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

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.
Competing Interests: Conflict of interest G.S. has nothing to disclose. E.M. received grants from Novartis. K.K. received travel support from AbbVie, Bristol-Myers Squibb, and Gilead. P.Sc. received consulting fees from PharmaIN, and travel support from Falk and Phenex Pharmaceuticals; S.H.-S. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Eisai, Gilead, and Intercept and received travel support from AbbVie and Gilead; A.Z. has nothing to disclose; D.B. received travel support from AbbVie and Gilead; D.C. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, and MSD, and received travel support from AbbVie, MSD, ViiV Healthcare and Gilead; B.Si. received travel support from AbbVie and Gilead. B.Sch. received travel support from AbbVie, Ipsen and Gilead. A.F.S. served as a speaker and/or consultant and/or advisory board member for Boehringer Ingelheim, Gilead, and MSD. M.Pi. served as a speaker and/or consultant and/or advisory board member for Bayer, Bristol-Myers Squibb, Ipsen, Eisai, Lilly, MSD, and Roche, and received travel support from Bayer and Bristol-Myers Squibb. R.S. has nothing to disclose. F.P.R. served as a speaker and/or consultant and/or advisory board member for AbbVie, Biotest, Gilead, and MSD, and received travel support from AbbVie, Biotest, and Gilead. H.G. has nothing to disclose. M.S. received speaking honoraria from BMS and travel support from Bristol-Myers Squibb, AbbVie, and MSD. C.S. has nothing to disclose. M.G. received grants from AbbVie, Gilead, and MSD; speaking honoraria/advisory board fees from AbbVie, Gilead, MSD, Janssen, Roche, Intercept, Norgine, AstraZeneca, Falk, and Shionogi. S.A.L. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, and MSD and received grants from AbbVie and Gilead. M.L.M. has nothing to disclose. A.A. received consulting and speaker fees from Abbvie and Gilead. R.B. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, and Janssen. M.Po. has nothing to disclose. S.R.-T. has nothing to disclose. J.G. has nothing to disclose. S.L. received grants from Gilead, speaker and advisory fees from Gilead, Abbvie and MSD. M.T. served as a speaker and/or consultant and/or advisory board member for Albireo, Boehringer Ingelheim, Bristol-Myers Squibb, Falk, Genfit, Gilead, Intercept, MSD, Novartis, Phenex, Regulus and Shire, and received travel support from AbbVie, Falk, Gilead, and Intercept, as well as grants/research support from Albireo, Cymabay, Falk, Gilead, Intercept, MSD, and Takeda. He is also co-inventor of patents on the medical use of 24-norursodeoxycholic acid. P.F. has served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol Myer-Squibb, Gilead, and MSD and has received research funding from Gilead. T.R. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bayer, Boehringer Ingelheim, Gilead, Intercept, MSD, Siemens, and W. L. Gore & Associates and received grants/research support from AbbVie, Boehringer Ingelheim, Gilead, MSD, Philips, and W. L. Gore & Associates as well as travel support from Boehringer Ingelheim and Gilead. M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Gilead, Collective Acumen, and W. L. Gore & Associates and received travel support from AbbVie, Bristol-Myers Squibb, and Gilead. Please refer to the accompanying ICMJE disclosure forms for further details.
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