The treatment of chronic hepatitis C virus (HCV) infection has made a breakthrough with the introduction of directacting antiviral agents (DAAs), effectively achieving sustained virological response (SVR) [
1-
5]. Hepatocellular carcinoma (HCC) risk is also significantly reduced after eradication of HCV by successful antiviral therapy (AVT) [
6] and DAA-induced SVR is associated with a 71% reduction in HCC risk [
7]. However, patients treated with DAA are still at risk of developing HCC even after achieving SVR, and the fibrotic burden of the liver is the most important factor in determining the need for continuous HCC surveillance [
1,
2,
8].
It is generally accepted that chronic hepatitis C (CHC) patients with cirrhosis should continue HCC surveillance after SVR. However, there are some discrepancies between recommendations for CHC patients with advanced fibrosis (F3). The European Association for the Study of the Liver recommends HCC surveillance in CHC patients with advanced fibrosis (F3) [
1], while American Association for the Study of Liver Disease does not [
9]. This discrepancy is partly due to the challenge of accurately identifying patients with F3 fibrosis, as they form a heterogeneous group. Some patients have F3–F4 fibrosis which carries a higher risk of HCC, while others have F2–F3 fibrosis which carries a lower risk of HCC. Furthermore, there is a risk of misclassifying cirrhosis, as fibrosis burden in some patients can be underestimated by non-invasive fibrosis markers, leading to an underestimation of their HCC risk. In clinical practice, a small proportion of HCC cases occur after SVR in patients with non-cirrhotic or pre-cirrhotic liver disease. However, there are currently no reliable tools to identify patients who have high risk of HCC such that they may benefit from HCC surveillance in spite of not having cirrhosis.
In the current issue of the
Clinical and Molecular Hepatology, Lee et al. [
10] suggest the clinical utility of fibrosis-4 (FIB-4) index and transient elastography (TE) in predicting HCC development among patients with CHC by assessing the performance and optimal cut-off values both pre-treatment and post-SVR. In this meta-analysis of 27 studies (n=169,911 CHC patients) [
10], the pooled area under the curves (AUCs) of pre-treatment TE >9.2–13 kPa and FIB-4 index >3.25 for prediction of HCC development were 0.79 and 0.73, respectively. TE >8.4–11 kPa (pooled AUC=0.77) and FIB-4 index >3.25 (pooled AUC=0.70) assessed after SVR also maintained good predictive performance. The optimal cut-off values for HCC development after SVR were 12.6 kPa (pre-treatment) and 11.2 kPa (after SVR) for TE, with FIB-4 index >3.25 [
10]. These findings showed that TE and FIB-4 index measured pre-treatment and after SVR might serve as important indicators to assess HCC risk after SVR, implying the utility of TE and FIB-4 index in clinical practice for guiding HCC surveillance strategies in patients with CHC achieved SVR.
However, the findings of this study cannot answer who should be under HCC surveillance in non-cirrhotic or precirrhotic patients with CHC after SVR. This occurs because the study included patients with all of fibrosis stages, particularly cirrhosis and thereby, optimal cut-off values of TE or FIB-4 index for prediction of HCC development might be elevated by proportion of cirrhotic patients in total population. In clinical practice where we should decide who does not need HCC surveillance in post-SVR patients with CHC, optimal cut-off values of TE or FIB-4 index for prediction of HCC development from subgroup analyses in non-cirrhotic or pre-cirrhotic patients are needed. Second, estimating HCC risk directly may be a better strategy than assessing patients’ risk only based on fibrosis stage. Although the question of whether to screen or not usually depends on fibrosis stage such as F3 or F4 [
1], fibrosis stage is not the only predictor of HCC. Multiple factors may influence HCC risk beyond fibrosis stage such as the impact of the emerging metabolic risk factors related to HCC development [
11-
16]. So, it is more reasonable to determine HCC surveillance in terms of patients’ individualized HCC risk.
To estimate HCC risk in post-SVR patients without cirrhosis, prediction models composed of multiple factors beyond fibrosis burden and further validation in diverse populations are needed.
FOOTNOTES
-
Authors’ contribution
Study concept and design: Minjong Lee; Acquisition of data: Minjong Lee, Ho Soo Chun; Drafting of the manuscript: Minjong Lee, Ho Soo Chun; Critical revision of the manuscript for important intellectual content: Minjong Lee, Ho Soo Chun; All authors have read and approved the manuscript.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
direct-acting antiviral agent
European Association for the Study of the Liver
sustained virological response
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