PAGE-B Score Research Articles

Validation of the CAMD Score in Patients With Chronic Hepatitis B Virus Infection Receiving Antiviral Therapy

Researchers previously developed a scoring system to determine the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection, based on the presence of cirrhosis, patient age, male sex, and diabetes (called the CAMD scoring system). We validated the CAMD scoring system and compared its performance with that of other risk assessment models in an independent cohort. We followed up 3277 patients with chronic HBV infection (mean age, 48.7 y; 62.6% male; 32.4% with cirrhosis) who were treated with entecavir (n= 1725) or tenofovir (n= 1552) as the first-line antiviral agent in 4 academic teaching hospitals in the Republic of Korea. The primary outcome was development of HCC. We evaluated the ability of the CAMD, PAGE-B, and mPAGE-B scoring systems to identify patients who would develop HCC using integrated area under the curve (iAUC) analysis. Over a median follow-up period of 58.2 months, 8.9% of the patients developed HCC. Patients who developed HCC were older, more likely to be male, and had higher proportions of cirrhosis and diabetes than patients who did not develop HCC (all P < .05). CAMD scores identified patients who developed HCC with an iAUC of 0.790, mPAGE-B scores with an iAUC of 0.769, and PAGE-B scores with an iAUC of 0.760. The 5-year cumulative risks of HCC were 1.3% in patients with low CAMD scores (<8), 8.0% in patients with intermediate CAMD scores (8-13), and 24.3% in patients with high CAMD scores (>13) (P < .001 for comparison of low- vs intermediate-score groups and between intermediate- vs high-score groups). The predicted and observed probabilities of HCC had excellent agreement. We validated the CAMD scoring system in determining the risk of HCC in patients with chronic HBV treatment receiving entecavir or tenofovir treatment. Validation was performed in a cohort of patients in the Republic of Korea, where most patients have genotype C2 HBV infection.

External validation of the modified PAGE-B score in Asian chronic hepatitis B patients receiving antiviral therapy.

The modified PAGE-B (mPAGE-B) score comprising age, gender, platelet count and albumin was recently proposed to predict hepatocellular carcinoma (HCC) risk among chronic hepatitis B (CHB) patients undergoing antivirals. Here, in the independent cohort, we externally validated the predictive performance of the mPAGE-B score and compared it with those of conventional HCC prediction models. We consecutively recruited CHB patients treated with lamivudine, entecavir or tenofovir as the first-line antiviral regimen. Patients with decompensated cirrhosis or HCC at baseline were excluded. Predictive performances of the mPAGE-B score and other models were assessed with comparison. Among 1330 patients, 9.6% developed HCC during follow-up. The mPAGE-B score provided the highest Harrell's c-index (0.769), followed by the GAG-HCC (0.751), PAGE (0.744), REACH-B (0.686) and CU-HCC (0.618) scores. The mPAGE-B score showed the similar performance to the PAGE-B and GAG-HCC scores and the better performance than the REACH-B and CU-HCC scores. Cumulative HCC probabilities at 5- and 7-years were 0.0% and 0.0% in low-risk group (mPAGE-B score≤8), 6.1% and 10.8% in intermediate-risk group (mPAGE-B score 9-12) and 18.7% and 26.7% in high-risk group (mPAGE-B score≥13) respectively (both P<0.001 between adjacent two groups). C-indices of the mPAGE-B score were 0.785 and 0.724 among subgroups treated with entecavir or tenofovir (n=1011) and with lamivudine (n=319), respectively, which are overall similar to those of the PAGE-B score. The mPAGE-B score showed acceptable predictive performances. Compared to the PAGE-B score, addition of albumin as a constituent provided the marginal benefit.

Non-virological factors are drivers of hepatocellular carcinoma in virosuppressed hepatitis B cirrhosis: Results of ANRS CO12 CirVir cohort.

Worldwide, hepatocellular carcinoma (HCC) occurs mainly in Asian patients with hepatitis B virus (HBV) infection. This study aimed to decipher the environmental and virological factors associated with HCC occurrence and validate risk scoring systems in a French multicentre prospective cohort of HBV cirrhotic patients. Patients with biopsy-proven Child-Pugh A viral cirrhosis included in the ANRS CO12 CirVir cohort who were HBsAg(+) without hepatitis C coinfection were selected for: (a) interview through a standardized questionnaire reporting coffee consumption and HCC familial history; (b) HBsAg quantification using baseline and sequential 2-year frozen sera; (c) baseline HBV genotype determination; and (d) assessment of risk factors and applicability of HCC risk scores (Kaplan-Meier analysis, Cox models). Among 317 patients studied (261 men, median age 53years, past or ongoing antiviral treatment 93.3% and baseline detectable HBV DNA in 88 patients), the baseline and 2-year median HBsAg levels were 810 and 463IU/mL, respectively. After a median follow-up of 65.2 months, 27 HCC cases were diagnosed (annual incidence: 1.6%). Three factors were independently associated with HCC occurrence: age>50years, platelets≤150×103 /mm3 and body mass index≥30kg/m2 . Two out of five risk scores were validated, and the most accurate was PAGE-B at 1year. Moreover, HCC in patients without maintained virological suppression seems more aggressive and less accessible to curative treatment. In conclusion, in French patients with HBV cirrhosis mostly virally suppressed, independent HCC risk factors were host-related (age, obesity) or linked to the severity of cirrhosis (thrombopenia), and the European PAGE-B score was the most accurate risk score.

From the Editor’s desk....: November 2018

From the Editor’s desk....: November 2018

Modified PAGE-B score predicts the risk of hepatocellular carcinoma in Asians with chronic hepatitis B on antiviral therapy

Recently, the PAGE-B score and Toronto HCC risk index (THRI) have been developed to predict the risk of hepatocellular carcinoma (HCC) in Caucasian patients with chronic hepatitis B (CHB). We aimed to validate PAGE-B scores and THRI in Asian patients with CHB and suggested modified PAGE-B scores to improve the predictive performance. From 2007 to 2017, we examined 3,001 Asian patients with CHB receiving entecavir/tenofovir therapy. We assessed the performances of PAGE-B, THRI, CU-HCC, GAG-HCC, and REACH-B for HCC development. A modified PAGE-B score (mPAGE-B) was developed (derivation set, n = 2,001) based on multivariable Cox models. Bootstrap for internal validation and external validation (validation set, n = 1,000) were performed. The five-year cumulative HCC incidence rates were 6.6% and 7.2% in the derivation and validation datasets after entecavir/tenofovir onset. In the derivation dataset, age, gender, serum albumin levels, and platelet counts were independently associated with HCC. The mPAGE-B score was developed based on age, gender, platelet counts, and serum albumin levels (time-dependent area under receiver operating characteristic curves [AUROC] = 0.82). In the validation set, the PAGE-B and THRI showed similar AUROCs to CU-HCC, GAG-HCC, and REACH-B at five years (0.72 and 0.73 vs. 0.70, 0.71, and 0.61 respectively; all p >0.05 except REACH-B), whereas the AUROC of mPAGE-B at five years was 0.82, significantly higher than the five other models (all p <0.01). HCC incidence rates after initiation of entecavir/tenofovir therapy in patients with CHB were significantly decreased in all risk groups in long-term follow-up periods. Although PAGE-B and THRI are applicable in Asian patients with CHB receiving entecavir/tenofovir therapy, mPAGE-B scores including additional serum albumin levels showed better predictive performance than the PAGE-B score. PAGE-B scores and Toronto HCC risk index were developed to predict the risk of hepatocellular carcinoma (HCC) in Caucasian patients with CHB under potent antiviral therapy. This study validated these two scores in Asian patients with CHB and suggested that modified PAGE-B scores could improve the predictive performance. A modified PAGE-B score, which is based only on a patient's age, gender, baseline platelet counts, and serum albumin levels at treatment initiation, represents a reliable and easily available risk score to predict HCC development during the first five years of antiviral treatment in Asian patients with CHB. With a scoring range from 0 to 21 points, a modified PAGE-B score differentiates the HCC risk. A modified PAGE-B score significantly differentiates the five-year HCC risk: low ≤8 points and high ≥13 points.

FRI-274 - Modified PAGE-B score predicts the risk of hepatocellular carcinoma in Asians with chronic hepatitis B on antiviral therapy

FRI-274 - Modified PAGE-B score predicts the risk of hepatocellular carcinoma in Asians with chronic hepatitis B on antiviral therapy

Prediction of long-term clinical outcome in a diverse chronic hepatitis B population: Role of the PAGE-B score.

An abundance of noninvasive scores have been associated with fibrosis and hepatocellular carcinoma (HCC) development. We aimed to compare the prognostic ability of these scores in relation to liver histology in chronic hepatitis B (CHB) patients. Liver biopsies from treatment-naïve CHB patients at one tertiary care centre were scored by a single hepato-pathologist. Laboratory values at liver biopsy were used to calculate the PAGE-B, REACH-B, GAG-HCC, CU-HCC and FIB-4 scores. Any clinical event was defined as HCC development, liver failure, transplantation and mortality. HCC and mortality data were obtained from national database registries. Of 557 patients, 40 developed a clinical event within a median follow-up of 10.1 (IQR 5.7-15.9) years. The PAGE-B score predicted any clinical event (C-statistic.86, 95% CI: 0.80-0.92), HCC development (C-statistic .91) and reduced transplant-free survival (C-statistic .83) with good accuracy, also when stratified by ethnicity, antiviral therapy after biopsy or advanced fibrosis. The C-statistics (95% CI) of the REACH-B, GAG-HCC, CU-HCC and FIB-4 scores for any event were .70 (0.59-0.81), .82 (0.75-0.89), .73 (0.63-0.84) and.79 (0.69-0.89), respectively. The PAGE-B event risk assessment improved modestly when combined with the Ishak fibrosis stage (C-statistic .87, 95% CI: 0.82-0.93). The PAGE-B score showed the best performance in assessing the likelihood of developing a clinical event among a diverse CHB population over 15years of follow-up. Additional liver histological characteristics did not appear to provide a clinically significant improvement.

Effectiveness and Safety of Entecavir or Tenofovir in a Spanish Cohort of Chronic Hepatitis B Patients: Validation of the Page-B Score to Predict Hepatocellular Carcinoma.

Long-term antiviral therapy has resulted in viral suppression and biochemical response in chronic hepatitis B, although the risk of hepatocellular carcinoma has not been abolished. The Page-B score could be useful to estimate the probability of HCC. To analyze the effectiveness and safety of entecavir or tenofovir for more than 4years and the usefulness of Page-B score in the real-world setting. Analysis of Caucasian chronic hepatitis B subjects treated with entecavir or tenofovir from the prospective, multicenter database CIBERHEP. A total of 611 patients were enrolled: 187 received entecavir and 424 tenofovir. Most were men, mean age 50years, 32% cirrhotic and 16.5% HBeAg-positive. Mean follow-up was 55 (entecavir) and 49 (tenofovir) months. >90% achieved HBV DNA <69IU/mL and biochemical normalization by months 12 and 36, respectively. Cumulative HBeAg loss and anti-HBe seroconversion were achieved by 33.7 and 23.8%. Four patients lost HBsAg; three HBeAg-positive. Renal function remained stable on long-term follow-up. Fourteen (2.29%) developed HCC during follow-up all of them with baseline Page-B ≥10. Nine were diagnosed within the first 5years of therapy. This contrasts with the 27 estimated by Page-B, a difference that highlights the importance of regular HCC surveillance even in patients with virological suppression. Entecavir and tenofovir achieved high biochemical and virological response. Renal function remained stable with both drugs. A Page-B cut-off ≥10 selected all patients at risk of HCC development.

Prediction models of hepatocellular carcinoma development in chronic hepatitis B patients.

Chronic hepatitis B virus (HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma (HCC). Applying the same strategies for antiviral therapy and HCC surveillance to all chronic hepatitis B (CHB) patients would be a burden worldwide. To properly manage CHB patients, it is necessary to identify and classify the risk for HCC development in such patients. Several HCC risk scores based on risk factors such as cirrhosis, age, male gender, and high viral load have been used, and have negative predictive values of ≥ 95%. Most of these have been derived from, and internally validated in, treatment-naïve Asian CHB patients. Herein, we summarized various HCC prediction models, including IPM (Individual Prediction Model), CU-HCC (Chinese University-HCC), GAG-HCC (Guide with Age, Gender, HBV DNA, Core Promoter Mutations and Cirrhosis-HCC), NGM-HCC (Nomogram-HCC), REACH-B (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B), and Page-B score. To develop a noninvasive test of liver fibrosis, we also introduced a new scoring system that uses liver stiffness values from transient elastography, including an LSM (Liver Stiffness Measurement)-based model, LSM-HCC, and mREACH-B (modified REACH-B).

PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy

Risk scores for hepatocellular carcinoma (HCC) developed in Asians offer poor-moderate predictability in Caucasian patients with chronic hepatitis B (CHB). This nine center cohort study aimed to develop and validate an accurate HCC risk score in Caucasian CHB patients treated with the current oral antivirals, entecavir/tenofovir. We included 1815 adult Caucasians with CHB and no HCC at baseline who received entecavir/tenofovir for ⩾12 months. Using data from eight centers (derivation dataset, n=1325), a HCC risk score was developed based on multivariable Cox models and points system for simplification. Harrell's c-index was used as discrimination, bootstrap for internal validation and the data from the 9(th) and largest center (validation dataset, n=490) for external validation. The 5-year cumulative HCC incidence rates were 5.7% and 8.4% in the derivation and validation dataset, respectively. In the derivation dataset, age, gender, platelets and cirrhosis were independently associated with HCC. The PAGE-B score was developed based on age, gender and platelets (c-index=0.82, 0.81 after bootstrap validation). The addition of cirrhosis did not substantially improve the discrimination (c-index=0.84). The predictability of PAGE-B score was similar (c-index=0.82) in the validation dataset. Patients with PAGE-B ⩽9, 10-17, ⩾18 had 5-year cumulative HCC incidence rates of 0%, 3%, 17% in the derivation and 0%, 4%, 16% in the validation dataset. PAGE-B, which is based only on baseline patients' age, gender and platelets, represents a simple and reliable score for prediction of the 5-year HCC risk in Caucasian CHB patients under entecavir/tenofovir.

P0644 : HCC risk scores: Application of the CU-HCC, GAG-HCC and page-B scores to chronic hepatitis B (CHB) patients treated with tenofovir disoproxil fumarate (TDF)

P0644 HCC RISK SCORES: APPLICATION OF THE CU-HCC, GAG-HCC AND PAGE-B SCORES TO CHRONIC HEPATITIS B (CHB) PATIENTS TREATED WITH TENOFOVIR DISOPROXIL FUMARATE (TDF) W.R. Kim, R. Loomba, T. Berg, R. Aguilar Schall, L. Yee, P. Dinh, J.F. Flaherty, E.B. Martins, I. Jacobson, S. Fung, S. Gurel, M. Buti, P. Marcellin. Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, Division of Gastroenterology, and Epidemiology, University of California at San Diego, La Jolla, United States; Department of Internal Medicine, Division of Gastroenterology and Rheumatology, Section of Heptology, Universitatsklinikum Leipzig, Leipzig, Germany; Gilead Sciences, Foster City, Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, United States; Department of Gastroenterology, University of Toronto, Toronto, Canada; Department of Gastroenterology, University of Uludag, Bursa, Turkey; Department of Hepatology, Hospital General Universitari Vall d’Hebron, Barcelona, Spain; Department of Hepatology, Hopital Beaujon, University of Paris, Clichy, France E-mail: Leland.yee@gilead.com