HCC risk stratification after cure of hepatitis C in patients with compensated advanced chronic liver disease

J Hepatol. 2022 Apr;76(4):812-821. doi: 10.1016/j.jhep.2021.11.025. Epub 2021 Dec 3.


Background & aims: 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.

Methods: We evaluated the occurrence of de novo HCC in a derivation cohort of 527 patients with pre-treatment ACLD and SVR to interferon-free therapy, in whom alpha-fetoprotein (AFP) and non-invasive surrogates of portal hypertension including liver stiffness measurement (LSM) were assessed pre-/post-treatment. We validated our results in 1,500 patients with compensated ACLD (cACLD) from other European centers.

Results: During a median follow-up (FU) of 41 months, 22/475 patients with cACLD (4.6%, 1.45/100 patient-years) vs. 12/52 decompensated patients (23.1%, 7.00/100 patient-years, p <0.001) developed de novo HCC. Since decompensated patients were at substantial HCC risk, we focused on cACLD for all further analyses. In cACLD, post-treatment-values showed a higher discriminative ability for patients with/without de novo HCC development during FU than pre-treatment values or absolute/relative changes. Models based on post-treatment AFP, alcohol consumption (optional), age, LSM, and albumin, accurately predicted de novo HCC development (bootstrapped Harrel's C with/without considering alcohol: 0.893/0.836). Importantly, these parameters also provided independent prognostic information in competing risk analysis and accurately stratified patients into low- (~2/3 of patients) and high-risk (~1/3 of patients) groups in the derivation (algorithm with alcohol consumption; 4-year HCC-risk: 0% vs. 16.5%) and validation (3.3% vs. 17.5%) cohorts. An alternative approach based on alcohol consumption (optional), age, LSM, and albumin (i.e., without AFP) also showed a robust performance.

Conclusions: Simple algorithms based on post-treatment age/albumin/LSM, and optionally, AFP and alcohol consumption, accurately stratified patients with cACLD based on their risk of de novo HCC after SVR. Approximately two-thirds were identified as having an HCC risk <1%/year in both the derivation and validation cohort, thereby clearly falling below the cost-effectiveness threshold for HCC surveillance.

Lay summary: Simple algorithms based on age, alcohol consumption, results of blood tests (albumin and α-fetoprotein), as well as liver stiffness measurement after the end of hepatitis C treatment identify a large proportion (approximately two-thirds) of patients with advanced but still asymptomatic liver disease who are at very low risk (<1%/year) of liver cancer development, and thus, might not need to undergo 6-monthly liver ultrasound.

Keywords: SVR; cACLD; hepatitis C; hepatocellular carcinoma; surveillance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albumins / therapeutic use
  • Antiviral Agents / therapeutic use
  • Carcinoma, Hepatocellular* / diagnosis
  • Carcinoma, Hepatocellular* / epidemiology
  • Carcinoma, Hepatocellular* / etiology
  • Hepacivirus
  • Hepatitis C* / drug therapy
  • Hepatitis C, Chronic* / complications
  • Hepatitis C, Chronic* / drug therapy
  • Hepatitis C, Chronic* / pathology
  • Humans
  • Liver Cirrhosis / complications
  • Liver Neoplasms* / epidemiology
  • Liver Neoplasms* / etiology
  • Risk Assessment / methods
  • Risk Factors
  • Sustained Virologic Response
  • alpha-Fetoproteins


  • Albumins
  • Antiviral Agents
  • alpha-Fetoproteins