Reassessing the accuracy of PAGE-B-related scores to predict hepatocellular carcinoma development in patients with chronic hepatitis B

doi:10.1016/j.jhep.2019.12.005

Journal of Hepatology

Volume 72, Issue 5, May 2020, Pages 847-854

https://doi.org/10.1016/j.jhep.2019.12.005 Get rights and content

Highlights

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PAGE-B and mPAGE-B scores exclude patients with low HCC risk on antiviral therapy.
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Patients classified as low HCC risk by either score have an annual risk of <0.2%.
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Low-risk patients identified by either score can be exempted from HCC surveillance.
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Caution is needed for patients with cirrhosis or other risk factors for HCC.

Background & Aims

PAGE-B and modified PAGE-B (mPAGE-B) scores were developed to predict the risk of hepatocellular carcinoma (HCC) in patients on nucleos(t)ide analogue therapy. However, how and when to use these risk scores in clinical practice is uncertain.

Methods

Consecutive adult patients with chronic hepatitis B who had received entecavir or tenofovir for at least 6 months between January 2005 and June 2018 were identified from a territory-wide database in Hong Kong. The performance of PAGE-B and mPAGE-B scores for HCC prediction at 5 years was assessed by area under the time-dependent receiver operating characteristic curve (AUROC), and different cut-off values of these 2 scores were evaluated by survival analysis.

Results

Of 32,150 identified patients with chronic hepatitis B, 20,868 (64.9%) were male. Their mean age was 53.0 ± 13.2 years. At a median (IQR) follow-up of 3.9 (1.8–5.0) years, 1,532 (4.8%) patients developed HCC. The AUROCs (95% CI) for the prediction of HCC at 5 years were 0.77 (0.76–0.78) and 0.80 (0.79–0.81), with PAGE-B and mPAGE-B scores, respectively (p <0.001). A total of 9,417 (29.3%) patients were classified as having a low HCC risk by either PAGE-B or mPAGE-B scores; their 5-year cumulative incidence of HCC was 0.6% (0.4%–0.8%). This classification achieved a negative predictive value of 99.5% (99.4%–99.7%) to exclude patients without HCC development at 5 years. The AUROCs for the prediction of HCC with PAGE-B and mPAGE-B scores were similar at baseline and after 2 years on treatment.

Conclusions

PAGE-B and mPAGE-B scores can be applied to identify patients on antiviral therapy who are at low risk of developing HCC. These patients could be exempted from HCC surveillance due to their very low HCC risk.

Lay summary

Risk scores have been developed to predict the likelihood of patients with chronic hepatitis B developing hepatocellular carcinoma (HCC). We investigated the role of 2 such scores, PAGE-B and modified PAGE-B, in predicting the risk of HCC in 32,150 nucleos(t)ide analogue-treated patients with chronic hepatitis B. These scores identified a group of patients at very low risk of developing HCC who could therefore be exempted from HCC surveillance.

Graphical abstract

Introduction

Chronic hepatitis B (CHB) is a major healthcare problem in Asia. Hepatocellular carcinoma (HCC) is a key complication and cause of mortality in patients with CHB.¹ To prevent mortality related to HCC, high-risk patients should be identified and treated. With the introduction of nucleos(t)ide analogues (NA), potent viral suppression leads to fibrosis and cirrhosis regression, reduction of cirrhotic complications, and reduced liver-related mortality.² Although the risk of HCC is reduced by NA, this dreadful complication still exists, particularly in cirrhotic patients.³^,⁴ In a long-term follow-up study in Europe, new cases of HCC still developed even after more than 5 years of NA treatment.⁵ A Korean report showed that the age-standardized death rate related to HCC only reduced modestly by 27% compared to a 75% reduction in liver-related death between 1999-2013 despite extensive use of antiviral agents.⁶

A second line of prevention of HCC-related mortality is regular surveillance by ultrasonography and alpha-fetoprotein testing. There are good data to suggest that half-yearly HCC surveillance can pick up early HCC that is still amenable to curative treatment, which may lead to improved patient survival.⁷ Owing to the residual HCC risk on NAs, patients should still undergo HCC surveillance even under NA treatment. However, HCC surveillance is resource intensive and demands long-term patient adherence to the program. As NA treatment regresses liver fibrosis and reduces the risk of HCC, the risk of HCC may be reduced to such a low level in some treated patients that HCC surveillance is not warranted. Based on the recommendations of The American Association for the Study of Liver Diseases, it is probably not cost-effective to include individuals with an annual HCC risk of <0.2% in HCC surveillance programs.⁸ It would therefore be useful to predict the HCC risk among patients on NAs, to identify low-risk patients who could be exempted from HCC surveillance.⁹

Numerous risk scores have been developed to predict the risk of HCC. Early scores were mostly developed in Asia in untreated patients with CHB, including the GAG-HCC,¹⁰ the CU-HCC,¹¹ the REACH-B,¹² and the liver stiffness measurement-HCC (LSM-HCC) scores.¹³ Among NA-treated patients, these scores have been found to have modest predictive ability for HCC risk in Asia, but their performances are not satisfactory in Caucasian patients.¹⁴^,¹⁵ As HBV DNA is usually suppressed in NA-treated patients, its role in predicting HCC development is much less significant in treated than in untreated patients. A simple risk score based on age, gender and platelets (PAGE-B) has been developed among Caucasian patients on entecavir (ETV) and tenofovir disoproxil fumarate (TDF) to predict HCC risk for up to 5 years.¹⁶ The PAGE-B score was subsequently modified slightly by Korean investigators by adding serum albumin and adjusting the weighting of age, gender and platelet count (mPAGE-B).¹⁷ As these scores are based on objective demographic and laboratory parameters, they have the potential to be widely used in clinical practice. However, how and when to use these risk scores remains undetermined.

In this study, we aimed to validate the performance of PAGE-B and mPAGE-B scores to predict HCC in NA-treated Chinese patients in Hong Kong, and to evaluate the use of these 2 scores to screen out patients who could be exempted from HCC surveillance during NA treatment.

Section snippets

Study design and data source

A retrospective cohort study was performed using data from the Clinical Data Analysis and Reporting System (CDARS) under the management of Hospital Authority, Hong Kong.¹⁸ CDARS is an electronic healthcare database that covers the patients' demographic, cause of death, diagnoses, procedures, drug prescription and dispensing history, and laboratory parameters from all public hospitals and clinics in Hong Kong. It represents in-patient and out-patient data of around 80% of the 7.4 million people

Demographic characteristics

We identified 56,031 individuals who received ETV or TDF treatment; 23,881 individuals were excluded according to the exclusion criteria, the majority due to cancer(s) before baseline (Fig. 1). Finally, 32,150 patients with CHB who were treated by ETV or TDF were included and analyzed. At baseline, the mean age was 53.0 ± 13.2 years; 20,868 (64.9%) were male; 4,625 (14.4%) had cirrhosis; 885 (2.8%) had decompensated cirrhosis; 28,242 (87.8%) and 3,908 (12.2%) patients were treated by ETV and

Discussion

In this territory-wide cohort study in Hong Kong, we have validated good prediction of HCC development at 3–5 years among patients on first-line antiviral treatments (ETV and TDF) for CHB. Although the mPAGE-B score had statistically better performance than the PAGE-B score, the discriminatory ability of these 2 scores for low-risk patients was excellent and similar. Under the low cut-off value of either score, the estimated annual HCC risk was below 0.2%. There was significant discordance in

Financial support

This work was supported by the Health and Medical Research Fund (HMRF) of the Food and Health Bureau (Reference no: 15160551) award to Grace Wong.

Conflict of interest

Terry Yip has served as a speaker for Gilead Sciences. Grace Wong has served as an advisory committee member for Gilead Sciences and Janssen, and as a speaker for Abbott, Abbvie, Bristol-Myers Squibb, Echosens, Gilead Sciences, Janssen and Roche. Vincent Wong has served as an advisory committee member for 3V-BIO, AbbVie, Allergan, Echosens, Gilead Sciences, Janssen, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer and Terns; and a speaker for Bristol-Myers Squibb, Echosens, Gilead

Authors' contributions

Henry Chan was responsible for study concept and design. Terry Yip, Grace Wong, and Yee-Kit Tse had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Terry Yip, Grace Wong, and Yee-Kit Tse were responsible for the acquisition and analysis of data. Terry Yip and Henry Chan were responsible to draft the paper. All authors were responsible for the interpretation of data and critical revision of the manuscript.

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The use of tenofovir disoproxil fumarate (TDF) is associated with a reduction in bone mineral density and an increase in bone metabolism biomarkers. However, data on clinical bone fractures remain limited. We evaluated the impact of TDF compared to entecavir on the risk of fracture in elderly patients with chronic hepatitis B (CHB).
Patients with CHB aged ≥60 years receiving entecavir or TDF between January 2008 and December 2022 were identified using a territory-wide database in Hong Kong. The risk of incident fracture in entecavir- and TDF-treated patients before and after month 24 were compared after propensity score matching.
A total of 41,531 patients with CHB (mean age 69.8±7.8 years, 61.6% male) receiving entecavir (n = 39,897 [96.1%]) and TDF (n = 1,634 [3.9%]) were analysed. At a median follow-up of 25.3 (9.1–58.5) months, 1,733 (4.2%) patients developed incident fracture. Patients with incident fracture were more likely to have diabetes, hypertension, congestive heart failure, rheumatoid arthritis, osteoporosis, and a history of fracture. Compared with propensity score-matched entecavir-treated patients, the risk of incident fracture in TDF-treated patients was comparable in the first 24 months (weighted subdistribution hazard ratio [sHR] 0.99, 95% CI 0.56–1.73, p = 0.960) but increased after month 24 (weighted sHR 1.80, 95% CI 1.11–2.93, p = 0.019). The 24-, 60-, and 96-month cumulative incidences (95% CI) of fracture in TDF-treated and entecavir-treated patients were 2.3% (1.6%–3.4%) vs. 2.6% (1.9%–3.5%), 6.4% (5.0%–8.2%) vs. 4.7% (3.8%–6.0%), and 10.2% (8.3%–12.6%) vs. 6.8% (5.4%–8.5%), respectively.
The risk of fracture increased with TDF treatment for ≥24 months in elderly patients with CHB. Selection of nucleos(t)ide analogues should be individualised based on age and comorbidities.
Previous literature suggested that the use of tenofovir disoproxil fumarate (TDF) is associated with a decrease in bone mineral density. However, data on the impact of TDF on long-term incident clinical fracture remains scarce. In this real-world territory-wide study of 41,531 treated patients with chronic hepatitis B in Hong Kong, patients who received TDF were at a higher risk of fracture after 2 years of treatment than those who received entecavir. Given the ageing population of patients with chronic hepatitis B and the rising prevalence of comorbidities, our findings support the current treatment guidelines that recommend selecting antiviral treatment based on age and comorbidities.
Diabetes Mellitus Impacts on the Performance of Hepatocellular Carcinoma Risk Scores in Chronic Hepatitis B Patients
2023, Clinical Gastroenterology and Hepatology
We examined whether changing clinical characteristics and presence of diabetes mellitus (DM) impact the performance of hepatocellular carcinoma (HCC) risk scores.
Adult patients with chronic hepatitis B (CHB) on ≥6 months of entecavir/tenofovir treatment between January 2005 and March 2020 were identified using a territory-wide electronic database in Hong Kong. DM was defined by antidiabetic agents, hemoglobin A1c ≥6.5%, fasting glucose ≥7 mmol/L, and/or diagnosis codes. PAGE-B, modified PAGE-B (mPAGE-B), and aMAP scores were assessed by area under the time-dependent receiver operating characteristic curves (AUROCs) and compared with CAMD and REAL-B scores with DM as a component.
Of 48,706 patients, 2792, 11,563, 15,471, and 18,880 started entecavir/tenofovir treatment between 2005–2008, 2009–2012, 2013–2016, and 2017–2020, respectively; DM prevalence rose from 15.5% in 2005–2008 to 24.3% in 2017–2020. AUROCs were comparable across the 4 periods in the 5 HCC risk scores (AUROCs ranged between 0.75 and 0.81). At a median follow-up of 4.4 years, 1512 non-diabetic (4.0%) and 645 (6.2%) diabetic patients developed HCC. AUROCs of all 5 scores were lower in diabetic patients than in non-diabetic patients (AUROCs ranged between 0.67–0.71 vs 0.78–0.82; all P < .001). REAL-B score achieved an AUROC of 0.71 in diabetic and 0.82 in non-diabetic patients. Both diabetic and non-diabetic patients in the low-risk group by REAL-B score had a low HCC incidence below the threshold of cost-effective HCC surveillance, ie, 0.2% annually.
REAL-B score is accurate and preferred in entecavir/tenofovir-treated CHB patients because of the increasing prevalence of DM.
Baveno VII criteria for recompensation predict transplant-free survival in patients with hepatitis B-related decompensated cirrhosis
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The latest Baveno VII consensus has provided guidance for identifying patients who have truly recompensated from those with hepatic decompensation. This study aimed to evaluate patients’ transplant-free survival in three different stages of cirrhosis.
All patients with chronic HBV infection and liver cirrhosis treated with oral nucleos(t)ide analogues from March 2006 to December 2022 were identified from a territory-wide database in Hong Kong. Patients with follow-up duration of <1 year were excluded. Participants were classified into three mutually exclusive groups: (1) no decompensated events (i.e. compensated group); (2) decompensated events occurred (i.e. decompensated group); or (3) decompensated events occurred followed by recompensation according to Baveno VII criteria (i.e. recompensated group). A time-dependent Cox proportional hazard model was adopted for evaluation. The follow-up period was 5 years.
A total of 4,701 patients with cirrhosis and HBV who were treated with entecavir, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF) were identified. During a median follow-up of 5 years (interquartile range 3.7, 5 years), 3,327 (70.8%), 1,347 (29.2%), and 265 (5.6%) patients had compensated, decompensated, and recompensated cirrhosis, respectively, at least once before the end of the study. In the time-dependent multivariable model, the recompensated group had similar transplant-free survival compared with the compensated group (adjusted hazard ratio 1.16; 95% CI 0.72–1.86; p = 0.536). The 5-year transplant-free survival rate was 89.3% for the compensated group, whereas it was 76.0% for the recompensated group, reflecting a minimal difference between the two groups.
The clinical significance of recompensation of cirrhosis in improving patient outcomes for individuals with CHB infection was highlighted in this study. Early identification and treatment with nucleos(t)ide analogues might promote hepatic recompensation and thus reduce mortality in patients with CHB.
The latest Baveno VII consensus introduces the new concept of hepatic recompensation, which refers to the reversal of the structural and functional changes of cirrhosis after removal, cure, or suppression of the aetiology of cirrhosis. It is essential to investigate the transplant-free survival rates of patients who are able to achieve hepatic recompensation, as this has significant implications for the medical resources required to manage liver failure and transplantation. This study features the clinical significance of hepatic recompensation by comparing patient outcomes of those who achieve it to those who do not. The early identification and use of antiviral treatment with nucleos(t)ide analogues is a pivotal strategy to promote hepatic recompensation, which has the potential to significantly reduce mortality rates in patients with chronic HBV infection and ultimately aid in the elimination of hepatitis.
External validation of the PAGE-B score for HCC risk prediction in people living with HIV/HBV coinfection
2023, Journal of Hepatology
HBV coinfection is common among people living with HIV (PLWH) and is the most important cause of hepatocellular carcinoma (HCC). While risk prediction tools for HCC have been validated in patients with HBV monoinfection, they have not been evaluated in PLWH. Thus, we performed an external validation of PAGE-B in people with HIV/HBV coinfection.
We included data on PLWH from four European cohorts who were positive for HBsAg and did not have HCC before starting tenofovir. We estimated the predictive performance of PAGE-B for HCC occurrence over 15 years in patients receiving tenofovir-containing antiretroviral therapy. Model discrimination was assessed after multiple imputation using Cox regression with the prognostic index as a covariate, and by calculating Harrell’s c-index. Calibration was assessed by comparing our cumulative incidence with the PAGE-B derivation study using Kaplan-Meier curves.
In total, 2,963 individuals with HIV/HBV coinfection on tenofovir-containing antiretroviral therapy were included. PAGE-B was <10 in 26.5%, 10–17 in 57.7%, and ≥18 in 15.7% of patients. Within a median follow-up of 9.6 years, HCC occurred in 68 individuals (2.58/1,000 patient-years, 95% CI 2.03–3.27). The regression slope of the prognostic index for developing HCC within 15 years was 0.93 (95% CI 0.61–1.25), and the pooled c-index was 0.77 (range 0.73–0.80), both indicating good model discrimination. The cumulative incidence of HCC was lower in our study compared to the derivation study. A PAGE-B cut-off of <10 had a negative predictive value of 99.4% for the development of HCC within 5 years. Restricting efforts to individuals with a PAGE-B of ≥10 would spare unnecessary HCC screening in 27% of individuals.
For individuals with HIV/HBV coinfection, PAGE-B is a valid tool to determine the need for HCC screening.
Chronic HBV infection is the most important cause of hepatocellular carcinoma (HCC) among people living with HIV. Valid risk prediction may enable better targeting of HCC screening efforts to high-risk individuals. We aimed to validate PAGE-B, a risk prediction tool that is based on age, sex, and platelets, in 2,963 individuals with HIV/HBV coinfection who received tenofovir-containing antiretroviral therapy. In the present study, PAGE-B showed good discrimination, adequate calibration, and a cut-off of <10 had a negative predictive value of 99.4% for the development of HCC within 5 years. These results indicate that PAGE-B is a simple and valid risk prediction tool to determine the need for HCC screening among people living with HIV and HBV.
Non-invasive diagnosis and follow-up of chronic infection with hepatitis B virus
2022, Clinics and Research in Hepatology and Gastroenterology
Citation Excerpt :
In untreated patients eligible for screening the indication of treatment should be considered (except in patients with inactive cirrhosis). In a recent study of 32150 patients, one third was considered to be at low risk [35]. The 5-year cumulative incidence was 0.6% in this group with a negative predictive value of 99.5%.
Diagnosis of chronic hepatitis B virus (HBV) infection, initial staging of infection and monitoring of treated and untreated patients are mainly based on clinical, biological and imaging criteria allowing a complete non-invasive management for the majority of patients. Along to the conventional virological tools, rapid diagnostic tests and blotting paper tests for HBV DNA are validated alternatives. After diagnosis, the initial work-up should include HIV, HCV and HDV serologies, HBeAg status, and HBsAg and HBV DNA quantification. Assessment of severity (inflammation and fibrosis) is based on ALT serum levels and non-invasive evaluation of liver fibrosis by elastography or blood tests, which must be interpreted cautiously using specific cut-offs and taking into account ALT levels. Taken together, these parameters allow disease classification and treatment decision. Decision of hepatocellular carcinoma screening by ultra-sound every six months may be difficult in non-cirrhotic patients and the use of risk-scores such as PAGE-B is encouraged. Chronic HBV infection often has a dynamic and often unpredictable profile and regular monitoring is mandatory. In untreated patients, regular (3-12 months) follow-up should include ALT and HBV DNA serum levels. Periodical HBsAg quantification and non-invasive evaluation of liver fibrosis may refine disease outcome and prognosis. In treated patients, checking efficacy is mainly based on HBV DNA negativity. In patients with advanced fibrosis, evolution of liver stiffness can be useful for portal hypertension evaluation, but its improvement should not be considered to stop hepatocellular carcinoma screening. Finally, new parameters (HBV RNA, HBcrAg) are promising but their use is still restricted for research.
Predictive Performance of CAGE-B and SAGE-B Models in Asian Treatment-Naive Patients Who Started Entecavir for Chronic Hepatitis B
2022, Clinical Gastroenterology and Hepatology
Citation Excerpt :
In addition, Jeon et al23 reported that dynamic LS-based risk prediction models during AVT are feasible in patients with CHB. The higher AUROCs of CAGE-B and SAGE-B models than that of PAGE-B model in our cohort might indicate that the HCC risk at 5 years of AVT is required to enhance the predictive accuracy of prediction models, because clinical and laboratory situations might be changed during long-term AVT.24 In our study, LS values at 2~3 years of AVT were available in 139 patients (18.9%).
Cirrhosis and age (CAGE-B) and stiffness and age (SAGE-B) models assess the risk of hepatocellular carcinoma (HCC) development in white patients with chronic hepatitis B (CHB) undergoing sustained antiviral therapy (AVT). Herein, we checked the predictive performance of these models in Asian patients with CHB.
We reviewed 734 treatment-naive patients with CHB who started entecavir between 2006 and 2011 and were followed up for more than 5 years without HCC development during AVT. The predictive performance of CAGE-B and SAGE-B models was calculated using area under the receiver operating characteristic curves (AUROCs).
Median liver stiffness assessed using transient elastography after 5 years of AVT was 6.8 kPa. Median CAGE-B and SAGE-B models after 5 years of AVT were 7.0 and 6.0, respectively. More than 5 years after AVT initiation, 66 patients (9.0%) developed HCC. The AUROCs of the CAGE-B and SAGE-B models were 0.764 and 0.785 after 7 years and 0.799 and 0.802 after 10 years of AVT, respectively. The cumulative incidence of HCC was significantly higher in the high-risk groups according to CAGE-B and SAGE-B risk stratification than in the medium- and low-risk groups (P < .05 in all cases). The SAGE-B model showed a higher likelihood ratio (χ²) (76.2 vs 71.4) and linear trend (χ²) (74.1 vs 58.6) than the CAGE-B model, whereas the CAGE-B model showed higher Akaike information criteria (64.3 vs 50.3).
Both SAGE-B and CAGE-B showed acceptable performance in predicting HCC after 5 years of AVT in Asian patients with CHB.

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Research ArticleReassessing the accuracy of PAGE-B-related scores to predict hepatocellular carcinoma development in patients with chronic hepatitis B

Highlights

Background & Aims

Methods

Results

Conclusions

Lay summary

Graphical abstract

Introduction

Section snippets

Study design and data source

Demographic characteristics

Discussion

Financial support

Conflict of interest

Authors' contributions

J Hepatol

J Hepatol

Lancet Oncol

J Hepatol

Gastroenterology

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

Lancet Gastroenterol Hepatol

Lancet Gastroenterol Hepatol

Infection and cancer: the case of hepatitis B

J Clin Oncol

Improvements in the management of chronic hepatitis B virus infection

Expert Rev Gastroenterol Hepatol

Okuda lecture: challenges of hepatitis B in the era of antiviral therapy

J Gastroenterol Hepatol

The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B

Hepatology

Increasing burden of liver cancer despite extensive use of antiviral agents in a hepatitis B virus-endemic population

Hepatology

Application of surveillance programs for hepatocellular carcinoma in the Asia-Pacific Region

J Gastroenterol Hepatol

Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance

Hepatology

Research Article
Reassessing the accuracy of PAGE-B-related scores to predict hepatocellular carcinoma development in patients with chronic hepatitis B