The recent study by Yim et al. [1] examining the switch from tenofovir disoproxil fumarate (TDF) to besifovir (BSV) in patients with chronic hepatitis B (CHB) represents a valuable addition to the growing literature on antiviral therapy optimization. The authors demonstrate that transitioning to BSV sustains potent antiviral efficacy while improving renal and bone outcomes over the study period. These findings are clinically meaningful given the increasing emphasis on long-term treatment safety in CHB, where therapy is often lifelong.

One important methodological consideration relates to the absence of a washout period between discontinuation of TDF and initiation of BSV. While TDF as a parent drug has a relatively short plasma half-life (to 17 hours), the situation is more complex when its active intracellular metabolite, tenofovir-diphosphate, is considered. Tenofovir-diphosphate may persist within peripheral blood mononuclear cells for days to weeks after cessation, as reported in studies of intracellular nucleotide analogue kinetics [2,3]. These sustained intracellular levels could continue to exert antiviral, renal, and bone mineral effects after TDF is stopped, potentially influencing early post-switch outcomes. Consequently, some of the renal and bone improvements observed shortly after switching might reflect natural recovery from TDF’s intracellular effects rather than being exclusively attributable to BSV’s pharmacological profile. Although complete elimination of tenofovir-diphosphate can vary among individuals, inclusion of a defined washout period, where clinically feasible, could help isolate the direct effects of the new agent. This approach would also support a clearer interpretation of BSV’s safety and efficacy in future trials.

A second point concerns subgroup analyses, particularly for patients with cirrhosis. In the current trial, 37 participants (28.5% of the total cohort) were identified as having cirrhosis. This proportion is not insignificant and offers an opportunity to provide more granular data on drug performance in a population at higher risk of adverse events and disease progression. Cirrhosis is often associated with altered drug distribution, metabolism, and excretion, as well as increased vulnerability to renal and bone complications. Moreover, given that the natural history of hepatitis B virus infection and the risk of hepatocellular carcinoma differ between cirrhotic and non-cirrhotic patients, the therapeutic benefit-risk balance of switching to BSV may not be identical across these groups. Conducting dedicated analyses, stratifying by cirrhosis status, would enhance the applicability of the findings and guide clinicians on tailoring antiviral transitions in real-world practice for high-risk patients [4].

In conclusion, the present study advances the clinical conversation on optimizing long-term antiviral therapy in CHB. By addressing the interplay between residual drug effects, intracellular pharmacokinetics, and patient subgroups with distinct physiological profiles, future work can build on these promising results to maximize therapeutic benefit while minimizing harm.

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