Dear Editor,
We read with great interest the recent nationwide cohort study investigating the survival benefit of direct-acting antiviral (DAA) therapy in patients with HCV-related hepatocellular carcinoma (HCC). This study provides valuable insights into the role of DAA therapy in different stages of HCC [
1]. However, closer examination reveals several critical methodological and conceptual limitations that warrant further discussion to refine the interpretation of these findings and guide future research.
A major limitation is the lack of stratification based on the biological heterogeneity of HCC. While the study distinguishes between patients with stage B and C liver cancer at the Barcelona Clinic, it does not take into account the wide molecular and clinical variability within these stages. Previous studies have shown that tumor differentiation grade, microvascular invasion and alpha-fetoprotein (AFP) levels significantly affect prognosis and may modify the effect of antiviral therapy [
2,
3]. The omission of these factors raises concerns that the reported survival benefits may not apply uniformly to all subgroups of HCC patients. For example, a poorly differentiated tumor with high AFP levels and aggressive molecular signatures (such as TP53 or CTNNB1 mutations) may respond differently to DAAs than a well-differentiated lesion with low AFP levels.
The second issue is the assessment of liver reserve and how it interacts with DAA therapy outcomes. The study relies primarily on Child-Turcotte-Pugh scores, which have well-documented limitations in reflecting the full spectrum of liver dysfunction in HCC patients. More sensitive measures such as albumin bilirubin grade, Model for End-Stage Liver Disease score and transient elastography would have provided a more accurate assessment of liver function. In addition, the study did not examine the trajectory of liver function improvement after sustained virological response (SVR), which is particularly important given that some patients with significant portal hypertension or decompensated cirrhosis may not achieve a substantial survival benefit despite viral eradication. The dynamic interaction between HCC progression, liver reserve and antiviral efficacy warrants further investigation.
Thirdly, the timing and sequencing of DAA therapy relative to HCC treatment represents another overlooked aspect. While the study shows that achieving SVR correlates with improved survival, it does not address whether the timing of DAA administration affects this benefit. Previous research has suggested that early DAA initiation in active HCC may alter the tumor microenvironment, potentially affecting treatment response to locoregional therapies such as transarterial chemoembolization or systemic therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors [
4]. Guarino et al. [
5] have even suggested an increased risk of early HCC recurrence following DAA therapy, although this remains controversial. A more detailed analysis, including the sequence of antiviral and oncological treatments, is needed to optimise treatment algorithms.
Finally, the study does not fully address the complex interplay between systemic inflammation, immune surveillance and HCC progression. While SVR is associated with reduced hepatic inflammation, the broader immunomodulatory effects of DAAs in the context of HCC remain underexplored. Studies have suggested that HCV clearance may lead to immune reconstitution, which may influence both tumor progression and response to immunotherapy [
4]. However, this study does not include immune profiling or biomarker analysis to elucidate these mechanisms. Future research should evaluate whether DAAs affect key immune checkpoints, tumor-infiltrating lymphocytes or cytokine signatures in HCC patients. In addition, from a methodological perspective, the study relies on Cox proportional hazards models for survival analysis, but does not incorporate competing risk analysis. Given that many HCC patients succumb to liver failure rather than tumor progression alone, ignoring competing risks could inflate the estimated effect of SVR on overall survival. Moreover, the study does not report subgroup analyses by major cause of death, which would provide further clarity on the true impact of DAA therapy. The use of more advanced statistical methods, such as the Fine and Gray competing risks model, could have strengthened the robustness of the results.
In conclusion, although this study provides compelling evidence for the role of DAA therapy in improving survival in HCC patients, its results must be interpreted with caution due to several unresolved methodological and biological issues. Future research should incorporate a more granular stratification of HCC biology, refine metrics to assess liver function, investigate the optimal sequencing of DAA and HCC therapies, explore the immunological consequences of HCV eradication, and apply more sophisticated statistical methods to account for competing risks. Addressing these critical gaps will be essential to optimise the integration of DAAs into comprehensive HCC management strategies.
FOOTNOTES
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Authors’ contribution
Qiong Wang, Zhongqing Qian, and Xiaodi Yang wrote the manuscript, Deyan Chen and Xiaojing Wang provided methodological and revised the manuscript, and Fuliang Chen provided financial support.
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Acknowledgements
Research Funds of Joint Research Center for Regional Diseases of IHM (2024bydjk006).
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Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
sustained virological response
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Citations
Citations to this article as recorded by
- Revisiting unmet needs in clinical research on direct-acting antiviral therapy for HCC patients: Correspondence to letter to the editor on “Direct-acting antiviral therapy for patients with HCV-related hepatocellular carcinoma: A nationwide cohort study”
Teng-Yu Lee, Pei-Chien Tsai, Shou-Wu Lee, Ming- Lung Yu
Clinical and Molecular Hepatology.2026; 32(1): e99. CrossRef
