Lusida MI, Soetjipto, Hayashi Y. Profile of Mutations in the Reverse Transcriptase and Overlapping Surface Genes of Hepatitis B Virus (HBV) in Treatment-Naïve Indonesian HBV Carriers. Jpn J Infect Dis 2017; 70:647-655. [PMID: 29093313 DOI: 10.7883/yoken.jjid.2017.078] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Mutations in the reverse transcriptase (RT) region of the hepatitis B virus (HBV) genome are an important factor in low therapeutic effectiveness. Nonetheless, the prevalence of these mutations in HBV strains isolated previously in Indonesia has not been systematically examined. Therefore, in this study, we investigated the profile of mutations in the RT region and the associations of these mutations with amino acid changes in the surface protein in the virus of treatment-naïve Indonesian HBV carriers. Overall, 96 sequences of the full-length Indonesian HBV genomes (genotype B, n = 54; genotype C, n = 42) were retrieved from the National Center for Biotechnology Information. Naturally occurring primary and/or compensatory drug resistance mutations were found in 6/54 (11.1%) genotype B strains and in 1/42 (2.4%) genotype C strains. The potential mutations underlying resistance to a nucleos(t)ide analog and/or pretreatment mutations were more frequent in both genotypes but more frequent in genotype C strains than in genotype B strains. The A-B interdomain region in the RT gene was more frequently mutated in genotype C than in genotype B (3.51 ± 2.53 vs. 1.08 ± 1.52, P ＜ 0.001). Knowledge about the mutational profiles of the RT gene and changes in the surface protein may help clinicians to select the most appropriate antiviral drug and vaccination or HBV immunoglobulin regimen for management of HBV infection in Indonesia.
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Affiliation(s)
| | - Yoshihiko Yano
- Center for Infectious Diseases, Kobe University Graduate School of Medicine.,Department of Gastroenterology, Kobe University Graduate School of Medicine
| | - Takako Utsumi
- Institute of Tropical Disease, Airlangga University.,Center for Infectious Diseases, Kobe University Graduate School of Medicine
| | | | - Hanggoro Tri Rinonce
- Department of Anatomical Pathology, Faculty of Medicine, Dr. Sardjito Hospital, Gadjah Mada University
| | - Dewiyani Indah Widasari
- Department of Anatomical Pathology, Faculty of Medicine, Dr. Sardjito Hospital, Gadjah Mada University
| | - Juniastuti
- Institute of Tropical Disease, Airlangga University
| | | | - Soetjipto
- Institute of Tropical Disease, Airlangga University
| | - Yoshitake Hayashi
- Center for Infectious Diseases, Kobe University Graduate School of Medicine
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Mulrooney-Cousins P, Michalak T. Molecular Testing in Hepatitis Virus Related Disease. DIAGNOSTIC MOLECULAR PATHOLOGY 2017:63-73. [DOI: 10.1016/b978-0-12-800886-7.00006-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Brah S, Moussa S, Inoua A, Alhousseini DM, Daou M, Madougou B, Romera MH, Hamadou A, Adehossi E, Parola P, Colson P. Molecular characterization of hepatitis B virus from chronically-infected patients in Niamey, Niger. Int J Infect Dis 2016; 45:18-23. [PMID: 26899956 DOI: 10.1016/j.ijid.2016.02.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2015] [Revised: 02/08/2016] [Accepted: 02/10/2016] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVES In Niger, 65% of hepatocarcinoma and 75% of cirrhosis cases were due to hepatitis B virus (HBV). We studied the genotypic characteristics of HBsAg in chronically HBV-infected patients in Niamey. METHODS We studied prospectively HBV genotypic patterns among hospitalized patients with HBV infection in the National Hospital of Niamey, Niger. Patients were screened for hepatitis B surface antigen (HBsAg) and HBV genotyping was performed on the HBsAg-positive patients. RESULTS In this study, we have confirmed the predominance of the HBV genotype E (HBV-E) in Niger and have identified 2 recombinant forms including HBV-E/D and HBV-A3/E reported previously among blood donors in Niger and Ghana, respectively. Amino acid substitutions found in HBV sequences obtained here included P120T, S143L, G145A and A194T. These substitutions were characterized as being associated with modified antigenicity and, notably, with impaired serological detection of HBsAg, while the A194T variant was found to have a controversial role in reduced susceptibility to tenofovir. CONCLUSIONS We have identified two recombinant HBV forms and rare genotypic patterns in Niger that may affect hepatitis B surface antigen antigenicity, and improve current knowledge of epidemiological, clinical and virological patterns of hepatitis B in this country.
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Affiliation(s)
- Souleymane Brah
- IHU Méditerranée Infection, Pôle des Maladies Infectieuses et Tropicales Clinique et Biologique, Service de Maladies Infectieuses, Centre Hospitalo-Universitaire Nord, Assistance Publique - Hôpitaux de Marseille, chemin des Bourrely, 13915 Marseille cedex 20; Service de médecine interne, Hôpital National de Niamey, BP 238 - Niger
| | - Sahada Moussa
- Service de maladies infectieuses, Hôpital National de Niamey, BP 238 - Niger
| | - Achirou Inoua
- Service de médecine interne, Hôpital National de Niamey, BP 238 - Niger
| | | | - Mamane Daou
- Service de médecine interne, Hôpital National de Niamey, BP 238 - Niger
| | - Boubacar Madougou
- Service de gastro entérologie, Hôpital National de Niamey, BP 238 - Niger
| | - Marie-Hélène Romera
- IHU Méditerranée Infection, Pôle des Maladies Infectieuses et Tropicales Clinique et Biologique, Fédération de Bactériologie-Hygiène-Virologie, Centre Hospitalo-Universitaire Timone, Assistance Publique-Hôpitaux de Marseille, 264 rue Saint-Pierre 13385, Marseille CEDEX 05, France
| | - Adamou Hamadou
- Service de médecine interne, Hôpital National de Niamey, BP 238 - Niger
| | - Eric Adehossi
- Service de médecine interne, Hôpital National de Niamey, BP 238 - Niger
| | - Philippe Parola
- IHU Méditerranée Infection, Pôle des Maladies Infectieuses et Tropicales Clinique et Biologique, Service de Maladies Infectieuses, Centre Hospitalo-Universitaire Nord, Assistance Publique - Hôpitaux de Marseille, chemin des Bourrely, 13915 Marseille cedex 20; Aix-Marseille University, URMITE UM 63 CNRS 7278 IRD 198 INSERM U1905, 27 boulevard Jean Moulin, 13385 Marseille CEDEX 05, France
| | - Philippe Colson
- Aix-Marseille University, URMITE UM 63 CNRS 7278 IRD 198 INSERM U1905, 27 boulevard Jean Moulin, 13385 Marseille CEDEX 05, France; IHU Méditerranée Infection, Pôle des Maladies Infectieuses et Tropicales Clinique et Biologique, Fédération de Bactériologie-Hygiène-Virologie, Centre Hospitalo-Universitaire Timone, Assistance Publique-Hôpitaux de Marseille, 264 rue Saint-Pierre 13385, Marseille CEDEX 05, France.
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Kim JH, Park YK, Park ES, Kim KH. Molecular diagnosis and treatment of drug-resistant hepatitis B virus. World J Gastroenterol 2014; 20:5708-5720. [PMID: 24914332 PMCID: PMC4024781 DOI: 10.3748/wjg.v20.i19.5708] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 01/29/2014] [Accepted: 03/19/2014] [Indexed: 02/07/2023] Open
Abstract
Oral antiviral agents have been developed in the last two decades for the treatment of chronic hepatitis B (CHB). However, antiviral resistance remains an important challenge for long-term CHB therapy. All of the clinically available oral antiviral agents are nucleoside or nucleotide analogues that target the activity of viral reverse transcriptase (RT), and all are reported to have resistant mutations. Since the hepatitis B virus (HBV) RT, like other viral polymerases, lacks proofreading activity, the emergence of drug-resistance occurs readily under selective pressure from the administration of antiviral agents. The molecular diagnosis of drug-resistant HBV is based on sequence variations, and current diagnostic methods include sequencing, restriction fragment polymorphism analysis, and hybridization. Here, we will discuss the currently available molecular diagnosis tools, in vitro phenotypic assays for validation of drug-resistant HBV, and treatment options for drug-resistant HBV.
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Molecular characterization of hepatitis B virus in liver disease patients and asymptomatic carriers of the virus in Sudan. BMC Infect Dis 2013; 13:328. [PMID: 23865777 PMCID: PMC3722059 DOI: 10.1186/1471-2334-13-328] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 07/16/2013] [Indexed: 12/12/2022] Open
Abstract
Background Hepatitis B virus is hyperendemic in Sudan. Our aim was to molecularly characterize hepatitis B virus from Sudanese individuals, with and without liver disease, because genotypes play an important role in clinical manifestation and treatment management. Methods Ninety-nine patients - 30 asymptomatic, 42 cirrhotic, 15 with hepatocellular carcinoma, 7 with acute hepatitis and 5 with chronic hepatitis- were enrolled. Sequencing of surface and basic core promoter/precore regions and complete genome were performed. Results The mean ± standard deviation, age was 45.7±14.8 years and the male to female ratio 77:22. The median (interquartile range) of hepatitis B virus DNA and alanine aminotransferase levels were 2.8 (2.2-4.2) log IU/ml and 30 (19–49) IU/L, respectively. Using three genotyping methods, 81/99 (82%) could be genotyped. Forty eight percent of the 99 patients were infected with genotype D and 24% with genotype E, 2% with putative D/E recombinants and 7% with genotype A. Patients infected with genotype E had higher frequency of hepatitis B e antigen-positivity and higher viral loads compared to patients infected with genotype D. Basic core promoter/precore region mutations, including the G1896A in 37% of HBeAg-negative individuals, could account for hepatitis B e antigen-negativity. Pre-S deletion mutants were found in genotypes D and E. Three isolates had the vaccine escape mutant sM133T. Conclusion Sudanese hepatitis B virus carriers were mainly infected with genotypes D or E, with patients infected with genotype E having higher HBeAg-positivity and higher viral loads. This is the first study to molecularly characterize hepatitis B virus from liver disease patients in Sudan.
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Song ZL, Cui YJ, Zheng WP, Teng DH, Zheng H. Diagnostic and therapeutic progress of multi-drug resistance with anti-HBV nucleos(t)ide analogues. World J Gastroenterol 2012; 18:7149-7157. [PMID: 23326119 PMCID: PMC3544016 DOI: 10.3748/wjg.v18.i48.7149] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Revised: 11/02/2012] [Accepted: 11/06/2012] [Indexed: 02/06/2023] Open
Abstract
Nucleos(t)ide analogues (NA) are a breakthrough in the treatment and management of chronic hepatitis B. NA could suppress the replication of hepatitis B virus (HBV) and control the progression of the disease. However, drug resistance caused by their long-term use becomes a practical problem, which influences the long-term outcomes in patients. Liver transplantation is the only choice for patients with HBV-related end-stage liver disease. But, the recurrence of HBV after transplantation often caused by the development of drug resistance leads to unfavorable outcomes for the recipients. Recently, the multi-drug resistance (MDR) has become a common issue raised due to the development and clinical application of a variety of NA. This may complicate the antiviral therapy and bring poorly prognostic outcomes. Although clinical evidence has suggested that combination therapy with different NA could effectively reduce the viral load in patients with MDR, the advent of new antiviral agents with high potency and high genetic barrier to resistance brings hope to antiviral therapy. The future of HBV researches relies on how to prevent the MDR occurrence and develop reasonable and effective treatment strategies. This review focuses on the diagnostic and therapeutic progress in MDR caused by the anti-HBV NA and describes some new research progress in this field.
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Abstract
Hepatitis B virus (HBV) is a hepatotropic DNA virus. The HBV genome is prone to variations. Based on genomic variations, HBV is divided into ten genotypes, many subgenotypes and quasispecies. These genotypes, subgenotypes and quasispecies have distinct race and geographic distribution and have been associated with outcome of HBV infection, disease progression and treatment.
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