Hepatitis B virus resistance to tenofovir: fact or fiction? A synthesis of the evidence to date
Mokaya J., McNaughton AL., Bester PA., Goedhals D., Barnes E., Marsden BD., Matthews PC.
<jats:p>Background: Tenofovir (TFV) is a widely used antiviral treatment for chronic hepatitis B virus (HBV) infection. However, therapy is not curative and long-term administration is therefore required in most cases, with a risk of selecting resistance-associated mutations (RAMs). There is a high genetic barrier to the selection of TFV resistance, but the distribution and clinical significance of TFV RAMs are not well understood, and the topic remains contentious. We here present assimilated evidence for TFV RAMs with the aim of cataloguing and characterising mutations that are likely to be of most clinical significance, and starting to develop relevant mechanistic insights. Methods: We 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 in order to map the likely sites of RAMs. Results: We identified 37 putative TFV RAMs in HBV RT, occurring within and outside sites of enzyme activity, which we have mapped onto a homologous HIV RT crystal structure. Most resistance arises as a result of suites of multiple RAMs. Other factors including adherence, HBV DNA viral load, HBeAg status, HIV coinfection and NA dosage may also influence viraemic suppression. Conclusion: There is emerging evidence for polymorphisms that reduce susceptibility to TVF. If clinically significant TFV resistance increases in prevalence, there will be a pressing need for the development of new agents. A better understanding of HBV drug resistance is imperative to ensure that these do not impact on the international elimination targets that are to be met by 2030. </jats:p>