A systematic review and meta-analysis of the risk of hepatitis B virus (HBV) genotypic resistance in people treated with entecavir or tenofovir

Background As nucleos/tide analogue (NA) therapy for chronic Hepatitis B virus (HBV) infection becomes more widely indicated and available, understanding drug resistance is essential. We performed a systematic review and meta-analysis to estimate the risk of genotypic resistance to tenofovir and entecavir.Methods We searched nine databases up to 29-Aug-23. We included studies of HBV infection featuring >10 individuals, written in English, reporting tenofovir or entecavir treatment ≥48 weeks, with assessment of HBV genotypic resistance. Data were analysed according to prior exposure history to NA, and treatment with tenofovir or entecavir. Analyses were performed in R.Results 62 studies involving a total of 12,358 participants were included. For tenofovir, pooled resistance risk was 0.0% at all time points, whether previously NA naive (11 studies; 3778 individuals) or experienced (19 studies; 2059 individuals). For entecavir, in treatment-naive individuals (22 studies; 4326 individuals), risk of resistance increased over time to 0.9% at ≥5 years (95%CI 0.1-2.3%). Entecavir resistance was increased in NA-experienced individuals (18 studies;1112 individuals), to 20.1% (95%CI 1.6-50.1%) at ≥5 years. There was a lack of consistent definitions, poor global representation and insufficient metadata to support subgroup analysis.Discussion Based on existing data, tenofovir has an excellent resistance profile. More resistance is seen with entecavir, particularly in treatment-experienced groups. Due to data gaps, we may have under-estimated the true risk of resistance. Robust prospective data collection is crucial as treatment is rolled out more widely.Competing Interest StatementCC receives doctoral funding support from GSK for a PhD supervised by PCM. YS receives research grant from Gilead Sciences.Clinical Protocols https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=424125 Funding StatementSFL is funded by a Wellcome Doctoral Training Fellowship. CC receives funding from Oxford University and GSK. CT is funded by the A*STAR programme. PCM has funding from the Wellcome Trust (grant ref 110110), UCLH NIHR Biomedical Research Centre, and core funding from the Francis Crick Institute.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data are available in the supplementary materials