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Risk stratification of hepatocellular carcinoma after hepatitis C virus eradication in patients with compensated advanced chronic liver disease in Japan
Corresponding author. Address: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel.: +81-3-3815-5411, fax: +81-3-3814-0021.
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, JapanDepartment of Gastroenterology, Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, 6-25-1 kamiyoga, Setagaya-ku, Tokyo 158-8531, Japan
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, JapanDepartment of Gastroenterology, Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, 6-25-1 kamiyoga, Setagaya-ku, Tokyo 158-8531, Japan
Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality in patients with advanced chronic liver disease (ACLD) caused by chronic hepatitis C who have achieved sustained virologic response (SVR). We developed risk stratification algorithms for de novo HCC development after SVR and validated them in an independent cohort.
The emergence of direct-acting antivirals has drastically changed the landscape of chronic hepatitis C (CHC) treatment. Because almost all patients with CHC can achieve a sustained virological response (SVR), the remaining issue is to identify those who need regular follow-up, especially for hepatocellular carcinoma (HCC) surveillance.
We have read with great interest the recent paper by Semmler et al. that evaluated the risk of HCC development in patients with CHC who achieved SVR with interferon (IFN)-free treatment.
In this multicenter retrospective study, the authors enrolled patients with compensated advanced chronic liver disease (cACLD), defined as baseline (BL)-liver stiffness measurement (LSM) ≥10 kPa, hepatic venous pressure gradient (HVPG) ≥5 mmHg, or advanced fibrosis/cirrhosis on liver histology before treatment,
and investigated the predictors of HCC development. They constructed a simple algorithm that facilitated risk stratification based on post-treatment AFP, alcohol consumption, age, LSM, and albumin levels. Based on the algorithm, approximately two-thirds of patients with cACLD were categorized as low-risk (<1%/year) and could be excluded from surveillance for HCC. Their approach has important advantages because it only requires a “one-time” assessment after treatment, which may promote its clinical application.
To validate the algorithm in Japan, where patients have a longer duration of HCV infection and thus a higher risk for HCC development, we conducted a single-center retrospective study enrolling HCC-naive patients with CHC who achieved SVR after IFN-free treatment between January 2012 and May 2020, and were followed up until December 2021. Our cohort comprised 624 patients with a median age of 66.3 (IQR, 57.1-74.5) years, of whom 39.4% were male and 18.9% were overweight (BMI ≥25 kg/m2); 11.4% had diabetes mellitus, and 7.9% were drinkers (>30 g/day and >20 g/day for males and females, respectively). During the median follow-up (FU) period of 54 months after the end of treatment, 24 patients developed HCC at a rate of 0.90/100 patient-years, which was comparable to that in our previous multicenter cohort study.
When a cut-off value of 10 kPa at the BL-LSM was applied, 183 (29.3%) and 441 (70.7%) patients were classified as cACLD and non-cACLD, respectively. The cACLD group was significantly older (67.8 vs. 65.7 years, p = 0.04), had higher BL-LSM (14.4 vs. 5.6 kPa, p <0.001), FU-LSM (11.8 vs. 5.1 kPa, p <0.001), BL-AFP (7.3 vs. 3.0 ng/ml, p <0.001), and FU-AFP (4.3 vs. 2.6 ng/ml, p <0.001), and lower BL-albumin (40.0 vs. 42.0 g/L, p <0.01) and FU-albumin (41.5 vs. 42.0 g/L, p <0.01) than the non-cACLD group, while there were no significant differences in the percentage who were overweight, had diabetes, or were drinkers. Among the 24 patients who developed HCC, 20 were in the cACLD group (4-year HCC risk, 9.8%; 2.9/100 patient-years) and 4 were in the non-cACLD group (4-year HCC-risk, 0.7%; 0.2/100 patient-years), with a significant difference (p <0.001, log-rank test) (Fig. 1A).
Fig. 1Cumulative incidence of HCC development in Japanese cohort.
(A) Cumulative incidence curves of HCC in cACLD and non-cACLD group stratified by pre-treatment (BL)-LSM: <10 kPa as non-cACLD; ≥10 kPa as cACLD. (B) Cumulative incidence curves of HCC stratified by post-treatment (FU) age/LSM/albumin-derived score (low-risk [0-3 points] vs. high-risk [4-9 points]) in patients with cACLD. 3 points are assigned for age ≥59 years, 2 points for alcohol consumption above the threshold, 2 points for FU-LSM ≥19 kPa, and 2 points for FU-albumin <42 g/L (0 points if the respective criterion is not met). (C) Similar analysis based on the AFP/age/alcohol/LSM/albumin-derived score. Cumulative incidences are displayed according to low risk (0-3 points) and high risk (4-9 points) assignment. 3 points are assigned for FU-AFP ≥4.6 ng/ml, 2 points for alcohol consumption above the threshold, 2 points for age ≥59 years, 1 point for FU-LSM ≥19 kPa, and 1 point for FU-albumin <42 g/L (0 points if the respective criterion is not met). The comparison of groups was performed by the log-rank test (level of significance: p value <0.05). AFP, alpha-fetoprotein; BL, baseline; cACLD, compensated advanced chronic liver disease; FU, follow-up; LSM, liver stiffness measurement.
We further assessed the predictive ability of the LSM/albumin-based model in the cACLD cohort (n = 183). According to the algorithm (age ≥59 years, FU-LSM ≥19 kPa, FU-albumin <42 g/L, and alcohol consumption), 94 (51.4%) and 89 (48.6%) patients were stratified into low-risk and high-risk groups, respectively. Although the incidence of HCC was significantly higher in the high-risk group (4-year HCC-risk: 14.3%, 4.4/100 patient-years; p = 0.04 by the log-rank test) than in the low-risk group (4-year HCC-risk, 4.3%; 1.6/100 patient-years), the incidence in the low-risk group was still above the threshold of 1.0%/year (Fig. 1B). When the AFP/LSM/albumin-based model was applied (FU-AFP ≥4.6 ng/ml was added to the above predictors), 106 (57.9%) and 77 (42.1%) patients were stratified into low- and high-risk groups, respectively. However, there was no significant difference in the incidence of HCC between the 2 groups (4-year HCC-risk: 5.8% vs. 15.2%; 1.9/100 vs. 4.2/100 patient-years; p = 0.09, log-rank test) (Fig. 1C).
Our findings suggest that limiting the candidates for HCC surveillance to cACLD patients defined as LSM ≥10 kPa may work in the Japanese CHC cohort, in line with previous reports on LSM in assessing the risk of HCC development in patients with CHC.
However, further risk stratification of patients with cACLD using the proposed models was unsuccessful. This is probably because our cohort was on average 10 years older than that reported by Semmler et al. Considering that older age is a strong risk factor for HCC development both before and after achieving SVR
and that most of our patients were over 59 years old, a higher age threshold may be appropriate for risk stratification. Because the reduced risk of mortality after SVR is more closely linked to reduced risk of liver failure than HCC,
patients with CHC are expected to live longer without liver failure and eventually develop HCC after SVR. Notably, a recent report revealed that HCC is the most frequent liver-related event in Western cohorts with HCV-related cACLD after SVR.
HCC risk stratification with multiple age-specific cut-off values will be necessary, even in the Western cohort, with an eye on the future.
Financial support
This research was supported by Grants-in-Aid for Scientific Research 21K15989 (TN) and 20K08352 (RT), the Research Program on Hepatitis from Japan Agency for Medical Research and Development (AMED) under Grant Number JP21fk0210090 (RT and KK) and JP21fk0210066 (RT), and the Health, Labour, and Welfare Policy Research Grants from the Ministry of Health, Labour, and Welfare of Japan H30-Kansei-Shitei-003 (RT and KK).
Authors’ contributions
TN: manuscript writing, data curation and analysis; RT: data curation and critical revision; RN and TM: data curation; KK: critical revision.
Conflict of interest
The authors declare no conflicts of interest that pertain to this work.
Please refer to the accompanying ICMJE disclosure forms for further details.
Supplementary data
The following are the supplementary data to this article:
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