Research ArticleDevelopment of a scoring system to predict hepatocellular carcinoma in Asians on antivirals for chronic hepatitis B
Graphical abstract
Introduction
Hepatitis B virus (HBV) infection is the leading aetiology of hepatocellular carcinoma (HCC) around the globe.[1], [2] The risk of HCC is a lifelong threat to patients with chronic hepatitis B (CHB).3 Antiviral therapy using nucleos(t)ide analogues (NAs) inhibits HBV replication,[4], [5], [6] ameliorates hepatic inflammation,7 reverses liver fibrosis,8 and may attenuate hepatocellular carcinogenesis. We and others have shown that NA treatment is associated with risk reduction of HCC in patients with CHB.[9], [10], [11], [12] In addition, the incidences of HCC decreased over the years while on therapies.[13], [14], [15] However, antiviral treatment does not completely eliminate the risk of HCC.16 Beyond viral suppression, it remains unclear how to lower the risk further.
Prior to the current era of antiviral therapy, several scoring systems, such as CU-HCC, GAG-HCC, and REACH-B, have been built to predict the occurrence of HCC in the natural history of CHB.[17], [18], [19] Although these systems were externally validated and could attain a fairly good performance in untreated patients, they do not adequately predict HCC in patients on NAs.[20], [21], [22] Because long-term suppressive treatment with potent NA currently remains the therapeutic strategy of choice, there is a need for an accurate tool to stratify patients at different risks of HCC during antiviral treatment. Such knowledge is pivotal to inform clinical practice and to direct resource allocation.
Previous studies have shown that age, cirrhosis, male sex, platelet count, liver stiffness, and diabetes mellitus (DM) are risk factors of HCC in patients with CHB receiving NAs.[23], [24], [25] In contrast, pretreatment viral load, HBeAg status, HBsAg quantity, and aminotransferase level are not predictive for treated patients, in contrast to their roles established in untreated populations.[26], [27], [28] Recently, we analysed the national healthcare database in Taiwan to uncover the HCC risk factors in patients continuously receiving entecavir or tenofovir for CHB. The relative impact of these factors and their interaction were quantified through an analysis of the population-level data.15 On the basis of these instrumental findings, the present study aimed at developing a simple scoring tool for risk prediction during continuous NA treatment in patients with CHB. External validation was carried out also using the population-wide data extracted from the state-run healthcare database in Hong Kong.
Section snippets
Data source
This study analysed the National Health Insurance Research Database (NHIRD) in Taiwan and the Hospital Authority (HA) database in Hong Kong. Both databases contained data collected from in- and outpatient services in the respective healthcare systems. Their characteristics have been detailed in prior researches.[10], [29] In brief, the NHIRD covers 99% of the 23.5 million Taiwan residents and the HA covers 70–80% of the 7.3 million Hong Kong citizens. They both applied the International
Characteristics of the study populations
The two cohorts differed in the baseline characteristics from demographics, co-morbidity, to drug exposure (Table 1). The Taiwan cohort had more patients with cirrhosis, while the Hong Kong cohort was older. During a median follow-up of 25.8 (IQR 12.7–35.7) months, 596 (2.50%) patients in the Taiwan cohort developed HCC with a cumulative incidence of 3.56 (95% CI 3.26–3.86) at three years (Fig. 1A). The annual incidences in the first, second, and third years were 1.40%, 0.94%, and 0.72%,
Discussion
Through an analysis of population-wide data from the independent healthcare systems in Taiwan and Hong Kong, we develop and validate a risk score to predict the risk of HCC in patients with CHB on entecavir or tenofovir therapy. On the basis of simple information (i.e. the status of cirrhosis, age, biological sex, and DM) that is readily available in everyday practice, the developed CAMD score accurately stratifies patients into distinct risk subgroups with a scoring range from 0 to 19 points.
Financial support
This study was funded by the Taiwan’s Ministry of Science and Technology (MOST 103-2314-B-650-002 and MOST 105-2314-B-650-001-MY2), Taipei Veterans General Hospital (107VACS-003, V107E-004-1), and the Tomorrow Medical Foundation (106-2).
Conflict of interest
Y-CH has served as an advisory committee member for Gilead Sciences. He also reported having received lecture fees from AbbVie, Bristol-Myers Squibb, and Gilead Sciences. VW-SW has served as an advisory committee member for AbbVie, Roche, Novartis, Gilead Sciences, and Otsuka. He has also served as a speaker for AbbVie, Bristol-Myers Squibb, Roche, Novartis, Abbott Diagnostics, and Echosens. GL-HW has served as an advisory committee member for Gilead Sciences. She has also served as a speaker
Authors’ contributions
Concept: Y-CH, M-SW, J-TL, C-YW. Design: Y-CH, TC-FY, VW-SW, HBE, GL-HW, C-YW. Data analysis: SJH, TC-FY. Data interpretation: Y-CH, SJH, VW-SW, YTH, HBE, TYL, GL-HW, C-YW. Manuscript drafting: Y-CH, TC-FY. Manuscript edition and final approval: all authors. Guarantor of the article: Y-CH
Acknowledgements
The preliminary results of this study were presented in the annual meeting of the American Association for the Study of Liver Diseases on 23 October 2017 in Washington, DC, USA. The authors would like to thank Taiwan’s Ministry of Science and Technology and the Tomorrow Medical Foundation.
References (53)
- et al.
Hepatocellular carcinoma from epidemiology to prevention: translating knowledge into practice
Clin Gastroenterol Hepatol
(2015) - et al.
Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study
Lancet
(2013) - et al.
Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy
J Hepatol
(2015) - et al.
Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B
J Hepatol
(2009) - et al.
Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score
Lancet Oncol
(2011) - et al.
Incidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir
J Hepatol
(2015) - et al.
PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy
J Hepatol
(2016) Epidemiology of viral hepatitis and hepatocellular carcinoma
Gastroenterology
(2012)- et al.
Lifetime risk and sex difference of hepatocellular carcinoma among patients with chronic hepatitis B and C
J Clin Oncol
(2011) - et al.
Tenofovir disoproxil fumarate vs. adefovir dipivoxil for chronic hepatitis B
N Engl J Med
(2008)
A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B
N Engl J Med
Entecavir vs. lamivudine for patients with HBeAg-negative chronic hepatitis B
N Engl J Med
Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B
Hepatology
Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma
Aliment Pharmacol Ther
Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B: a nationwide cohort study
Gastroenterology
Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis
Hepatology
Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection
Hepatology
Hepatocellular carcinoma risk in chronic hepatitis B virus-infected compensated cirrhosis patients with low viral load
Hepatology
The risk of hepatocellular carcinoma decreases after the first five years of entecavir or tenofovir in Caucasians with chronic hepatitis B
Hepatology
Temporal trend and risk determinants of hepatocellular carcinoma in chronic hepatitis B patients on entecavir or tenofovir
J Viral Hepat
Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers
J Clin Oncol
Impact of long-term tenofovir disoproxil fumarate on incidence of hepatocellular carcinoma in patients with chronic hepatitis B
Cancer
Lower observed hepatocellular carcinoma incidence in chronic hepatitis B patients treated with entecavir: results of the ENUMERATE study
Am J Gastroenterol
The incidence of hepatocellular carcinoma is reduced in patients with chronic hepatitis B on long-term nucleos(t)ide analogue therapy
Aliment Pharmacol Ther
Determinants of hepatocellular carcinoma in cirrhotic patients treated with nucleos(t)ide analogues for chronic hepatitis B
J Antimicrob Chemother
Incidence of hepatocellular carcinoma in untreated subjects with chronic hepatitis B: a systematic review and meta-analysis
Liver Int
Cited by (120)
Applicability of Risk Scores to an Indian Cohort of Hepatitis B-Related Hepatocellular Carcinoma Patients
2024, Journal of Clinical and Experimental HepatologyA Liver Stiffness–Based Etiology-Independent Machine Learning Algorithm to Predict Hepatocellular Carcinoma
2024, Clinical Gastroenterology and HepatologyPrediction model of hepatitis B virus-related hepatocellular carcinoma in patients receiving antiviral therapy
2023, Journal of the Formosan Medical AssociationDiabetes Mellitus Impacts on the Performance of Hepatocellular Carcinoma Risk Scores in Chronic Hepatitis B Patients
2023, Clinical Gastroenterology and HepatologyElectronic health record for artificial intelligence health care, and application to liver disease
2023, Artificial Intelligence, Machine Learning, and Deep Learning in Precision Medicine in Liver Diseases: Concept, Technology, Application and Perspectives
- †
These authors contributed equally as joint first authors.
- ‡
These authors contributed equally as the corresponding senior authors.