Letter: “Tenofovir Alafenamide—The ‘Star of Potential’ for Long-Term Chronic Hepatitis B Treatment. A Deep-Dive Analysis of Phase 3 Clinical Trials.” Authors' Reply

Abstract

We thank Drs. Dai and Zhu for their comments on our manuscript, ‘Eight-year efficacy and safety of tenofovir alafenamide for treatment of chronic hepatitis B virus infection: Final results from two randomized phase 3 trials’, and for highlighting the long-term benefits of tenofovir alafenamide (TAF) in chronic hepatitis B (CHB) management [1].

We agree that assessing fibrosis regression, cirrhosis reversal, and hepatocellular carcinoma (HCC) incidence is critical to understanding the full impact of long-term antiviral therapy [2]. While serial liver biopsies were not performed, we employed validated non-invasive markers such as FibroTest, endorsed by international guidelines [3]. Indeed, guidelines have shifted away from recommending invasive percutaneous biopsies. At baseline, approximately 10% of patients had compensated cirrhosis; those with decompensated disease were excluded. By Year 8, cirrhosis prevalence substantially declined across all treatment groups [4]. Most patients with cirrhosis at baseline shifted to lower fibrosis categories, and no patients with compensated cirrhosis experienced hepatic decompensation. The overall 8-year HCC incidence was low (1.8%), notably below predictions from established HCC risk scores [5]. HCC was a predefined adverse event of interest with patients screened per local standard of care. Importantly, prospective surveillance with hepatic ultrasonography was introduced at Week 96 and conducted biannually thereafter. In a recent 5-year analysis of these trials, TAF and tenofovir disoproxil fumarate (TDF) were associated with significantly lower HCC incidence than predicted for untreated patients, with a 68% and 44% reduction in the TAF and TDF-TAF groups, respectively [6]. An extended 8-year analysis is underway. Collectively, these findings underscore the long-term capacity of TAF to alter the natural history of HBV, supporting its role as a preferred therapeutic option for patients with CHB.

We also agree that broader inclusion of patients with co-infections, advanced liver disease, and diverse racial and ethnic backgrounds would enhance the generalisability of TAF's safety and efficacy profiles across broader patient populations [2]. The two phase 3 trials for TAF enrolled a global population, while subsequent studies have examined TAF in diverse populations such as in patients with renal/hepatic impairment and HIV/HBV coinfection [7, 8]. Future real-world studies should aim to capture underrepresented groups to inform clinical practice across diverse settings. Despite bearing a high burden of HBV, patients from Sub-Saharan Africa remain underrepresented in clinical trials [9]. Greater inclusion of these and other underserved groups is essential to ensure CHB treatment strategies are globally relevant and equitable.

Although economic factors were beyond our manuscript's scope, we recognise that cost may limit access in resource-constrained settings [2]. However, cost-effectiveness analyses should consider not only drug costs but also the long-term benefits of improved safety profiles, reduced incidence of renal and bone adverse events, and gains in quality-adjusted life years. A recent study in China found TAF's cost effectiveness ratio comparable to TDF [10], suggesting viability in the setting of cost constraints. Furthermore, generic formulations of TAF are available in countries like India and China, potentially improving access.

We appreciate the authors' insights and share their commitment to advancing CHB care through inclusive research, collaboration, and equitable access to effective therapies.

Maria Buti: conceptualization, writing – original draft, writing – review and editing.

This article is linked to Buti et al. papers. To view these articles, visit https://doi.org/10.1111/apt.18278 and https://doi.org/10.1111/apt.70343.