Dear Editor,
We appreciate the opportunity to refine our response to the manuscript discussing the benefits of direct-acting antivirals (DAAs) in hepatitis C virus (HCV) patients with hepatocellular carcinoma (HCC) [
1]. We congratulate Lee et al. for their valuable contribution. The study by Lee et al. provides compelling evidence supporting the use of DAAs in patients with HCC, demonstrating high sustained virological response (SVR) rates and associated survival benefits [
2]. This data reinforces the notion that DAA therapy should be considered for HCC patients, rather than withheld.
The high SVR rates observed among HCC patients and the associated benefits offer valuable insights for our clinical practice. In the evolving landscape of HCC treatment, particularly with advancements in systemic therapies, achieving SVR may lead to improvements in liver synthetic function [
3-
5]. This, in turn, could potentially allow for extended courses of systemic treatments, enhancing overall survival in patients with HCC. Given the well-established safety profile of DAAs across multiple studies [
5-
9], Lee et al provided another strong rationale for considering DAA therapy in all eligible HCC patients. However, these findings may not be fully generalizable to genotypes other than genotypes 1 and 2 (which accounted for 91% of the cohort), as SVR12 rates can vary by genotype. In particular, patients with genotype 3 decompensated cirrhosis, as well as those with genotype 3b cirrhosis, may have lower SVR12 rates (85–88.2% and 50%, respectively) even when receiving pangenotypic DAAs [
7,
10]. Additionally, genotype 3 is more prevalent in South and Southeast Asia, including Thailand, India, and Pakistan [
11].
We agree with the authors that it is not always possible to include a control group or to distinguish between liver-related death and death from HCC recurrence due to study design. In a large multicentre cohort study, DAA use was associated with a significantly lower risk of liver-related death (16.3% vs. 34.0%,
P=0.03) compared to DAA-untreated controls, while the death from HCC recurrence remained similar (30.2% vs. 29.1%,
P=0.89) [
12]. In particular, the benefit of DAA is more pronounced in patients who remained recurrence-free (hazard ratio 0.09, 95% confidence interval 0.02–0.29).
As clinicians, the decisions regarding HCV treatment in HCC patients should be individualized, taking into account overall prognosis and potential benefits of DAA. Current guidelines suggest DAA should be considered in HCC patients with complete tumor response [
13], aligning with the majority of supportive studies behind this recommendation [
12,
14]. It is important to consider that the clinical benefits of achieving SVR may require a prolonged period to become apparent, and HCC itself presents a competing risk for overall survival before this benefit become apparent. Several studies, including the current one [
2], suggest that DAA therapy may have limited impact on overall survival within the first year [
2,
14]. For patients with progressive HCC, poor functional status, severe liver dysfunction (for example Child-Pugh Class C), or limited life expectancy less than a year [
13,
15], the benefits of DAA therapy may be limited. In these patients, the ethical concerns of withholding DAA treatment can likely be dismissed. Indeed, the current study had appropriately excluded patients with terminal-stage HCC [
2].
In conclusion, the recent study by Lee et al. provides valuable evidence supporting the use of DAAs in HCV-related HCC in eligible patients. The decisions regarding HCV treatment in HCC patients should be tailored to individual circumstances, considering overall prognosis and potential benefits. We look forward to future studies that will further refine our understanding of which intermediate-stage HCC patients, particularly those receiving systemic treatment, who are most likely to benefit from HCV treatment. Once again, we appreciate the opportunity to contribute to this important discussion, and thank the authors for their significant contribution to the field.
FOOTNOTES
-
Authors’ contribution
Study conception: Yu Jun Wong. Manuscript draft: Yu Jun Wong. Critical review of the manuscript and final review: All authors.
-
Acknowledgements
Dr. WYJ is supported by the Nurturing Clinician Scientist Scheme (NCCS) award from the SingHealth Duke-NUS Academic Medical Center.
-
Conflicts of Interest
Apichat Kaewdech received research grants or support from Roche, Roche Diagnostics, and Abbott Laboratories, and honoraria from Roche, Roche Diagnostics, Abbott Laboratories, and Esai. Yu Jun Wong received research grant support from Gilead Science, and honoraria from Giliead Science and AbbVie. The other authors have no relevant conflict of interest to declare.
Abbreviations
sustained virological response
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