The introduction of direct-acting antiviral (DAA) therapy has transformed the treatment landscape of hepatitis C virus (HCV) infection, offering exceptional efficacy and tolerability, even in patients with decompensated cirrhosis [
1-
6]. While the benefit of DAA treatment in HCV patients with early hepatocellular carcinoma (HCC) who have received curative treatments are well established [
7,
8], its role in patients with active HCV-related HCC, particularly those with intermediate stage HCC, has been a subject of ongoing discussion. Traditionally, the impact on intermediate-stage HCC has been debated due to the inherent challenges in deciphering the confounding effect of HCC itself from the overall survival. Concerns also existed regarding the extended timeframe needed to observe the sustainable clinical improvements from fibrosis regression and portal pressure reduction.
Firstly, the survival benefit of DAA among patients with intermediate stage HCC was largely unknown due to the confounding effect of HCC on patients’ survival. Secondly, longer duration beyond SVR12 is needed to observed the clinical improvement in fibrosis regression, portal pressure reduction and clinical recompensation [
9,
10]. Concerns also existed regarding the lower sustained virological response (SVR12) observed in patients with HCC [
2,
11].
In the current issue, Lee et al.’s study provides compelling evidence supporting the use of DAA among patients with HCV-related HCC [
12]. This large-scale analysis of the Taiwan nationwide HCV registry included 23,774 HCV patients (2,205 HCC, 21,569 no HCC) treated with DAA between 2013 to 2020, found a lower SVR12 rate in patients with HCC (96.6% vs. 98.8%,
P<0.001). Of note, majority of the HCC patients in this cohort have good adherence (>80%) to DAA, and about 800 (36.3%) had non-cirrhotic HCV-related HCC. Moreover, achieving SVR12 (vs. no SVR12) was associated with better survival in HCC patients (aHR 0.41, 95% CI 0.28–0.59;
P<0.001). This benefit persists even after accounting for cirrhosis, BCLC stage, gender, diabetes mellitus and chronic kidney disease. Collectively, both the high SVR12 rates and survival benefit supports the use of DAA in patients with intermediate-stage HCC, which is potentially practice changing.
This study is commendable as it addresses previous gaps regarding DAA use in patients with intermediate-stage HCC. While SVR status did not significantly influence the 1-year survival in patients with HCC (SVR 95.2% vs. no-SVR 93.1%), the survival benefit of SVR became more pronounced over time, with the gap widening at 2-year and 3-year post treatment (2 years 87.2% vs. 70.6%; 3 years 79.2% vs. 48.3%). The observation on the diverging survival curves of SVR12 after one year may guide patient selection for DAA in the HCC patients with limited prognosis.
The improvement in overall survival should be interpreted in the context of other confounding factors. Firstly, the HCC treatment options had rapidly expanded over the study period. A stratified analysis comparing SVR12-related survival benefits between different of HCC treatments modalities (ablation, locoregional therapy, systemic chemotherapy, or immunotherapy) would provide more nuanced insights. The potential synergistic effects of SVR-induced liver function improvement on systemic therapy outcomes warrant further investigation. This is particularly relevant for the 9% of patients with BCLC stage C HCC who may benefit from newer systemic therapies.
Secondly, distinguishing between HCC-related outcomes in patients with and without SVR12 is crucial, especially given the conflicting data on the risk of HCC recurrence after DAA treatment [
8]. To understand the biological plausibility of survival benefits of SVR, liver-related death (acute chronic liver failure, hepatorenal syndrome or spontaneous bacterial peritonitis) should be analysed separately from HCC-related death (recurrence of advanced staged HCC). One may postulate the survival benefit of SVR being largely driven by the decrease in liver-related death through recompensation and decrease in portal pressure.
Thirdly, the absence of a control group comprising untreated HCV-related HCC patients raise the concern of potential selection bias, since patients receiving DAA therapy might have inherently better liver function or access to specialised care. The validity of the survival benefit from attaining SVR12 could be strengthen with inclusion of a well-matched cohort of untreated HCC patients.
Lastly, the severity of underlying cirrhosis affects both prognosis and likelihood of achieving SVR in patients with HCV-related HCC. A stratified analysis by Child-Turcotte- Pugh class or MELD score would help differentiate whether the survival benefit is primarily driven by SVR or by better baseline liver function [
13].
The current study significantly contributes to the growing body of evidences supporting the safety and tolerability of DAA in patients with HCV-related HCC, even in intermediate or advanced-stage -stage disease. With expanding armamentarium of HCC treatment, DAA-attained SVR12 may improve liver function, offering hope for patients with intermediate and advanced-stage HCC [
14].
FOOTNOTES
-
Authors’ contribution
Study conception: Yu Jun Wong. Manuscript draft: Yan Ling Ong. Critical review of the manuscript and final review: Daniel Huang, Apichat Kaewdech, Yu Jun Wong.
-
Acknowledgements
Dr. WYJ is supported by the Nurturing Clinician Scientist Scheme (NCCS) award from the SingHealth Duke-NUS Academic Medical Center.
-
Conflicts of Interest
All authors of no relevant conflict of interest to declare.
Abbreviations
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Citations
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- Emerging evidence supports direct-acting antiviral therapy for HCC patients beyond the early stage
Teng-Yu Lee, Pei-Chien Tsai, Shou-Wu Lee, Ming- Lung Yu
Clinical and Molecular Hepatology.2025;[Epub] CrossRef
