{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:51:20Z","timestamp":1788137480767,"version":"build-2803163510"},"reference-count":33,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T00:00:00Z","timestamp":1721260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004361","name":"Swiss Cancer League","doi-asserted-by":"publisher","award":["KFS-4131-02-2017"],"award-info":[{"award-number":["KFS-4131-02-2017"]}],"id":[{"id":"10.13039\/501100004361","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004361","name":"Swiss Cancer League","doi-asserted-by":"publisher","award":["SNSF 163878"],"award-info":[{"award-number":["SNSF 163878"]}],"id":[{"id":"10.13039\/501100004361","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004361","name":"Swiss Cancer League","doi-asserted-by":"publisher","award":["PP003_202660"],"award-info":[{"award-number":["PP003_202660"]}],"id":[{"id":"10.13039\/501100004361","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Swiss National Science Foundation","award":["KFS-4131-02-2017"],"award-info":[{"award-number":["KFS-4131-02-2017"]}]},{"name":"Swiss National Science Foundation","award":["SNSF 163878"],"award-info":[{"award-number":["SNSF 163878"]}]},{"name":"Swiss National Science Foundation","award":["PP003_202660"],"award-info":[{"award-number":["PP003_202660"]}]},{"name":"Stiftung f\u00fcr Leberkrankheiten\u2013Swissliver","award":["KFS-4131-02-2017"],"award-info":[{"award-number":["KFS-4131-02-2017"]}]},{"name":"Stiftung f\u00fcr Leberkrankheiten\u2013Swissliver","award":["SNSF 163878"],"award-info":[{"award-number":["SNSF 163878"]}]},{"name":"Stiftung f\u00fcr Leberkrankheiten\u2013Swissliver","award":["PP003_202660"],"award-info":[{"award-number":["PP003_202660"]}]},{"name":"Swiss National Science Foundation","award":["KFS-4131-02-2017"],"award-info":[{"award-number":["KFS-4131-02-2017"]}]},{"name":"Swiss National Science Foundation","award":["SNSF 163878"],"award-info":[{"award-number":["SNSF 163878"]}]},{"name":"Swiss National Science Foundation","award":["PP003_202660"],"award-info":[{"award-number":["PP003_202660"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Introduction: The use of direct-acting antivirals (DAAs) has drastically changed the management of HCV-infected patients by achieving a 95\u201398% sustained virologic response (SVR) and reducing morbidity and mortality in this population. However, despite their effectiveness, controversy exists concerning the occurrence of oncologic events following DAA therapy. Aims and Methods: A retrospective analysis was conducted on data from the Swiss Hepatitis C Cohort Study, a prospective cohort involving patients with positive HCV viremia upon inclusion, enrolled in various Swiss centers from September 2000 to November 2021. To examine potential differences in the risk of intrahepatic tumor (IHT) occurrence and death among patients treated with direct-acting antivirals (DAAs), untreated patients, and those receiving interferon (IFN)-based therapy, a semiparametric competing risk proportional hazards regression model was used. Results: Among 4082 patients (63.1% male, median age 45 years; genotype 1: 54.1%; cirrhosis: 16.1%), 1026 received exclusive treatment with IFN-based regimens, and 1180 were treated solely with DAAs. Over a median follow-up of 7.8 years (range: 3.8\u201311.9), 179 patients (4.4%) developed intrahepatic tumors (IHT), and 168 (4.1%) experienced extrahepatic tumors (EHT). The 5-year cumulative incidence of IHT was 1.55% (95% CI 0.96\u20132.48) for IFN-based therapy, 4.27% (95% CI 2.93\u20136.2) for DAA and 0.89% (95% CI 0.4\u20131.99) for untreated patients. There was no statistically significant difference in the risk of developing IHT (HR = 1.34; 95% CI = [0.70; 2.58]; p = 0.380) or death (HR = 0.66; 95% CI = [0.43; 1.03]; p = 0.066) between patients treated with DAAs and those treated with IFN. Conclusions: The DAAs reduced the risk of death and were not associated with an increased risk of extrahepatic tumors (EHT). In the adjusted model, accounting for cirrhosis and high liver stiffness, the DAA treatment was associated with a higher risk of IHT occurrence compared with untreated patients, emphasizing the relevance of implementing standardized hepatocellular carcinoma (HCC) screening post-DAA treatment.<\/jats:p>","DOI":"10.3390\/cancers16142573","type":"journal-article","created":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T10:39:26Z","timestamp":1721299166000},"page":"2573","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Effect of Direct Acting Antiviral Drugs on the Occurrence and Recurrence of Intra- and Extra-Hepatic Malignancies in Patients with Chronic Hepatitis C Virus Infection"],"prefix":"10.3390","volume":"16","author":[{"given":"Pompilia","family":"Radu","sequence":"first","affiliation":[{"name":"Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Becchetti","sequence":"additional","affiliation":[{"name":"Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6346-8362","authenticated-orcid":false,"given":"Jonas","family":"Schropp","sequence":"additional","affiliation":[{"name":"Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Schmid","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St. Gallen, 9000 St. Gallen, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"K\u00fcnzler-Heule","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Cantonal Hospital St. Gallen, 9000 St. Gallen, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Mertens","sequence":"additional","affiliation":[{"name":"Gastroenterology und Hepatology, University Hospital Z\u00fcrich, 8091 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darius","family":"Moradpour","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beat","family":"M\u00fcllaupt","sequence":"additional","affiliation":[{"name":"Gastroenterology und Hepatology, University Hospital Z\u00fcrich, 8091 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Semela","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Cantonal Hospital St. Gallen, 9000 St. Gallen, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Negro","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, University Hospitals Geneva, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Heim","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, University Hospital Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Clerc","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Infectious Diseases, Pourtal\u00e8s Hospital, 2000 Neuch\u00e2tel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maroussia","family":"Roelens","sequence":"additional","affiliation":[{"name":"Institute of Global Health, University of Geneva, 1205 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Keiser","sequence":"additional","affiliation":[{"name":"Institute of Global Health, University of Geneva, 1205 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4562-9016","authenticated-orcid":false,"given":"Annalisa","family":"Berzigotti","sequence":"additional","affiliation":[{"name":"Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Swiss Hepatitis C Cohort Study","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1080\/14656566.2021.1921737","article-title":"An update on direct antiviral agents for the treatment of hepatitis C","volume":"22","author":"Stanciu","year":"2021","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.jhep.2016.10.017","article-title":"Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication","volume":"66","author":"Feld","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1111\/jvh.13022","article-title":"Liver transplant listing for hepatitis C-associated cirrhosis and hepatocellular carcinoma has fallen in the United Kingdom since the introduction of direct-acting antiviral therapy","volume":"26","author":"Vaziri","year":"2019","journal-title":"J. Viral Hepat."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"329","DOI":"10.7326\/0003-4819-158-5-201303050-00005","article-title":"Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: A meta-analysis of observational studies","volume":"158","author":"Morgan","year":"2013","journal-title":"Ann. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S2468-1253(17)30045-6","article-title":"Hepatitis C virus prevalence and level of intervention required to achieve the WHO targets for elimination in the European Union by 2030: A modelling study","volume":"2","year":"2017","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Rockey, D.C., and Friedman, S.L. (2021). Fibrosis Regression After Eradication of Hepatitis C Virus: From Bench to Bedside. Gastroenterology, 160.","DOI":"10.1053\/j.gastro.2020.09.065"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/j.jhep.2020.05.050","article-title":"Clinical outcome and hemodynamic changes following HCV eradication with oral antiviral therapy in patients with clinically significant portal hypertension","volume":"73","author":"Lens","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/j.jhep.2020.11.021","article-title":"Clinical outcomes following DAA therapy in patients with HCV-related cirrhosis depend on disease severity","volume":"74","author":"Krassenburg","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2584","DOI":"10.1001\/jama.2012.144878","article-title":"Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis","volume":"308","author":"Veldt","year":"2012","journal-title":"JAMA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.jhep.2016.04.008","article-title":"Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy","volume":"65","author":"Reig","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.jhep.2016.06.015","article-title":"Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals","volume":"65","author":"Conti","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"The ANRS Collaborative Study Group on Hepatocellular Carcinoma (ANRS CO22 HEPATHER, CO12 CirVir and CO23 CUPILT Cohorts) (2016). Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: Data from three ANRS cohorts. J. Hepatol., 65, 734\u2013740.","DOI":"10.1016\/j.jhep.2016.05.045"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1136\/gutjnl-2020-323663","article-title":"Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: An individual patient data meta-analysis","volume":"71","author":"Sapena","year":"2022","journal-title":"Gut"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1016\/j.jhep.2017.07.025","article-title":"Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: A systematic review, meta-analyses, and meta-regression","volume":"67","author":"Waziry","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1111\/jvh.13859","article-title":"Dynamic risk assessment for hepatocellular carcinoma in patients with chronic hepatitis C","volume":"30","author":"Lu","year":"2023","journal-title":"J. Viral Hepat."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Hamdane, N., Juhling, F., Crouchet, E., El Saghire, H., Thumann, C., Oudot, M.A., Bandiera, S., Saviano, A., Ponsolles, C., and Roca Suarez, A.A. (2019). HCV-Induced Epigenetic Changes Associated with Liver Cancer Risk Persist After Sustained Virologic Response. Gastroenterology, 156.","DOI":"10.1053\/j.gastro.2019.02.038"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Perez, S., Kaspi, A., Domovitz, T., Davidovich, A., Lavi-Itzkovitz, A., Meirson, T., Alison Holmes, J., Dai, C.Y., Huang, C.F., and Chung, R.T. (2019). Hepatitis C virus leaves an epigenetic signature post cure of infection by direct-acting antivirals. PLoS Genet., 15.","DOI":"10.1371\/journal.pgen.1008181"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1053\/j.gastro.2017.01.041","article-title":"Genome-Wide Association Study Identifies TLL1 Variant Associated with Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection","volume":"152","author":"Matsuura","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1111\/liv.15624","article-title":"Hepatocellular organellar abnormalities following elimination of hepatitis C virus","volume":"43","author":"Aoyagi","year":"2023","journal-title":"Liver Int."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (2020). EASL recommendations on treatment of hepatitis C: Final update of the series. J. Hepatol., 73, 1170\u20131218.","DOI":"10.1016\/j.jhep.2020.08.018"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1177\/0962280217713032","article-title":"Propensity score analysis with partially observed covariates: How should multiple imputation be used?","volume":"28","author":"Leyrat","year":"2019","journal-title":"Stat. Methods Med. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.jhep.2019.03.027","article-title":"Direct-acting antivirals after successful treatment of early hepatocellular carcinoma improve survival in HCV-cirrhotic patients","volume":"71","author":"Cabibbo","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Singal, A.G., Rich, N.E., Mehta, N., Branch, A.D., Pillai, A., Hoteit, M., Volk, M., Odewole, M., Scaglione, S., and Guy, J. (2019). Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection Is Associated with Increased Survival in Patients with a History of Hepatocellular Carcinoma. Gastroenterology, 157.","DOI":"10.1053\/j.gastro.2019.07.040"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/hep.28535","article-title":"Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis C virus infection","volume":"64","author":"Kanwal","year":"2016","journal-title":"Hepatology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"955","DOI":"10.5009\/gnl15321","article-title":"Clinical Model for Predicting Hepatocellular Carcinomas in Patients with Post-Sustained Virologic Responses of Chronic Hepatitis C: A Case Control Study","volume":"10","author":"Zeng","year":"2016","journal-title":"Gut Liver"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1097\/MLR.0000000000001870","article-title":"Impact of Direct-acting Antivirals on Hepatocellular Carcinoma and Mortality Among Medicaid Beneficiaries with Hepatitis C","volume":"61","author":"Jiang","year":"2023","journal-title":"Med. Care"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1159\/000513705","article-title":"Impact of Obesity and Heavy Alcohol Consumption on Hepatocellular Carcinoma Development after HCV Eradication with Antivirals","volume":"10","author":"Minami","year":"2021","journal-title":"Liver Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1111\/liv.15577","article-title":"Metabolic dysfunction outperforms ultrasonographic steatosis to stratify hepatocellular carcinoma risk in patients with advanced hepatitis C cured with direct-acting antivirals","volume":"43","author":"Pelusi","year":"2023","journal-title":"Liver Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1016\/j.jhep.2021.11.023","article-title":"Liver cancer risk after HCV cure in patients with advanced liver disease without non-characterized nodules","volume":"76","author":"Marino","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Villani, R., Facciorusso, A., Bellanti, F., Tamborra, R., Piscazzi, A., Landriscina, M., Vendemiale, G., and Serviddio, G. (2016). DAAs Rapidly Reduce Inflammation but Increase Serum VEGF Level: A Rationale for Tumor Risk during Anti-HCV Treatment. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0167934"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.jhep.2020.03.030","article-title":"Undefined\/non-malignant hepatic nodules are associated with early occurrence of HCC in DAA-treated patients with HCV-related cirrhosis","volume":"73","author":"Sangiovanni","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1002\/hep.32434","article-title":"Risk factors for HCC in contemporary cohorts of patients with cirrhosis","volume":"77","author":"Kanwal","year":"2023","journal-title":"Hepatology"},{"key":"ref_33","unstructured":"European Association for the Study of the Liver (2018). EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J. Hepatol., 69, 182\u2013236."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/14\/2573\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:18:55Z","timestamp":1760109535000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/14\/2573"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,18]]},"references-count":33,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["cancers16142573"],"URL":"https:\/\/doi.org\/10.3390\/cancers16142573","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,18]]}}}