Letter: Reconsidering Tenofovir Disoproxil Fumarate Use in Light of Emerging Safety Evidence

Recent 5-year data from East Asian patients with chronic hepatitis B by Wong et al. [1] demonstrated sustained virological suppression with both tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), but with improved renal and bone safety following transition to TAF. These findings provide important ethnicity-specific evidence supporting the long-term safety advantages of TAF without compromising antiviral efficacy. Tenofovir alafenamide, a newer prodrug of tenofovir, achieves similar antiviral potency with lower systemic exposure due to enhanced intracellular delivery [2]. Consequently, TAF has consistently demonstrated a more favourable renal and skeletal safety profile compared with TDF across clinical trials and real-world studies [3, 4]. Improvements in estimated glomerular filtration rate and bone mineral density following switching from TDF further reinforce its safety advantage [1, 3]. In contrast, accumulating evidence has raised concerns regarding the long-term safety of TDF. Observational cohorts and mechanistic studies have demonstrated associations with nephrotoxicity, decline in renal function, and proximal tubular injury [5, 6]. Additionally, reductions in bone mineral density and increased fracture risk have been reported, particularly with prolonged exposure [7]. These adverse effects may be especially consequential in populations with baseline vulnerability, including older individuals and those with comorbid conditions. While TDF-associated lipid-lowering effects are reversed upon switching to TAF, overall cardiovascular risk indicators appear to remain stable, suggesting that the clinical relevance of lipid changes may be limited in the context of improved renal and bone safety [1]. Collectively, these findings support a growing consensus that TAF provides a safer long-term therapeutic option without compromising efficacy [3, 8]. Despite this, TDF-based regimens continue to be widely used in national programmes, particularly in resource-limited settings. In countries such as India, where a substantial burden of HIV exists and comorbidities such as malnutrition and chronic kidney disease are not uncommon, the cumulative toxicity of prolonged TDF exposure warrants careful reconsideration [9]. A phased approach—prioritising TAF for high-risk individuals and gradually expanding access—may represent a pragmatic strategy for India where antiretroviral medications like TDF are available free of cost to the HIV patients via National AIDS Control Program. Economic burden assessment of TDF related comorbidities(bone and renal) with respective treatment cost versus TAF treatment cost can be an interesting question to answer in near future. It is acknowledged that TAF is not without limitations, including cost considerations and the need for continued pharmacovigilance. However, as evidence continues to evolve, aligning treatment policies with contemporary safety data is essential to optimise long-term patient outcomes. In conclusion, emerging long-term and ethnicity-specific evidence supports a re-evaluation of TDF-centric treatment strategies in favour of safer alternatives such as TAF, particularly for patients at increased risk of renal or skeletal complications. Priyadarshini Zula: writing – review and editing, formal analysis. Ashish Kakkar: writing – review and editing. Lekha Saha: writing – review and editing. Amol N. Patil: conceptualization, formal analysis, writing – original draft. The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. This article is linked to Wong et al. papers. To view this article, visit https://doi.org/10.1111/apt.70327. The data that support the findings of this study are available from the corresponding author upon reasonable request.