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      Hepatitis B virus resistance to tenofovir: fact or fiction? A systematic literature review and structural analysis of drug resistance mechanisms

      systematic-review

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          Abstract

          Background: Tenofovir (TFV) is a widely used treatment for chronic hepatitis B virus (HBV) infection. There is a high genetic barrier to the selection of TFV resistance-associated mutations (RAMs), but the distribution and clinical significance of TFV RAMs are not well understood. We here present assimilated evidence for putative TFV RAMs with the aims of cataloguing and characterising mutations that have been reported, and starting to develop insights into mechanisms of resistance.

          Methods: We carried out a systematic literature search in PubMed and Scopus to identify clinical, in vitro and in silico evidence of TFV resistance. We included peer-reviewed studies presenting original data regarding virological TFV breakthrough, using published methods to assess the quality of each study. We generated a list of RAMs that have been reported in association with TFV resistance, developing a ‘long-list’ (all reported RAMs) and a ‘short-list’ (a refined list supported by the most robust evidence). We assessed the potential functional and structural consequences by mapping onto the crystal structure for HIV reverse transcriptase (RT), as the structure of HBV RT has not been solved.

          Results: We identified a ‘long-list’ of 37 putative TFV RAMs in HBV RT, occurring within and outside sites of enzyme activity, some of which can be mapped onto a homologous HIV RT structure. A ‘short-list’ of nine sites are supported by the most robust evidence. If clinically significant resistance arises, it is most likely to be in the context of suites of multiple RAMs. Other factors including adherence, viral load, HBeAg status, HIV coinfection and NA dosage may also influence viraemic suppression.

          Conclusion: There is emerging evidence for polymorphisms that may reduce susceptibility to TVF. However, good correlation between viral sequence and treatment outcomes is currently lacking; further studies are essential to optimise individual treatment and public health approaches.

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          Most cited references54

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          MAFFT online service: multiple sequence alignment, interactive sequence choice and visualization

          Abstract This article describes several features in the MAFFT online service for multiple sequence alignment (MSA). As a result of recent advances in sequencing technologies, huge numbers of biological sequences are available and the need for MSAs with large numbers of sequences is increasing. To extract biologically relevant information from such data, sophistication of algorithms is necessary but not sufficient. Intuitive and interactive tools for experimental biologists to semiautomatically handle large data are becoming important. We are working on development of MAFFT toward these two directions. Here, we explain (i) the Web interface for recently developed options for large data and (ii) interactive usage to refine sequence data sets and MSAs.
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            Hepatitis B virus resistance to nucleos(t)ide analogues.

            Patients with chronic hepatitis B (CHB) can be successfully treated using nucleos(t)ide analogs (NA), but drug-resistant hepatitis B virus (HBV) mutants frequently arise, leading to treatment failure and progression to liver disease. There has been much research into the mechanisms of resistance to NA and selection of these mutants. Five NA have been approved by the US Food and Drug Administration for treatment of CHB; it is unlikely that any more NA will be developed in the near future, so it is important to better understand mechanisms of cross-resistance (when a mutation that mediates resistance to one NA also confers resistance to another) and design more effective therapeutic strategies for these 5 agents. The genes that encode the polymerase and envelope proteins of HBV overlap, so resistance mutations in polymerase usually affect the hepatitis B surface antigen; these alterations affect infectivity, vaccine efficacy, pathogenesis of liver disease, and transmission throughout the population. Associations between HBV genotype and resistance phenotype have allowed cross-resistance profiles to be determined for many commonly detected mutants, so genotyping assays can be used to adapt therapy. Patients that experience virologic breakthrough or partial response to their primary therapy can often be successfully treated with a second NA, if this drug is given at early stages of these events. However, best strategies for preventing NA resistance include first-line use of the most potent antivirals with a high barrier to resistance. It is important to continue basic research into HBV replication and pathogenic mechanisms to identify new therapeutic targets, develop novel antiviral agents, design combination therapies that prevent drug resistance, and decrease the incidence of complications of CHB.
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              Human immunodeficiency virus reverse transcriptase and protease sequence database.

              The HIV reverse transcriptase and protease sequence database is an on-line relational database that catalogues evolutionary and drug-related sequence variation in the human immunodeficiency virus (HIV) reverse transcriptase (RT) and protease enzymes, the molecular targets of antiretroviral therapy (http://hivdb.stanford.edu). The database contains a compilation of nearly all published HIV RT and protease sequences, including submissions to GenBank, sequences published in journal articles and sequences of HIV isolates from persons participating in clinical trials. Sequences are linked to data about the source of the sequence, the antiretroviral drug treatment history of the person from whom the sequence was obtained and the results of in vitro drug susceptibility testing. Sequence data on two new molecular targets of HIV drug therapy--gp41 (cell fusion) and integrase--will be added to the database in 2003.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data CurationRole: Formal AnalysisRole: Funding AcquisitionRole: InvestigationRole: MethodologyRole: Project AdministrationRole: VisualizationRole: Writing – Original Draft PreparationRole: Writing – Review & Editing
                Role: Writing – Review & Editing
                Role: VisualizationRole: Writing – Review & Editing
                Role: Writing – Review & Editing
                Role: SupervisionRole: Writing – Review & Editing
                Role: Formal AnalysisRole: Visualization
                Role: ConceptualizationRole: Data CurationRole: Formal AnalysisRole: Funding AcquisitionRole: InvestigationRole: MethodologyRole: Project AdministrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – Original Draft PreparationRole: Writing – Review & Editing
                Journal
                Wellcome Open Res
                Wellcome Open Res
                Wellcome Open Res
                Wellcome Open Research
                F1000 Research Limited (London, UK )
                2398-502X
                29 June 2020
                2020
                : 5
                : 151
                Affiliations
                [1 ]Nuffield Department of Medicine, University of Oxford, Medawar Building, South Parks Road, Oxford, OX1 3SY, UK
                [2 ]Division of Virology, National Health Laboratory Service/University of the Free State, Bloemfontein, South Africa
                [3 ]Department of Hepatology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK
                [4 ]National Institutes of Health Research Health Informatics Collaborative, NIHR Oxford Biomedical Research Centre, Garsington Road, Oxford, OX4 2PG, UK
                [5 ]Structural Genomics Consortium, University of Oxford, Oxford, UK
                [6 ]Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, UK
                [7 ]Department of Microbiology and Infectious Diseases, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK
                [1 ]Department of Medical Virology, University of Pretoria and National Health Laboratory Service, Tshwane Academic Division, Pretoria, South Africa
                [1 ]Institute of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital (Beijing 302 Hospital), Beijing, China
                Author notes

                No competing interests were disclosed.

                Competing interests: No competing interests were disclosed.

                Competing interests: No competing interests were disclosed.

                Author information
                https://orcid.org/0000-0001-8398-0689
                https://orcid.org/0000-0002-7436-8727
                https://orcid.org/0000-0002-1937-4091
                https://orcid.org/0000-0002-4036-4269
                Article
                10.12688/wellcomeopenres.15992.1
                8033640
                33869791
                cf7aaa41-8615-4961-855d-27ae02a4b629
                Copyright: © 2020 Mokaya J et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 June 2020
                Funding
                Funded by: Wellcome Trust
                Award ID: 110110
                Funded by: Leverhulme Trust
                Funded by: Medical Research Council
                Funded by: NIHR Oxford Biomedical Research Centre
                Funded by: National Institute for Health Research
                This work was supported by the Wellcome Trust [110110; to PCM], the Leverhulme Mandela Rhodes Scholarship to JM, the Medical Research Council UK to EB, the Oxford NIHR Biomedical Research Centre to EB. EB is an NIHR Senior Investigator. The views expressed in this article are those of the author and not necessarily those of the NHS, the NIHR, or the Department of Health. ALM is funded through NIHR Research Capability Funding.
                The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Systematic Review
                Articles

                hepatitis b virus,hbv,tenofovir,tdf,taf,tfv,resistance,rams
                hepatitis b virus, hbv, tenofovir, tdf, taf, tfv, resistance, rams

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