Hepatitis B virus resistance to tenofovir: fact or fiction? A synthesis of the evidence to date

ABSTRACTBackgroundTenofovir (TFV) is a widely used antiviral 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, and the topic remains contentious. 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 the mechanisms of resistance and potential clinical significance.MethodsWe carried out a systematic literature search in PubMed to identify clinical, in vitro and in silico evidence of TFV resistance. The structure of HBV reverse transcriptase (RT) has not been solved; we therefore compared HBV RT to the crystal structure for HIV RT to map the likely sites of RAMs.ResultsWe 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. Based on quality and quantity of supporting data, we generated a ‘short-list’ of nine sites that are supported by the most robust evidence. Most resistance arises as a result of suites of multiple RAMs. Other factors including adherence, viral load, HBeAg status, HIV coinfection and NA dosage may also influence viraemic suppression.ConclusionThere is emerging evidence for polymorphisms that may reduce susceptibility to TVF. A better understanding of HBV drug resistance is imperative to optimise approaches to public health elimination targets.