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

Wellcome Open Research

article

Jolynne Mokaya¹  Anna L. McNaughton¹  Phillip A Bester²  Dominique Goedhals²  Eleanor Barnes¹  Brian D Marsden⁵  Philippa C. Matthews¹ 

[1] Nuffield Department of Medicine, University of Oxford;Division of Virology, National Health Laboratory Service/University of the Free State;Department of Hepatology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital;National Institutes of Health Research Health Informatics Collaborative, NIHR Oxford Biomedical Research Centre;Structural Genomics Consortium, University of Oxford;Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford;Department of Microbiology and Infectious Diseases, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital

关键词: Hepatitis B virus;    HBV;    Tenofovir;    TDF;    TAF;    TFV;    resistance;    RAMs;   

DOI  :  10.12688/wellcomeopenres.15992.1

学科分类：内科医学

来源: Wellcome

【 摘 要 】

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 andin 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.

【 授权许可】

CC BY