Evidence for a relationship between concentrations of nucleos/tide analogue agents and treatment outcome in chronic hepatitis B infection: A systematic review

Introduction: Treatment of hepatitis B virus (HBV) primarily relies on nucleos(t)ide analogues to achieve viral suppression, with tenofovir or entecavir as first-line agents. Expanding treatment and improving its outcomes are crucial strategies to support advances towards targets for the elimination of viral hepatitis as a public health threat by 2030. However, therapeutic drug monitoring has not been systematically applied to optimize HBV therapy. Methods We conducted a systematic review (PROSPERO CRD420250599139) to identify studies that reported treatment outcomes of HBV in English from PubMed, Scopus and Web of Science. We collated the evidence for the relationship between drug concentrations and therapeutic outcomes in HBV. Our primary search included people living with HBV with or without Human Immunodeficiency Virus (HIV) coinfection, treated with tenofovir and/or entecavir linked to clinical or laboratory-based assessment of treatment outcome. Results We identified six studies reporting drug concentrations in people with HBV infection, of which five reported on HIV/HBV coinfection, and one on HBV monoinfection. Across all studies, tenofovir concentrations > 800 fmol/punch in dried blood spots were typically associated with viraemic suppression for both HIV and HBV. Evidence suggests that higher tenofovir concentrations (e.g. 1000–1500 fmol/punch) may be required for consistent suppression of HBV. However, evidence from HBV monoinfection was limited, and a therapeutic concentration for HBV could not be defined. Only one study reported entecavir concentrations in HBV and data are inconclusive. Discussion A therapeutic threshold cannot currently be defined for concentrations of tenofovir or entecavir in HBV. Larger cohort studies that focus on HBV monoinfection are needed to define therapeutic drug thresholds to optimize personalized care for people living with HBV and improve population health outcomes.