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Original article
Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians
  1. Pauline Arends1,
  2. Milan J Sonneveld1,
  3. Roeland Zoutendijk1,
  4. Ivana Carey2,
  5. Ashley Brown3,
  6. Massimo Fasano4,
  7. David Mutimer5,
  8. Katja Deterding6,
  9. Jurriën G P Reijnders1,
  10. Ye Oo5,
  11. Jörg Petersen7,
  12. Florian van Bömmel8,
  13. Robert J de Knegt1,
  14. Teresa Santantonio4,
  15. Thomas Berg8,
  16. Tania M Welzel9,
  17. Heiner Wedemeyer6,
  18. Maria Buti10,
  19. Pierre Pradat11,
  20. Fabien Zoulim11,
  21. Bettina Hansen1,
  22. Harry L A Janssen1,12
  23. for the VIRGIL Surveillance Study Group
  1. 1Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
  2. 2Department of Hepatology and Gastroenterology, Kings College London, London, UK
  3. 3Department of Hepatology and Gastroenterology, Imperial College London, London, UK
  4. 4Infectious Diseases, Department of Clinical and Experimental Medicine, University of Foggia, Italy
  5. 5NIHR Biomedical Research Unit, Centre for Liver Research, Queen Elizabeth Hospital, Birmingham, UK
  6. 6Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Hannover, Germany
  7. 7Ifi Institute, Asklepios Klinik St. Georg, Hamburg, Germany
  8. 8Department of Gastroenterology and Rheumatology, Hepatology Section, University Clinic Leipzig, Leipzig, Germany
  9. 9Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany
  10. 10Department of Hepatology, Hospital Vall de Hebron and Ciberehd del Instituto Carlos III, Barcelona, Spain
  11. 11Department of Hepatology, Hôpital de la Croix-Rousse Hospices Civils de Lyon, Lyon, France
  12. 12Liver Clinic, Toronto Western & General Hospital, University Health Network, Toronto, Ontario, Canada
  1. Correspondence to Professor H L A Janssen, University of Toronto & Erasmus University Rotterdam, University Health Network, 399 Bathurst Street, 6B FP, Room 164, Toronto, Ontario, Canada M5T 2S8; harry.janssen{at}


Background Hepatocellular carcinoma (HCC) risk-scores may predict HCC in Asian entecavir (ETV)-treated patients. We aimed to study risk factors and performance of risk scores during ETV treatment in an ethnically diverse Western population.

Methods We studied all HBV monoinfected patients treated with ETV from 11 European referral centres within the VIRGIL Network.

Results A total of 744 patients were included; 42% Caucasian, 29% Asian, 19% other, 10% unknown. At baseline, 164 patients (22%) had cirrhosis. During a median follow-up of 167 (IQR 82–212) weeks, 14 patients developed HCC of whom nine (64%) had cirrhosis at baseline. The 5-year cumulative incidence rate of HCC was 2.1% for non-cirrhotic and 10.9% for cirrhotic patients (p<0.001). HCC incidence was higher in older patients (p<0.001) and patients with lower baseline platelet counts (p=0.02). Twelve patients who developed HCC achieved virologic response (HBV DNA <80 IU/mL) before HCC. At baseline, higher CU-HCC and GAG-HCC, but not REACH-B scores were associated with development of HCC. Discriminatory performance of HCC risk scores was low, with sensitivity ranging from 18% to 73%, and c-statistics from 0.71 to 0.85. Performance was further reduced in Caucasians with c-statistics from 0.54 to 0.74. Predicted risk of HCC based on risk-scores declined during ETV therapy (all p<0.001), but predictive performances after 1 year were comparable to those at baseline.

Conclusions Cumulative incidence of HCC is low in patients treated with ETV, but ETV does not eliminate the risk of HCC. Discriminatory performance of HCC risk scores was limited, particularly in Caucasians, at baseline and during therapy.


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