Temporal change in etiology and clinical characteristics of hepatocellular carcinoma in a large cohort of patients with hepatocellular carcinoma in New South Wales, Australia

Background Viral hepatitis and alcohol-related liver disease (ALRD) are the main risk factors for hepatocellular carcinoma (HCC) in many countries. In Australia, given the access to hepatitis C virus (HCV) direct-acting antiviral (DAA) therapy since 2016, a temporal change in HCC etiology was hypothesized. This study evaluated the temporal change in the etiology and characteristics of HCC in New South Wales (NSW). Methods Patients diagnosed with HCC, admitted to three public hospitals in NSW between 2008-21, were included in analyses. We assessed the annual frequency of each HCC etiology and the distribution of HCC characteristics in participants. Results Among 1,370 patients, the most common HCC etiologies were HCV (n=483, 35%), ALRD (n=452, 33%), non-alcoholic fatty liver disease (n=347, 25%), and hepatitis B virus (n=301, 22%). The proportion of HCV-related HCC was the highest in 2011-16 (41%), and significantly declined to 30% in 2017-21 (OR: 0.53, 95%CI 0.35–0.79; p=0.002). The proportion of HCC with earlier diagnosis (BCLC stage O/A) increased from 41% in 2008-09 to 56% in 2020-21 (OR per annum: 1.05; 95%CI: 1.02–1.08; p=0.002), and proportion of patients receiving curative HCC management increased from 29% in 2008-09 to 41% in 2020-21 (OR per annum: 1.06; 95%CI: 1.03–1.10; p<0.001). Conclusion The contribution of HCV to HCC burden has been decreasing in the DAA era, suggesting the role of HCV elimination in decreasing HCC risk. Increasing frequency of less advanced HCC at diagnosis over time suggests improved HCC surveillance. Lay Summary In New South Wales, the trend of liver cancer caused by hepatitis C increased during 2008-2016, and then significantly declined after 2016, most probably due to wide access to new hepatitis C treatment (direct-acting antiviral therapy). During 2008-2021, the proportion of patients with liver cancer whose cancer was diagnosed at early stage and proportion of those receiving curative liver cancer management increased. ### Competing Interest Statement GJD is a consultant or adviser for, and has received research grants from, AbbVie, Abbot Diagnostics, Gilead Sciences, Bristol Myers Squibb, Cepheid, GlaxoSmithKline, Merck, Janssen, and Roche. MD has received speaker fees and travel support from Gilead, AbbVie and Merck. JG is on the speaker's bureau or a member of advisory board for Gilead Sciences, Merck, Janssen, Roche, Pharmaxis, Bristol Myers Squibb, AbbVie GlaxoSmithKline and Pfizer and has received travel support from Gilead Sciences, Merck, Bristol Myers Squibb, AbbVie and Roche. MTL has received research support from Gilead Sciences and AbbVie and speaker fees from Bayer and Falk. Other authors have no conflicts of interest in connection with this manuscript. ### Funding Statement The Kirby Institute is funded by the Australian Government Department of Health and Ageing. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the St Vincent's Hospital, Sydney Human Research Ethics Committee (2019/STE16231), and the local ethics committees of the involved hospital sites. The approval included patient consent waivers and met the ethical guidelines of the Declaration of Helsinki. The study involved the use of the UNSW Research Electronic Data Capture, as a secure online database, to ensure patient confidentiality. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.