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Inoue J, Minami S, Abe K, Kida M, Haga H, Iino C, Numao H, Kuroda H, Ninomiya M, Tsuruoka M, Sato K, Onuki M, Sawahashi S, Ouchi K, Watanabe K, Akahane T, Kobayashi T, Ohira H, Ueno Y, Masamune A. Validation Study of Scores Predicting Hepatocellular Carcinoma Risk in Chronic Hepatitis B Patients Treated With Nucleos(t)ide Analogues. J Viral Hepat 2025; 32:e70021. [PMID: 40052685 PMCID: PMC11887419 DOI: 10.1111/jvh.70021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 02/02/2025] [Accepted: 02/23/2025] [Indexed: 03/10/2025]
Abstract
Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC) worldwide. Nucleos(t)ide analogues (NAs) are widely used in chronically HBV-infected patients, but the risk of HCC still remains in NA-treated patients. In this study, we aimed to validate the HCC risk scores for HBV-infected patients treated with nucleos(t)ide analogues (NAs). Among a total of 360 chronically HBV-infected patients who were treated with NAs, 253 patients without a history of HCC were used to validate the PAGE-B, mPAGE-B, PAGED-B, APA-B, and aMAP scores, as well as a recently developed score, the FAL-1 score, which consists of the FIB-4 index and ALT at 1 year of NA. In this cohort, the cumulative incidence of HCC at 5, 10, and 15 years was 2.9%, 7.8% and 11.0%, respectively. Most scores significantly stratified the HCC incidence and, for the FAL-1 score, the cumulative incidence of HCC at 10 years was 0%, 11.3% and 17.2% for the score-0 (n = 91), score-1 (n = 129) and score-2 (n = 30) groups, respectively. Compared with the other scores, the FAL-1 score was shown to efficiently identify patients at very low risk of HCC. An analysis using both this validation and the previously reported derivation cohorts demonstrated the utility in patients with either HBV genotype B or C. In conclusion, the utility of the FAL-1 score was reproduced in this validation study as well as other scores. In particular, the FAL-1 score may be useful to efficiently identify patients with a low risk of HCC.
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Affiliation(s)
- Jun Inoue
- Division of GastroenterologyTohoku University Graduate School of MedicineSendaiJapan
- Institute for Excellence in Higher EducationTohoku UniversitySendaiJapan
| | - Shinichiro Minami
- Department of GastroenterologyAkita University Graduate School of MedicineAkitaJapan
| | - Kazumichi Abe
- Department of GastroenterologyFukushima Medical University School of MedicineFukushimaJapan
| | - Mami Kida
- Department of Internal MedicineKurihara Central HospitalKuriharaJapan
| | - Hiroaki Haga
- Department of Gastroenterology, Faculty of MedicineYamagata UniversityYamagataJapan
| | - Chikara Iino
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Hiroshi Numao
- Department of GastroenterologyAomori Prefectural Central HospitalAomoriJapan
| | - Hidekatsu Kuroda
- Division of Gastroenterology and Hepatology, Department of Internal MedicineIwate Medical University School of MedicineYahabaJapan
| | - Masashi Ninomiya
- Division of GastroenterologyTohoku University Graduate School of MedicineSendaiJapan
- Institute for Excellence in Higher EducationTohoku UniversitySendaiJapan
| | - Mio Tsuruoka
- Division of GastroenterologyTohoku University Graduate School of MedicineSendaiJapan
| | - Kosuke Sato
- Division of GastroenterologyTohoku University Graduate School of MedicineSendaiJapan
| | - Masazumi Onuki
- Division of GastroenterologyTohoku University Graduate School of MedicineSendaiJapan
| | - Satoko Sawahashi
- Division of GastroenterologyTohoku University Graduate School of MedicineSendaiJapan
| | - Keishi Ouchi
- Division of GastroenterologyTohoku University Graduate School of MedicineSendaiJapan
| | - Kengo Watanabe
- Division of GastroenterologyTohoku University Graduate School of MedicineSendaiJapan
| | - Takehiro Akahane
- Department of GastroenterologyJapanese Red Cross Ishinomaki HospitalIshinomakiJapan
| | - Tomoo Kobayashi
- Department of GastroenterologyTohoku Rosai HospitalSendaiJapan
| | - Hiromasa Ohira
- Department of GastroenterologyFukushima Medical University School of MedicineFukushimaJapan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Faculty of MedicineYamagata UniversityYamagataJapan
| | - Atsushi Masamune
- Division of GastroenterologyTohoku University Graduate School of MedicineSendaiJapan
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Ramier C, Protopopescu C, Di Beo V, Parlati L, Marcellin F, Carrat F, Asselah T, Bourlière M, Carrieri P. Behaviour-Based Predictive Scores of Hepatocellular Carcinoma in People With Chronic Hepatitis B (ANRS CO22 HEPATHER). Liver Int 2025; 45:e70065. [PMID: 40087922 PMCID: PMC11909585 DOI: 10.1111/liv.70065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 01/21/2025] [Accepted: 03/05/2025] [Indexed: 03/17/2025]
Abstract
BACKGROUND AND AIMS Early assessment of hepatocellular carcinoma (HCC) risk could improve long-term outcomes in people with chronic hepatitis B virus (HBV) infection. Some existing HCC predictive scores are not easily implementable. We developed easy-to-use HCC predictive scores based on behavioural and routine bio-clinical data in people with chronic HBV infection. METHODS Eight-year follow-up data was analysed from people with chronic HBV infection enrolled in the French ANRS CO22 HEPATHER cohort. Patients were randomly split into two samples (training/testing). A multivariable Cox model for time to HCC was estimated on the training sample. The HCC predictive score was computed by summing the points assigned to model predictors, normalising their coefficients over a 10-year age increment, and rounding to the nearest integer. The Youden index identified the score's optimal risk threshold. Comparisons with existing predictive scores were performed on the testing sample. RESULTS In the study population (N = 4370; 63% of men; 65% of < 50 years old), 56 HCC cases occurred during 25,900 follow-up person-years. Two HCC predictive scores were defined: SADAPTT (daily soft drink consumption, age, hepatitis Delta infection, unhealthy alcohol use, platelet count, heavy tobacco smoking, and HBV treatment) and ADAPTT (the same predictors except for daily soft drink consumption), with ranges 0-13 and 0-14, respectively, and values ≥ 3 indicating a high HCC risk. Their performances were similar to existing scores. CONCLUSIONS We developed two effective behaviour-based HCC predictive scores, implementable in many settings, including primary care and decentralised areas. Further studies are needed to validate these scores in other datasets.
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Affiliation(s)
- Clémence Ramier
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Économiques and Sociales de la Santé and Traitement de l'Information MédicaleMarseilleFrance
| | - Camelia Protopopescu
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Économiques and Sociales de la Santé and Traitement de l'Information MédicaleMarseilleFrance
| | - Vincent Di Beo
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Économiques and Sociales de la Santé and Traitement de l'Information MédicaleMarseilleFrance
| | - Lucia Parlati
- Département d'Hépatologie/AddictologieUniversité de Paris Cité; INSERM U1016, AP‐HP, Hôpital CochinParisFrance
| | - Fabienne Marcellin
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Économiques and Sociales de la Santé and Traitement de l'Information MédicaleMarseilleFrance
| | - Fabrice Carrat
- Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Sorbonne UniversitéParisFrance
- Hôpital Saint‐Antoine, Unité de Santé Publique, Assistance Publique‐Hôpitaux de Paris (AP‐HP)ParisFrance
| | - Tarik Asselah
- Department of HepatologyCentre de Recherche Sur l'Inflammation, INSERM UMR 1149, Hôpital Beaujon, Université de Paris‐CitéClichyFrance
| | - Marc Bourlière
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Économiques and Sociales de la Santé and Traitement de l'Information MédicaleMarseilleFrance
- Département d'hépatologie et GastroentérologieHôpital Saint JosephMarseilleFrance
| | - Patrizia Carrieri
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Économiques and Sociales de la Santé and Traitement de l'Information MédicaleMarseilleFrance
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Mak LY. Disease modifiers and novel markers in hepatitis B virus-related hepatocellular carcinoma. JOURNAL OF LIVER CANCER 2024; 24:145-154. [PMID: 39099070 PMCID: PMC11449577 DOI: 10.17998/jlc.2024.08.03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 07/25/2024] [Accepted: 08/03/2024] [Indexed: 08/06/2024]
Abstract
Chronic hepatitis B (CHB) infection is responsible for 40% of the global burden of hepatocellular carcinoma (HCC) with a high case fatality rate. The risk of HCC differs among CHB subjects owing to differences in host and viral factors. Modifiable risk factors include viral load, use of antiviral therapy, co-infection with other hepatotropic viruses, concomitant metabolic dysfunctionassociated steatotic liver disease or diabetes mellitus, environmental exposure, and medication use. Detecting HCC at early stage improves survival, and current practice recommends HCC surveillance among individuals with cirrhosis, family history of HCC, or above an age cut-off. Ultrasonography with or without serum alpha feto-protein (AFP) every 6 months is widely accepted strategy for HCC surveillance. Novel tumor-specific markers, when combined with AFP, improve diagnostic accuracy than AFP alone to detect HCC at an early stage. To predict the risk of HCC, a number of clinical risk scores have been developed but none of them are clinically implemented nor endorsed by clinical practice guidelines. Biomarkers that reflect viral transcriptional activity and degree of liver fibrosis can potentially stratify the risk of HCC, especially among subjects who are already on antiviral therapy. Ongoing exploration of these novel biomarkers is required to confirm their performance characteristics, replicability and practicability.
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Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Liver Research, The Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
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Chen CH, Wang JH, Lai HC, Hu TH, Hung CH, Lu SN, Peng CY. Mac-2 binding protein glycosylation isomer at 5 years of antiviral therapy predict hepatocellular carcinoma and mortality beyond year 5 in chronic hepatitis B patients with cirrhosis. Am J Cancer Res 2024; 14:2465-2477. [PMID: 38859836 PMCID: PMC11162690 DOI: 10.62347/dagb7277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 05/09/2024] [Indexed: 06/12/2024] Open
Abstract
Whether serum Mac-2 binding protein glycosylation isomer (M2BPGi) level at year 5 of treatment could predict hepatocellular carcinoma (HCC) development and mortality beyond year 5 of entecavir or tenofovir disoproxil fumarate (TDF) treatment in chronic hepatitis B (CHB) patients with cirrhosis remain unclear. This retrospective study investigated the role of M2BPGi level at year 5 of treatment in predicting HCC and mortality beyond year 5 in CHB patients with cirrhosis. This study analyzed 1385 cirrhotic patients receiving entecavir or TDF treatment. Of them, 899 patients who did not develop HCC within the first 5 years of treatment were enrolled. In the entire cohort, there was no significant difference in the annual incidence of HCC before and after year 5 of entecavir or TDF treatment (P = 0.455). Multivariable Cox analysis identified old age, higher AFP and M2BPGi levels at 5 years of treatment as independent predictors of HCC occurrence beyond year 5. We developed the HCC risk prediction model, AMA, based on age, M2BPGi and AFP levels at 5 years of treatment, with the total score ranging from 0 to 8. The AMA model accurately categorized patients into low (≤2), medium (2-5), and high (≥5) risk groups in the development and validation groups (P<0.001) and exhibited good discriminant function in predicting HCC beyond year 5 in cirrhotic patients (AUROC: 0.743 at 5 years). The M2BPGi of 1.0 COI at 5 years of treatment stratified the risk of all-cause and liver-related mortality beyond year 5 (P<0.001). In conclusions, M2BPGi level at 5 years of treatment is a useful marker for predicting HCC development and mortality beyond year 5 of entecavir or TDF therapy in CHB patients with cirrhosis.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
| | - Hsueh-Chou Lai
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University HospitalTaichung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University HospitalTaichung, Taiwan
- School of Medicine, China Medical UniversityTaichung, Taiwan
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Hao X, Fan R, Zeng HM, Hou JL. Hepatocellular Carcinoma Risk Scores from Modeling to Real Clinical Practice in Areas Highly Endemic for Hepatitis B Infection. J Clin Transl Hepatol 2023; 11:1508-1519. [PMID: 38161501 PMCID: PMC10752803 DOI: 10.14218/jcth.2023.00087] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 05/04/2023] [Accepted: 06/02/2023] [Indexed: 01/03/2024] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and represents a global health challenge. Liver cancer ranks third in cancer-related mortality with 830,000 deaths and sixth in incidence with 906,000 new cases annually worldwide. HCC most commonly occurs in patients with underlying liver disease, especially chronic hepatitis B virus (HBV) infection in highly endemic areas. Predicting HCC risk based on scoring models for patients with chronic liver disease is a simple, effective strategy for identifying and stratifying patients to improve the early diagnosis rate and prognosis of HCC. We examined 23 HCC risk scores published worldwide in CHB patients with (n=10) or without (n=13) antiviral treatment. We also described the characteristics of the risk score's predictive performance and application status. In the future, higher predictive accuracy could be achieved by combining novel technologies and machine learning algorithms to develop and update HCC risk score models and integrated early warning and diagnosis systems for HCC in hospitals and communities.
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Affiliation(s)
- Xin Hao
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Institute of Liver Diseases, Guangzhou, Guangdong, China
| | - Rong Fan
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Institute of Liver Diseases, Guangzhou, Guangdong, China
| | - Hong-Mei Zeng
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jin-Lin Hou
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Institute of Liver Diseases, Guangzhou, Guangdong, China
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Huang YH, Shen CW, Chen CY, Bair MJ. Comparative effectiveness of tenofovir versus entecavir in patients with hepatitis B virus-related cirrhosis in Taiwan: a retrospective cohort study. Front Pharmacol 2023; 14:1301120. [PMID: 38174221 PMCID: PMC10763146 DOI: 10.3389/fphar.2023.1301120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 11/30/2023] [Indexed: 01/05/2024] Open
Abstract
Background: Tenofovir and entecavir demonstrated substantial effectiveness in the reversion of fibrosis and reversed cirrhosis in patients with hepatitis B virus (HBV)-related cirrhosis. However, there has not been a definitive conclusion regarding the association between entecavir and tenofovir on the risk of cirrhosis-related complications. Therefore, this study aimed to investigate the comparative effectiveness between tenofovir and entecavir in HBV-related cirrhosis patients. Methods: This was a retrospective study using Taiwan's Health Insurance Research Database. We enrolled newly diagnosed HBV-related cirrhosis patients who initiated entecavir and tenofovir between 2011 and 2019. Treatment groups were determined by the initial HBV antiviral medication prescribed. The primary composite outcome was the development of hepatocellular carcinoma (HCC), death from any causes, and liver transplantation. The secondary outcomes included all the individual components of the primary outcome. The incidence rate was calculated for each outcome for both treatment groups using the Fine-Gray subdistribution hazard models. Propensity score adjustment was used to balance treatment groups. Results: A total of 7,316 propensity score-matched treatment-naïve patients and 3,524 propensity score-matched treatment-experienced patients were included. Within treatment-naïve patients, those receiving tenofovir showed significantly lower hazards of developing the composite outcome (HR, 0.79; p < 0.0001), hepatocellular carcinoma (HR, 0.86; p = 0.027), mortality (HR, 0.75; p < 0.0001), and liver transplantation (HR, 0.70; p = 0.0189) than those receiving entecavir. As for treatment-experienced patients, tenofovir was associated with a significantly lower risk of the composite outcome (HR, 0.82; p = 0.0033) and hepatocellular carcinoma (HR, 0.60; p < 0.0001), but it did not show a significantly different risk of all-cause mortality (HR, 0.93; p = 0.3374) or liver transplantation (HR, 1.17; p = 0.5112) compared to entecavir. Conclusion: Tenofovir presented a significantly lower incidence of cirrhosis-related complications than entecavir in patients with hepatitis B virus-related cirrhosis. However, no statistically significant difference in death and liver transplantation was seen in treatment-experienced patients.
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Affiliation(s)
- Yu-Han Huang
- Department of Pharmacy, Pingtung Veterans General Hospital, Pingtung, Taiwan
- Master Program in Clinical Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chuan-Wei Shen
- Master Program in Clinical Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Yu Chen
- Master Program in Clinical Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Jong Bair
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei, Taiwan
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Xu X, Jiang L, Zeng Y, Pan L, Lou Z, Ruan B. HCC prediction models in chronic hepatitis B patients receiving entecavir or tenofovir: a systematic review and meta-analysis. Virol J 2023; 20:180. [PMID: 37582759 PMCID: PMC10428529 DOI: 10.1186/s12985-023-02145-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 07/28/2023] [Indexed: 08/17/2023] Open
Abstract
BACKGROUND Our study aimed to compare the predictive performance of different hepatocellular carcinoma (HCC) prediction models in chronic hepatitis B patients receiving entecavir or tenofovir, including discrimination, calibration, negative predictive value (NPV) in low-risk, and proportion of low-risk. METHODS We conducted a systematic literature research in PubMed, EMbase, the Cochrane Library, and Web of Science before January 13, 2022. The predictive performance was assessed by area under receiver operating characteristic curve (AUROC), calibration index, negative predictive value, and the proportion in low-risk. Subgroup and meta-regression analyses of discrimination and calibration were conducted. Sensitivity analysis was conducted to validate the stability of the results. RESULTS We identified ten prediction models in 23 studies. The pooled 3-, 5-, and 10-year AUROC varied from 0.72 to 0.84, 0.74 to 0.83, and 0.76 to 0.86, respectively. REAL-B, AASL-HCC, and HCC-RESCUE achieved the best discrimination. HCC-RESCUE, PAGE-B, and mPAGE-B overestimated HCC development, whereas mREACH-B, AASL-HCC, REAL-B, CAMD, CAGE-B, SAGE-B, and aMAP underestimated it. All models were able to identify people with a low risk of HCC accurately. HCC-RESCUE and aMAP recognized over half of the population as low-risk. Subgroup analysis and sensitivity analysis showed similar results. CONCLUSION Considering the predictive performance of all four aspects, we suggest that HCC-RESCUE was the best model to utilize in clinical practice, especially in primary care and low-income areas. To confirm our findings, further validation studies with the above four components were required.
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Affiliation(s)
- Xiaolan Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Shangcheng District, Hangzhou, 310000, China
- Center for General Practice Medicine, Department of Infectious Diseases, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310000, China
| | - Lushun Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Shangcheng District, Hangzhou, 310000, China
| | - Yifan Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Shangcheng District, Hangzhou, 310000, China
| | - Liya Pan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Shangcheng District, Hangzhou, 310000, China
| | - Zhuoqi Lou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Shangcheng District, Hangzhou, 310000, China
| | - Bing Ruan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Shangcheng District, Hangzhou, 310000, China.
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Lee YT, Fujiwara N, Yang JD, Hoshida Y. Risk stratification and early detection biomarkers for precision HCC screening. Hepatology 2023; 78:319-362. [PMID: 36082510 PMCID: PMC9995677 DOI: 10.1002/hep.32779] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/25/2022] [Accepted: 08/28/2022] [Indexed: 12/08/2022]
Abstract
Hepatocellular carcinoma (HCC) mortality remains high primarily due to late diagnosis as a consequence of failed early detection. Professional societies recommend semi-annual HCC screening in at-risk patients with chronic liver disease to increase the likelihood of curative treatment receipt and improve survival. However, recent dynamic shift of HCC etiologies from viral to metabolic liver diseases has significantly increased the potential target population for the screening, whereas annual incidence rate has become substantially lower. Thus, with the contemporary HCC etiologies, the traditional screening approach might not be practical and cost-effective. HCC screening consists of (i) definition of rational at-risk population, and subsequent (ii) repeated application of early detection tests to the population at regular intervals. The suboptimal performance of the currently available HCC screening tests highlights an urgent need for new modalities and strategies to improve early HCC detection. In this review, we overview recent developments of clinical, molecular, and imaging-based tools to address the current challenge, and discuss conceptual framework and approaches of their clinical translation and implementation. These encouraging progresses are expected to transform the current "one-size-fits-all" HCC screening into individualized precision approaches to early HCC detection and ultimately improve the poor HCC prognosis in the foreseeable future.
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Affiliation(s)
- Yi-Te Lee
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California
| | - Naoto Fujiwara
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California; Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, Los Angeles, California; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
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Nishida N, Ohashi J, Suda G, Chiyoda T, Tamaki N, Tomiyama T, Ogasawara S, Sugiyama M, Kawai Y, Khor SS, Nagasaki M, Fujimoto A, Tsuchiura T, Ishikawa M, Matsuda K, Yano H, Yoshizumi T, Izumi N, Hasegawa K, Sakamoto N, Mizokami M, Tokunaga K. Prediction Model with HLA-A*33:03 Reveals Number of Days to Develop Liver Cancer from Blood Test. Int J Mol Sci 2023; 24:ijms24054761. [PMID: 36902191 PMCID: PMC10003621 DOI: 10.3390/ijms24054761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/23/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
The development of liver cancer in patients with hepatitis B is a major problem, and several models have been reported to predict the development of liver cancer. However, no predictive model involving human genetic factors has been reported to date. For the items incorporated in the prediction model reported so far, we selected items that were significant in predicting liver carcinogenesis in Japanese patients with hepatitis B and constructed a prediction model of liver carcinogenesis by the Cox proportional hazard model with the addition of Human Leukocyte Antigen (HLA) genotypes. The model, which included four items-sex, age at the time of examination, alpha-fetoprotein level (log10AFP) and presence or absence of HLA-A*33:03-revealed an area under the receiver operating characteristic curve (AUROC) of 0.862 for HCC prediction within 1 year and an AUROC of 0.863 within 3 years. A 1000 repeated validation test resulted in a C-index of 0.75 or higher, or sensitivity of 0.70 or higher, indicating that this predictive model can distinguish those at high risk of developing liver cancer within a few years with high accuracy. The prediction model constructed in this study, which can distinguish between chronic hepatitis B patients who develop hepatocellular carcinoma (HCC) early and those who develop HCC late or not, is clinically meaningful.
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Affiliation(s)
- Nao Nishida
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa 272-8516, Japan
- Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
- Correspondence: ; Tel.: +81-473723501
| | - Jun Ohashi
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan
| | - Takehiro Chiyoda
- Hepato-Biliary-Pancreatic Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino 180-8610, Japan
| | - Takahiro Tomiyama
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Sachiko Ogasawara
- Department of Pathology, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Masaya Sugiyama
- Department of Viral Pathogenesis and Controls, National Center for Global Health and Medicine, Ichikawa 272-8516, Japan
| | - Yosuke Kawai
- Genome Medical Science Project-Toyama, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Seik-Soon Khor
- Genome Medical Science Project-Toyama, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Masao Nagasaki
- Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8507, Japan
| | - Akihiro Fujimoto
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0003, Japan
| | - Takayo Tsuchiura
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa 272-8516, Japan
| | - Miyuki Ishikawa
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa 272-8516, Japan
| | - Koichi Matsuda
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 108-8639, Japan
| | - Hirohisa Yano
- Department of Pathology, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino 180-8610, Japan
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan
| | - Masashi Mizokami
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa 272-8516, Japan
| | - Katsushi Tokunaga
- Genome Medical Science Project-Toyama, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
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10
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Wang HW, Chen CY, Lai HC, Hu TH, Su WP, Lu SN, Hung CH, Chuang PH, Wang JH, Chen CH, Peng CY. Prediction model of hepatocellular carcinoma in patients with hepatitis B virus-related compensated cirrhosis receiving antiviral therapy. Am J Cancer Res 2023; 13:526-537. [PMID: 36895986 PMCID: PMC9989609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 01/15/2023] [Indexed: 03/11/2023] Open
Abstract
The feasibility and performance of predicting hepatocellular carcinoma (HCC) using a combined albumin-bilirubin (ALBI) and fibrosis-4 (FIB-4)-based model remain unclear in patients with compensated cirrhosis and chronic hepatitis B (CHB) receiving long-term nucleos(t)ide analog (NA) therapy. We enrolled 1158 NA-naïve patients with compensated cirrhosis and CHB treated with entecavir or tenofovir disoproxil fumarate. The patients' baseline characteristics, hepatic reserve, and fibrosis indices were analyzed. The combination of ALBI and FIB-4 was used to develop a prediction model of HCC. In this cohort, the cumulative incidence rates of HCC at 3, 5, and 10 years were 8.1%, 13.2%, and 24.1%, respectively. The combination of ALBI and FIB-4, Diabetes mellitus, and Alpha-fetoprotein (AFDA) were independent risk factors for HCC. The combined ALBI and FIB-4-based prediction model (i.e., AFDA) stratified the cumulative risk of HCC into three groups (with risk scores of 0, 1-3, 4-6) among all patients (P < 0.001). AFDA exhibited the highest area under the receiver operating characteristic (0.6812) for predicting HCC, which was higher than those of aMAP (0.6591), mPAGE-B (0.6465), CAMD (0.6379), and THRI (0.6356) and significantly higher than those of PAGE-B (0.6246), AASL-HCC (0.6242), and HCC-RESCUE (0.6242). Patients with a total score of 0 (n = 187, 16.1% of total patients) had the lowest cumulative HCC incidence of 3.4% at 5 years. The combined ALBI and FIB-4-based prediction model can stratify the risk of HCC in patients with compensated cirrhosis and CHB receiving NA therapy.
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Affiliation(s)
- Hung-Wei Wang
- Centre for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital Taichung, Taiwan.,School of Medicine, China Medical University Taichung, Taiwan
| | - Chi-Yi Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital Chia-Yi, Taiwan
| | - Hsueh-Chou Lai
- Centre for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital Taichung, Taiwan.,School of Chinese Medicine, China Medical University Taichung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Taiwan
| | - Wen-Pang Su
- Centre for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital Taichung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Taiwan
| | - Po-Heng Chuang
- Centre for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital Taichung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Taiwan
| | - Cheng-Yuan Peng
- Centre for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital Taichung, Taiwan.,School of Medicine, China Medical University Taichung, Taiwan
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11
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Kaneko S, Kurosaki M, Mashiba T, Marusawa H, Kondo M, Kojima Y, Uchida Y, Fujii H, Akahane T, Yagisawa H, Kusakabe A, Kobashi H, Abe T, Yoshida H, Ogawa C, Furuta K, Tamaki N, Tsuji K, Matsushita T, Izumi N. Risk factors for hepatocellular carcinoma at baseline and 1 year after initiation of nucleos(t)ide analog therapy for chronic hepatitis B. J Med Virol 2023; 95:e28210. [PMID: 36222204 DOI: 10.1002/jmv.28210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 10/01/2022] [Accepted: 10/07/2022] [Indexed: 01/11/2023]
Abstract
Nucleos(t)ide analogs (NAs) cannot completely suppress the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study aimed to identify the risk factors for HCC development in naïve CHB patients treated with current NA. Patients receiving NA (n = 905) were recruited retrospectively from the 17 hospitals of the Japanese Red Cross Liver Study Group. All treatment-naïve patients had been receiving current NA continuously for more than 1 year until the end of the follow-up. We analyzed the accuracy of predictive risk score using the area under receiver operating characteristic curve. The albumin-bilirubin (ALBI) score was significantly improved by NA therapy (-0.171 ± 0.396; p < 0.001 at Week 48). A total of 72 (8.0%) patients developed HCC over a median follow-up of 6.2 (1.03-15.7) years. An independent predictive factor of HCC development was older age, cirrhosis, lower platelet counts at baseline and ALBI score, and alpha-fetoprotein (AFP) at 1 year after NA therapy according to multivariate analysis. The accuracy was assessed using the PAGE-B, mPAGE-B, aMAP, APA-B, and REAL-B scores that included these factors. Discrimination was generally acceptable for these models. aMAP and REAL-B demonstrated high discrimination with 0.866/0.862 and 0.833/0.859 for 3- and 5-year prediction from the status of 1 year after NA therapy, respectively. Baseline age and platelet count, as well as ALBI and AFP one year after NA, were useful for stratifying carcinogenesis risk. The aMAP and REAL-B scores were validated with high accuracy in Japanese CHB patients.
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Affiliation(s)
- Shun Kaneko
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Toshie Mashiba
- Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology, Japanese Red Cross Osaka Hospital, Osaka, Japan
| | - Masahiko Kondo
- Department of Gastroenterology, Japanese Red Cross Otsu Hospital, Shiga, Japan
| | - Yuji Kojima
- Department of Gastroenterology, Japanese Red Cross Ise Hospital, Ise, Mie, Japan
| | - Yasushi Uchida
- Department of Gastroenterology, Japanese Red Cross Matsue Hospital, Matsue, Shimane, Japan
| | - Hideki Fujii
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan
| | - Takehiro Akahane
- Department of Gastroenterology, Japanese Red Cross Ishinomaki Hospital, Ishinomaki, Miyagi, Japan
| | - Hitoshi Yagisawa
- Department of Gastroenterology, Japanese Red Cross Akita Hospital, Akita, Japan
| | - Atsunori Kusakabe
- Department of Gastroenterology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan
| | - Haruhiko Kobashi
- Department of Hepatology, Japanese Red Cross Okayama Hospital, Okayama, Japan
| | - Takehiko Abe
- Department of Gastroenterology, Japanese Red Cross Maebashi Hospital, Maebashi, Gunma, Japan
| | - Hideo Yoshida
- Department of Gastroenterology, Japanese Red Cross Medical Center, Tokyo, Japan
| | - Chikara Ogawa
- Department of Gastroenterology, Japanese Red Cross Takamatsu Hospital, Takamatsu, Kagawa, Japan
| | - Koichiro Furuta
- Department of Gastroenterology, Japanese Red Cross Masuda Hospital, Masuda, Shimane, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Keiji Tsuji
- Department of Gastroenterology, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | | | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
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12
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Lee JS, Lim TS, Lee HW, Kim SU, Park JY, Kim DY, Ahn SH, Lee HW, Lee JI, Kim JK, Min IK, Kim BK. Suboptimal Performance of Hepatocellular Carcinoma Prediction Models in Patients with Hepatitis B Virus-Related Cirrhosis. Diagnostics (Basel) 2022; 13:3. [PMID: 36611295 PMCID: PMC9818663 DOI: 10.3390/diagnostics13010003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/14/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
This study aimed to evaluate the predictive performance of pre-existing well-validated hepatocellular carcinoma (HCC) prediction models, established in patients with HBV-related cirrhosis who started potent antiviral therapy (AVT). We retrospectively reviewed the cases of 1339 treatment-naïve patients with HBV-related cirrhosis who started AVT (median period, 56.8 months). The scores of the pre-existing HCC risk prediction models were calculated at the time of AVT initiation. HCC developed in 211 patients (15.1%), and the cumulative probability of HCC development at 5 years was 14.6%. Multivariate Cox regression analysis revealed that older age (adjusted hazard ratio [aHR], 1.023), lower platelet count (aHR, 0.997), lower serum albumin level (aHR, 0.578), and greater LS value (aHR, 1.012) were associated with HCC development. Harrell’s c-indices of the PAGE-B, modified PAGE-B, modified REACH-B, CAMD, aMAP, HCC-RESCUE, AASL-HCC, Toronto HCC Risk Index, PLAN-B, APA-B, CAGE-B, and SAGE-B models were suboptimal in patients with HBV-related cirrhosis, ranging from 0.565 to 0.667. Nevertheless, almost all patients were well stratified into low-, intermediate-, or high-risk groups according to each model (all log-rank p < 0.05), except for HCC-RESCUE (p = 0.080). Since all low-risk patients had cirrhosis at baseline, they had unneglectable cumulative incidence of HCC development (5-year incidence, 4.9−7.5%). Pre-existing risk prediction models for patients with chronic hepatitis B showed suboptimal predictive performances for the assessment of HCC development in patients with HBV-related cirrhosis.
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Affiliation(s)
- Jae Seung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
| | - Tae Seop Lim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Division of Gastroenterology, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University Health System, Gyeonggi-do, Seoul 03722, Republic of Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
| | - Hyun Woong Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Division of Gastroenterology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University Health System, Seoul 06273, Republic of Korea
| | - Jung Il Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Division of Gastroenterology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University Health System, Seoul 06273, Republic of Korea
| | - Ja Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Division of Gastroenterology, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University Health System, Gyeonggi-do, Seoul 03722, Republic of Korea
| | - In Kyung Min
- Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
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13
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A Mac-2 Binding Protein Glycosylation Isomer-Based Risk Model Predicts Hepatocellular Carcinoma in HBV-Related Cirrhotic Patients on Antiviral Therapy. Cancers (Basel) 2022; 14:cancers14205063. [PMID: 36291847 PMCID: PMC9599873 DOI: 10.3390/cancers14205063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/13/2022] [Accepted: 10/14/2022] [Indexed: 11/17/2022] Open
Abstract
Mac-2 binding protein glycosylation isomer (M2BPGi) has not been used in a risk score to predict hepatocellular carcinoma (HCC). We enrolled 1003 patients with chronic hepatitis B and cirrhosis receiving entecavir or tenofovir therapy for more than12 months to construct an HCC risk score. In the development cohort, Cox regression analysis identified male gender, age, platelet count, AFP and M2BPGi levels at 12 months of treatment as independent risk factors of HCC. We developed the HCC risk prediction model, the ASPAM-B score, based on age, sex, platelet count, AFP and M2BPGi levels at 12 months of treatment, with the total scores ranging from 0 to 11.5. This risk model accurately classified patients into low (0−3.5), medium (4−7), and high (>7) risk in the development and validation groups (p < 0.001). The areas under the receiver operating characteristic curve (AUROC) of 3-, 5- and 9-year risks of HCC were 0.742, 0.728 and 0.719, respectively, in the development cohort. All AUROC between the ASPAM-B and APA-B, PAGE-B, RWS-HCC and THRI scores at 3−9 years were significantly different. The M2BPGi-based risk model exhibited good discriminant function in predicting HCC in cirrhotic patients who received long-term antiviral treatment.
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14
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Hsu WF, Lai HC, Chuang PH, Su WP, Chen SH, Chen HY, Wang HW, Huang GT, Peng CY. Posttreatment nonalcoholic fatty liver disease fibrosis scores for predicting liver-related complications in patients with chronic hepatitis C receiving direct-acting antiviral agents. J Viral Hepat 2022; 29:785-794. [PMID: 35657121 DOI: 10.1111/jvh.13715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 05/10/2022] [Accepted: 05/25/2022] [Indexed: 12/09/2022]
Abstract
Patients with chronic hepatitis C (CHC) have a higher prevalence of hepatic steatosis and dyslipidaemia than healthy individuals. We analysed noninvasive fibrosis assessments, especially nonalcoholic fatty liver disease (NAFLD)-related noninvasive fibrosis tests, for predicting liver-related complications and hepatocellular carcinoma (HCC) occurrence in patients with CHC. This retrospective study enrolled 590 consecutive patients with CHC having a sustained virologic response (SVR) to direct-acting antiviral agent (DAA) therapy. The NAFLD fibrosis score (NFS) exhibiting the highest value of area under the receiver operating characteristic curve (AUROC) was selected for comparison with the fibrosis-4 index (FIB-4). Of the 590 patients, 188 had metabolic syndrome. A multivariate Cox regression analysis identified total bilirubin at 3 or 6 months after DAA therapy (PW12), NFS at PW12 (hazard ratio [HR]: 2.125, 95% confidence interval [CI]: 1.058-4.267, p = .034) and alpha-fetoprotein (AFP) at PW12 (HR: 1.071, 95% CI: 1.005-1.142, p = .034) as the independent predictors of liver-related complications in all patients. In patients with metabolic syndrome, NFS and AFP values at PW12 were independent predictors of liver-related complications and HCC occurrence. Time-dependent NFS AUROC values at PW12 for 1-, 2- and 3-year liver-related complications were higher than NFS values at baseline in patients with metabolic syndrome. NFS at baseline or PW12 is a more effective predictor of liver-related complications than FIB-4 values in all patients. NFS at PW12 may be a useful predictor of liver-related complications and HCC development in patients with CHC with an SVR to DAA therapy, especially in those with metabolic syndrome.
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Affiliation(s)
- Wei-Fan Hsu
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.,School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Hsueh-Chou Lai
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Po-Heng Chuang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Wen-Pang Su
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Sheng-Hung Chen
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Medicine, China Medical University, Taichung, Taiwan
| | - Hung-Yao Chen
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Hung-Wei Wang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Medicine, China Medical University, Taichung, Taiwan
| | - Guan-Tarn Huang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Medicine, China Medical University, Taichung, Taiwan
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Medicine, China Medical University, Taichung, Taiwan
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15
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Poynard T, Lacombe JM, Deckmyn O, Peta V, Akhavan S, Zoulim F, de Ledinghen V, Samuel D, Mathurin P, Ratziu V, Thabut D, Housset C, Fontaine H, Pol S, Carrat F. External Validation of LCR1-LCR2, a Multivariable Hepatocellular Carcinoma Risk Calculator, in a Multiethnic Cohort of Patients With Chronic Hepatitis B. GASTRO HEP ADVANCES 2022; 1:604-617. [PMID: 39132068 PMCID: PMC11308549 DOI: 10.1016/j.gastha.2022.02.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 02/09/2022] [Indexed: 08/13/2024]
Abstract
Background and Aims The liver cancer risk test (LCR1-LCR2) is a multianalyte blood test combining proteins involved in liver cell repair (apolipoprotein A1, haptoglobin), hepatocellular carcinoma (HCC) risk factors (gender, age, gamma glutamyl transpeptidase), a marker of fibrosis (alpha2-macroglobulin), and alpha-fetoprotein, a specific marker of HCC. The aim was to externally validate LCR1-LCR2 in hepatitis B. Methods Preincluded patients were from the Hepather cohort, a multicenter, multiethnic prospective study in 6071 patients. The coprimary study outcome was the negative predictive value of LCR1-LCR2 at 5 years for the occurrence of HCC and survival without HCC according to the predetermined LCR1-LCR2 cutoffs, adjusted for risk covariables and for chronic hepatitis B treatment and quantified using time-dependent Cox proportional hazards models. A post hoc analysis compared the number of patients needed to screen one cancer by LCR1-LCR2 and PAGE-B. Results A total of 3520 patients, 191 (5.4%) with cirrhosis, with at least 1 year of follow-up were included. A total of 76 HCCs occurred over a median (interquartile range) of 6.0 years (4.8-7.3) of follow-up. Among the 3367 patients with low-risk LCR1-LCR2, the 5-year negative predictive value was 99.3% (95% confidence interval = 99.0-99.6), with a significant Cox hazard ratio (6.4, 3.1-13.0; P < .001) obtained after adjustment for exposure to antivirals, age, gender, geographical origin, HBe-Ag status, alcohol consumption, and type-2 diabetes. LCR1-LCR2 outperformed PAGE-B for number of patients needed to screen mean (95% CI), 8.5 (3.2-8.1) vs 26.3 (17.5-38.5; P < .0001), respectively. Conclusion The performance of LCR1-LCR2 to identify patients with chronic hepatitis B at very low risk of HCC at 5 years was externally validated. ClinicalTrials.gov: NCT01953458.
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Affiliation(s)
- Thierry Poynard
- Department of Hepato-Gastroenterology, Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Paris, France
- INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Paris, France
| | - Jean Marc Lacombe
- INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, Sorbonne Université, Paris, France
| | | | - Valentina Peta
- INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Paris, France
- Research Unit, BioPredictive, Paris, France
| | - Sepideh Akhavan
- Department of Hepato-Gastroenterology, Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Paris, France
| | - Fabien Zoulim
- Hepatology Unit Hôpital Haut-Lévêque, Pessac, and INSERM U1053, Université Bordeaux Segalen, Bordeaux, France
| | - Victor de Ledinghen
- Department of Hepatology, Hospices civils de Lyon, Hôpital Croix Rousse, INSERM U1052, Université de Lyon, Lyon, France
| | - Didier Samuel
- Hepatology Department, AP-HP, Hospital Paul Brousse, UMR-S1193, Villejuif, Université Paris-Saclay, and Hepatinov, Villejuif, France
| | | | - Vlad Ratziu
- Department of Hepato-Gastroenterology, Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Paris, France
- INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Paris, France
| | - Dominique Thabut
- Department of Hepato-Gastroenterology, Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Paris, France
- INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Paris, France
| | - Chantal Housset
- INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Paris, France
| | - Hélène Fontaine
- Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Hepato-Gastroenterology, AP-HP, Hôpital Cochin, Hepatology Department, Paris, France
| | - Stanislas Pol
- Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Hepato-Gastroenterology, AP-HP, Hôpital Cochin, Hepatology Department, Paris, France
| | - Fabrice Carrat
- INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, Sorbonne Université, Paris, France
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16
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Hepatitis B Virus-Associated Hepatocellular Carcinoma. Viruses 2022; 14:v14050986. [PMID: 35632728 PMCID: PMC9146458 DOI: 10.3390/v14050986] [Citation(s) in RCA: 89] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/02/2022] [Accepted: 05/03/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) is DNA-based virus, member of the Hepadnaviridae family, which can cause liver disease and increased risk of hepatocellular carcinoma (HCC) in infected individuals, replicating within the hepatocytes and interacting with several cellular proteins. Chronic hepatitis B can progressively lead to liver cirrhosis, which is an independent risk factor for HCC. Complications as liver decompensation or HCC impact the survival of HBV patients and concurrent HDV infection worsens the disease. The available data provide evidence that HBV infection is associated with the risk of developing HCC with or without an underlying liver cirrhosis, due to various direct and indirect mechanisms promoting hepatocarcinogenesis. The molecular profile of HBV-HCC is extensively and continuously under study, and it is the result of altered molecular pathways, which modify the microenvironment and lead to DNA damage. HBV produces the protein HBx, which has a central role in the oncogenetic process. Furthermore, the molecular profile of HBV-HCC was recently discerned from that of HDV-HCC, despite the obligatory dependence of HDV on HBV. Proper management of the underlying HBV-related liver disease is fundamental, including HCC surveillance, viral suppression, and application of adequate predictive models. When HBV-HCC occurs, liver function and HCC characteristics guide the physician among treatment strategies but always considering the viral etiology in the treatment choice.
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17
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Kubota N, Fujiwara N, Hoshida Y. Liver cancer risk-predictive molecular biomarkers specific to clinico-epidemiological contexts. Adv Cancer Res 2022; 156:1-37. [PMID: 35961696 PMCID: PMC7616039 DOI: 10.1016/bs.acr.2022.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Hepatocellular carcinoma (HCC) risk prediction is increasingly important because of the low annual HCC incidence in patients with the rapidly emerging non-alcoholic fatty liver disease or cured HCV infection. To date, numerous clinical HCC risk biomarkers and scores have been reported in literature. However, heterogeneity in clinico-epidemiological context, e.g., liver disease etiology, patient race/ethnicity, regional environmental exposure, and lifestyle-related factors, obscure their real clinical utility and applicability. Proper characterization of these factors will help refine HCC risk prediction according to certain clinical context/scenarios and contribute to improved early HCC detection. Molecular factors underlying the clinical heterogeneity encompass various features in host genetics, hepatic and systemic molecular dysregulations, and cross-organ interactions, which may serve as clinical-context-specific biomarkers and/or therapeutic targets. Toward the goal to enable individual-risk-based HCC screening by incorporating the HCC risk biomarkers/scores, their assessment in patient with well-defined clinical context/scenario is critical to gauge their real value and to maximize benefit of the tailored patient management for substantial improvement of the poor HCC prognosis.
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Affiliation(s)
- Naoto Kubota
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Naoto Fujiwara
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States; Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States.
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18
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Comparative performance of risk prediction models for hepatitis B-related hepatocellular carcinoma in the United States. J Hepatol 2022; 76:294-301. [PMID: 34563579 PMCID: PMC8786210 DOI: 10.1016/j.jhep.2021.09.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 08/24/2021] [Accepted: 09/03/2021] [Indexed: 01/29/2023]
Abstract
BACKGROUND & AIMS Guidelines recommend hepatocellular carcinoma (HCC) surveillance in patients with chronic HBV infection. Several HCC risk prediction models are available to guide surveillance decisions, but their comparative performance remains unclear. METHODS Using a retrospective cohort of patients with HBV treated with nucleos(t)ide analogues at 130 Veterans Administration facilities between 9/1/2008 and 12/31/2018, we calculated risk scores from 10 HCC risk prediction models (REACH-B, PAGE-B, m-PAGE-B, CU-HCC, HCC-RESCUE, CAMD, APA-B, REAL-B, AASL-HCC, RWS-HCC). We estimated the models' discrimination and calibration. We calculated HCC incidence in risk categories defined by the reported cut-offs for all models. RESULTS Of 3,101 patients with HBV (32.2% with cirrhosis), 47.0% were treated with entecavir, 40.6% tenofovir, and 12.4% received both. During a median follow-up of 4.5 years, 113 patients developed HCC at an incidence of 0.75/100 person-years. AUC values for 3-year HCC risk were the highest for RWS-HCC, APA-B, REAL-B, and AASL-HCC (all >0.80). Of these, 3 (APA-B, RWS-HCC, REAL-B) incorporated alpha-fetoprotein. AUC values for the other models ranged from 0.73 for PAGE-B to 0.79 for CAMD and HCC-RESCUE. Of the 7 models with AUC >0.75, only APA-B was poorly calibrated. In total, 10-20% of the cohort was deemed low-risk based on the published cut-offs. None of the patients in the low-risk groups defined by PAGE-B, m-PAGE-B, AASL-HCC, and REAL-B developed HCC during the study timeframe. CONCLUSION In this national cohort of US-based patients with HBV on antiviral treatment, most models performed well in predicting HCC risk. A low-risk group, in which no cases of HCC occurred within a 3-year timeframe, was identified by several models (PAGE-B, m-PAGE-B, CAMD, AASL-HCC, REAL-B). Further studies are warranted to examine whether these patients could be excluded from HCC surveillance. LAY SUMMARY Risk prediction models for hepatocellular carcinoma (HCC) in patients infected with hepatitis B virus (HBV) could guide HCC surveillance decisions. In this large cohort of US-based patients receiving treatment for HBV, most published models discriminated between those who did or did not develop HCC, although the RWS-HCC, REAL-B, and AASL-HCC performed the best. If confirmed in future studies, these models could help identify a low-risk subset of patients on antiviral treatment who could be excluded from HCC surveillance.
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19
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Yu JH, Cho SG, Jin YJ, Lee JW. The best predictive model for hepatocellular carcinoma in patients with chronic hepatitis B infection. Clin Mol Hepatol 2021; 28:351-361. [PMID: 34823308 PMCID: PMC9293610 DOI: 10.3350/cmh.2021.0281] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/25/2021] [Indexed: 11/06/2022] Open
Abstract
Chronic hepatitis B (CHB) seriously threatens human health. About 820,000 deaths annually are due to related complications such as hepatitis B and hepatocellular carcinoma (HCC). Recently, the use of oral antiviral agents has significantly improved the prognosis of patients with CHB infection and reduced the risk of HCC. However, hepatitis B virus still remains a major factor in the development of HCC, raising many concerns. Therefore, numerous studies have been conducted to assess the risk of HCC in patients with CHB infection and many models have been proposed to predict the risk of developing HCC. However, as each study has different models for predicting HCC development that can be applied depending on the use of antiviral agents or the type of antiviral agents, it is necessary to properly understand characteristics of each model when using it for the evaluation of HCC in patients with CHB infection. In addition, because different variables such as host factor, viral activity, and cirrhosis are used to evaluate the risk of HCC development, it is necessary to assess the risk by carefully verifying which variables are used. Recently, studies have also evaluated the risk of HCC using risk prediction models through transient elastography and artificial intelligence (AI) system. These HCC risk predication models are also noteworthy. In this review, we aimed to compare HCC risk prediction models in patients with CHB infection reported to date to confirm variables used and specificity between each model to determine an appropriate HCC risk prediction method.
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Affiliation(s)
- Jung Hwan Yu
- Department of Internal Medicine, Inha University Hospital and School of Medicine, Incheon, South Korea
| | - Soon Gu Cho
- Department of Radiology, Inha University Hospital and School of Medicine, Incheon, South Korea
| | - Young-Joo Jin
- Department of Internal Medicine, Inha University Hospital and School of Medicine, Incheon, South Korea
| | - Jin-Woo Lee
- Department of Internal Medicine, Inha University Hospital and School of Medicine, Incheon, South Korea
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20
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Zhang X, Guan L, Tian H, Zeng Z, Chen J, Huang D, Sun J, Guo J, Cui H, Li Y. Risk Factors and Prevention of Viral Hepatitis-Related Hepatocellular Carcinoma. Front Oncol 2021; 11:686962. [PMID: 34568017 PMCID: PMC8458967 DOI: 10.3389/fonc.2021.686962] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 08/20/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common cancer in the world, and its incidence is increasing yearly. Hepatitis B virus (HBV) infection and hepatitis C virus (HCV) infection are important causes of HCC. Liver cirrhosis, age, sex, smoking and drinking, and metabolic risk factors will increase the risk of cancer in HBV/HCV patients. And viral load, APRI, FIB-4, and liver stiffness can all predict the risk of HCC in patients with viral infection. In addition, effective prevention strategies are essential in reducing the risk of HCC. The prevention of HCC involves mainly tertiary prevention strategies, while the primary prevention is based on standardized vaccine injections to prevent the occurrence of HBV/HCV. Eliminating the route of transmission and vaccination will lead to a decrease in the incidence of HCC. Secondary prevention involves effective antiviral treatment of HBV/HCV to prevent the disease from progressing to HCC, and tertiary prevention is actively treating HCC to prevent its recurrence.
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Affiliation(s)
- Xinhe Zhang
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Lin Guan
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Haoyu Tian
- The 3rd Clinical Department of China Medical University, Shenyang, China
| | - Zilu Zeng
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jiayu Chen
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Die Huang
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Ji Sun
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jiaqi Guo
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Huipeng Cui
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yiling Li
- Gastroenterology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
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21
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Demirtas CO, Brunetto MR. Surveillance for hepatocellular carcinoma in chronic viral hepatitis: Is it time to personalize it? World J Gastroenterol 2021; 27:5536-5554. [PMID: 34588750 PMCID: PMC8433616 DOI: 10.3748/wjg.v27.i33.5536] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 04/28/2021] [Accepted: 08/02/2021] [Indexed: 02/06/2023] Open
Abstract
Surveillance with abdominal ultrasound with or without alpha-fetoprotein is recommended by clinical practice guidelines for patients who are considered to be at risk of developing hepatocellular carcinoma (HCC), including those with cirrhosis, advanced fibrosis and special subgroups of chronic hepatitis B (CHB). Application of the standard surveillance strategy to all patients with chronic liver disease (CLD) with or without cirrhosis imposes major sustainability and economic burdens on healthcare systems. Thus, a number of HCC risk scores were constructed, mainly from Asian cohorts, to stratify the HCC prediction in patients with CHB. Similarly, even if less than for CHB, a few scoring systems were developed for chronic hepatitis C patients or cirrhotic patients with CLD of different etiologies. Recently, a few newsworthy HCC-risk algorithms were developed for patients with cirrhosis using the combination of serologic HCC markers and clinical parameters. Overall, the HCC risk stratification appears at hand by several validated multiple score systems, but their optimal performance is obtained only in populations who show highly homogenous clinic-pathologic, epidemiologic, etiologic and therapeutic characteristics and this limitation poses a major drawback to their sustainable use in clinical practice. A better understanding of the dynamic process driving the progression from CLD to HCC derived from studies based on molecular approaches and genetics, epigenetics and liquid biopsy will enable the identification of new biomarkers to define the individual risk of HCC in the near future, with the possibility to achieve a real and cost/effective personalization of surveillance.
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Affiliation(s)
- Coskun Ozer Demirtas
- Department of Gastroenterology and Hepatology, Marmara University, School of Medicine, Istanbul 34854, Turkey
| | - Maurizia Rossana Brunetto
- Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa 56125, Italy
- Hepatology Unit, University Hospital of Pisa, Pisa 56125, Italy
- Biostructure and Bio-imaging Institute, National Research Council of Italy, Naples 56125, Italy
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22
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Hsu YC, Tseng CH, Huang YT, Yang HI. Application of Risk Scores for Hepatocellular Carcinoma in Patients with Chronic Hepatitis B: Current Status and Future Perspective. Semin Liver Dis 2021; 41:285-297. [PMID: 34161993 DOI: 10.1055/s-0041-1730924] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Accurate risk prediction for hepatocellular carcinoma (HCC) among patients with chronic hepatitis B (CHB) may guide treatment strategies including initiation of antiviral therapy and also inform implementation of HCC surveillance. There have been 26 risk scores developed to predict HCC in CHB patients with (n = 14) or without (n = 12) receiving antiviral treatment; all of them invariably include age in the scoring formula. Virological biomarkers of replicative activities (i.e., hepatitis B virus DNA level or hepatitis B envelope antigen status) are frequently included in the scores derived from patients with untreated CHB, whereas measurements that gauge severity of liver fibrosis and/or reserve of hepatic function (i.e., cirrhosis diagnosis, liver stiffness measurement, platelet count, or albumin) are essential components in the scores developed from treated patients. External validation is a prerequisite for clinical application but not yet performed for all scores. For the future, higher predictive accuracy may be achieved with machine learning based on more comprehensive data.
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Affiliation(s)
- Yao-Chun Hsu
- Center for Liver Diseases, E-Da Hospital, Kaohsiung, Taiwan.,School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan.,Department of Medicine, Fu-Jen Catholic University Hospital, New Taipei, Taiwan.,Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan
| | - Cheng-Hao Tseng
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan.,Division of Gastroenterology and Hepatology, E-Da Cancer Hospital, Kaohsiung, Taiwan
| | - Yen-Tsung Huang
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan
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23
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Lok J, Agarwal K. Screening for Hepatocellular Carcinoma in Chronic Hepatitis B: An Update. Viruses 2021; 13:v13071333. [PMID: 34372539 PMCID: PMC8309969 DOI: 10.3390/v13071333] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 06/27/2021] [Accepted: 07/06/2021] [Indexed: 11/24/2022] Open
Abstract
(1) Background: Hepatocellular carcinoma (HCC) is an important cause of mortality in individuals with chronic hepatitis B infection, with screening of high-risk groups recommended in all major international guidelines. Our understanding of the risk factors involved has improved over time, encouraging researchers to develop models that predict future risk of HCC development. (2) Methods: A literature search of the PubMed database was carried out to identify studies that derive or validate models predicting HCC development in patients with chronic hepatitis B. Subsequently, a second literature search was carried out to explore the potential role of novel viral biomarkers in this field. (3) Results: To date, a total of 23 models have been developed predicting future HCC risk, of which 12 have been derived from cohorts of treatment-naïve individuals. Most models have been developed in Asian populations (n = 20), with a smaller number in Caucasian cohorts (n = 3). All of the models demonstrate satisfactory performance in their original derivation cohorts, but many lack external validation. In recent studies, novel viral biomarkers have demonstrated utility in predicting HCC risk in patients with chronic hepatitis B, amongst both treated and treatment-naïve patients. (4) Conclusion: Several models have been developed to predict the risk of HCC development in individuals with chronic hepatitis B infection, but many have not been externally validated outside of the Asian population. Further research is needed to refine these models and facilitate a more tailored HCC surveillance programme in the future.
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Affiliation(s)
- James Lok
- Department of Gastroenterology, St. George’s Hospital, London SW17 0QT, UK
- Correspondence:
| | - Kosh Agarwal
- Institute of Liver Studies, King’s College Hospital, London SE5 9RS, UK;
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24
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Sachar Y, Brahmania M, Dhanasekaran R, Congly SE. Screening for Hepatocellular Carcinoma in Patients with Hepatitis B. Viruses 2021; 13:1318. [PMID: 34372524 PMCID: PMC8310362 DOI: 10.3390/v13071318] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/05/2021] [Accepted: 07/05/2021] [Indexed: 12/18/2022] Open
Abstract
Chronic hepatitis B (CHB) infection is a significant risk factor for developing hepatocellular carcinoma (HCC). As HCC is associated with significant morbidity and mortality, screening patients with CHB at a high risk for HCC is recommended in an attempt to improve these outcomes. However, the screening recommendations on who to screen and how often are not uniform. Identifying patients at the highest risk of HCC would allow for the best use of health resources. In this review, we evaluate the literature on screening patients with CHB for HCC, strategies for optimizing adherence to screening, and potential risk stratification tools to identify patients with CHB at a high risk of developing HCC.
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Affiliation(s)
- Yashasavi Sachar
- London Health Sciences Center, Department of Medicine, Division of Gastroenterology, Western University, London, ON N6A 5A5, Canada; (Y.S.); (M.B.)
| | - Mayur Brahmania
- London Health Sciences Center, Department of Medicine, Division of Gastroenterology, Western University, London, ON N6A 5A5, Canada; (Y.S.); (M.B.)
- Centre for Quality, Innovation and Safety, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5W9, Canada
| | - Renumathy Dhanasekaran
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA 94305, USA;
| | - Stephen E. Congly
- Department of Medicine, Division of Gastroenterology and Hepatology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada
- O’Brien Institute of Public Health, University of Calgary, Calgary, AB T2N 4Z6, Canada
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25
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Ahn SB, Choi J, Jun DW, Oh H, Yoon EL, Kim HS, Jeong SW, Kim SE, Shim JJ, Cho YK, Lee HY, Han SW, Nguyen MH. Twelve-month post-treatment parameters are superior in predicting hepatocellular carcinoma in patients with chronic hepatitis B. Liver Int 2021; 41:1652-1661. [PMID: 33550661 DOI: 10.1111/liv.14820] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 01/25/2021] [Accepted: 01/26/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS There are currently several prediction models for hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) receiving oral antiviral therapy. However, most models are based on pre-treatment clinical parameters. The current study aimed to develop a novel and practical prediction model for HCC by using both pre- and post-treatment parameters in this population. METHODS We included two treatment-naïve CHB cohorts who were initiated on oral antiviral therapies: the derivation cohort (n = 1480, Korea prospective SAINT cohort) and the validation cohort (n = 426, the US retrospective Stanford Bay cohort). We employed logistic regression, decision tree, lasso regression, support vector machine and random forest algorithms to develop the HCC prediction model and selected the most optimal method. RESULTS We evaluated both pre-treatment and the 12-month clinical parameters on-treatment and found the 12-month on-treatment values to have superior HCC prediction performance. The lasso logistic regression algorithm using the presence of cirrhosis at baseline and alpha-foetoprotein and platelet at 12 months showed the best performance (AUROC = 0.843 in the derivation cohort. The model performed well in the external validation cohort (AUROC = 0.844) and better than other existing prediction models including the APA, PAGE-B and GAG models (AUROC = 0.769 to 0.818). CONCLUSIONS We provided a simple-to-use HCC prediction model based on presence of cirrhosis at baseline and two objective laboratory markers (AFP and platelets) measured 12 months after antiviral initiation. The model is highly accurate with excellent validation in an external cohort from a different country (AUROC 0.844) (Clinical trial number: KCT0003487).
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Affiliation(s)
- Sang Bong Ahn
- Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University College of Medicine, Seoul, South Korea
| | - Jun Choi
- Department of Fusion Data Analytics, School of Industrial Management Engineering, Korea University, Seoul, South Korea
| | - Dae Won Jun
- Department of Internal Medicine, College of Medicine, Hanyang University, Seoul, South Korea
| | - Hyunwoo Oh
- Department of Internal Medicine, Uijeongbu Eulji Medical Center, Eulji University College of Medicine, Gyeonggi-do, South Korea
| | - Eileen L Yoon
- Department of Internal Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, South Korea
| | - Hyoung Su Kim
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Soonchunhyang University Seoul Hospital, Seoul, South Korea
| | - Sung Eun Kim
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang-si, South Korea
| | - Jae-Jun Shim
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, South Korea
| | - Yong Kyun Cho
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hyo Young Lee
- Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University College of Medicine, Seoul, South Korea
| | - Sung Won Han
- Department of Biostatistical Consulting and Research Lab, School of Medicine, Korea University, Seoul, South Korea
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
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26
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Peng CY, Chen CH. On-treatment predictors of hepatocellular carcinoma in patients with chronic hepatitis B. Liver Int 2021; 41:1700-1701. [PMID: 33966332 DOI: 10.1111/liv.14934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Affiliation(s)
- Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Medicine, China Medical University, Taichung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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27
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Guo J, Gao XS. Prediction models for development of hepatocellular carcinoma in chronic hepatitis B patients. World J Clin Cases 2021; 9:3238-3251. [PMID: 34002133 PMCID: PMC8107908 DOI: 10.12998/wjcc.v9.i14.3238] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/11/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) is a major health problem in Asian-Pacific regions. Antiviral therapy reduces, but does not completely prevent, HCC development. Thus, there is a need for accurate risk prediction to assist prognostication and decisions on the need for antiviral therapy and HCC surveillance. A few risk scores have been developed to predict the occurrence of HCC in CHB patients. Initially, the scores were derived from untreated CHB patients. With the development and extensive clinical application of nucleos(t)ide analog(s) (NA), the number of risk scores based on treated CHB patients has increased gradually. The components included in risk scores may be categorized into host factors and hepatitis B virus factors. Hepatitis activities, hepatitis B virus factors, and even liver fibrosis or cirrhosis are relatively controlled by antiviral therapy. Therefore, variables that are more dynamic during antiviral therapy have since been included in risk scores. However, host factors are more difficult to modify. Most existing scores derived from Asian populations have been confirmed to be accurate in predicting HCC development in CHB patients from Asia, while these scores have not offered excellent predictability in Caucasian patients. These findings support that more relevant variables should be considered to provide individualized predictions that are easily applied to CHB patients of different ethnicities. CHB patients should receive different intensities of HCC surveillance according to their risk category.
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Affiliation(s)
- Jiang Guo
- Department of Interventional Oncology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xue-Song Gao
- Department of General Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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28
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Tseng TC, Choi J, Nguyen MH, Peng CY, Siakavellas S, Papatheodoridis G, Wang CC, Lim YS, Lai HC, Trinh HN, Wong C, Wong C, Zhang J, Li J, Kao JH. One-year Fibrosis-4 index helps identify minimal HCC risk in non-cirrhotic chronic hepatitis B patients with antiviral treatment. Hepatol Int 2021; 15:105-113. [PMID: 33547557 PMCID: PMC7863859 DOI: 10.1007/s12072-020-10124-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 12/15/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Fibrosis-4 (FIB-4) index is a HCC predictor in chronic hepatitis B (CHB) patients. However, little is known about whether FIB-4 helps identify non-cirrhotic CHB patients with minimal HCC risk after prolonged nucleos(t)ide analogue (NA) therapy. METHODS A total of 1936 ethnically diverse, non-cirrhotic CHB patients were enrolled in this retrospective multi-national study. All patients received prolonged NA treatment, including entecavir and tenofovir disoproxil fumarate. We explored whether FIB-4 cutoff of 1.30, a marker indicative of mild fibrosis severity, could stratify HCC risks in these patients. RESULTS A total of 48 patients developed HCC after a mean follow-up of 6.98 years. FIB-4 level at 1 year after treatment (1-year FIB-4) was shown to be associated with HCC development and was superior to pre-treatment FIB-4 value. When patients were stratified by 1-year FIB-4 of 1.30, the high FIB-4 group was at an increased HCC risk compared to the low FIB-4 group, with a hazard ratio of 4.87 (95% confidence interval: 2.48-9.55). Multivariable analysis showed that sex and 1-year FIB-4 were independent predictors, with none of the 314 female patients with low 1-year FIB-4 developing HCC. Finally, 1-year FIB-4 of 1.30 consistently stratified HCC risks in patients with low PAGE-B score, a score composed of baseline age, sex and platelet count, and the annual incidence rate of HCC was 0.11% in those with PAGE-B < 10 + 1-year FIB-4 < 1.30. CONCLUSIONS In non-cirrhotic CHB patients receiving prolonged NA therapy, 1-year FIB-4 < 1.30 is useful for identifying those with minimal HCC risk by combining with female sex or low PAGE-B score.
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Affiliation(s)
- Tai-Chung Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te St, Taipei, 10002, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
| | - Cheng-Yuan Peng
- School of Medicine, China Medical University, Taizhong, Taiwan
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taizhong, Taiwan
| | - Spyros Siakavellas
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
| | - George Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
| | - Chia-Chi Wang
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, New Taipei City, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hsueh-Chou Lai
- School of Medicine, China Medical University, Taizhong, Taiwan
| | - Huy N Trinh
- San Jose Gastroenterology, San Jose, CA, USA
| | | | | | - Jian Zhang
- Chinese Hospital, San Francisco, CA, USA
| | - Jiayi Li
- Gastroenterology, Palo Alto Medical Foundation, Mountain View, CA, USA
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te St, Taipei, 10002, Taiwan.
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
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Stratification of Hepatocellular Carcinoma Risk Following HCV Eradication or HBV Control. J Clin Med 2021; 10:jcm10020353. [PMID: 33477752 PMCID: PMC7832303 DOI: 10.3390/jcm10020353] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/07/2021] [Accepted: 01/13/2021] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) incidence has dramatically decreased in patients infected with HCV and HBV due to the widespread use of highly effective antiviral agents. Nevertheless, a substantial proportion of patients with advanced fibrosis or cirrhosis following HCV clearance of in case of HBV control whatever the stage of fibrosis remains at risk of liver cancer development. Cancer predictors in these virus-free patients include routine parameters estimating coexisting comorbidities, persisting liver inflammation or function impairment, and results of non-invasive tests which can be easily combined into HCC risk scoring systems. The latter enables stratification according to various liver cancer incidences and allocation of patients into low, intermediate or high HCC risk probability groups. All international guidelines endorse lifelong surveillance of these patients using semi-annual ultrasound, with known sensibility issues. Refining HCC prediction in this growing population ultimately will trigger personalized management using more effective surveillance tools such as contrast-enhanced imaging techniques or circulating biomarkers while taking into account cost-effectiveness parameters.
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Chang JW, Lee JS, Lee HW, Kim BK, Park JY, Kim DY, Ahn SH, Seo YS, Lee HA, Kim MN, Lee YR, Hwang SG, Rim KS, Um SH, Tak WY, Kweon YO, Park SY, Kim SU. Validation of risk prediction scores for hepatocellular carcinoma in patients with chronic hepatitis B treated with entecavir or tenofovir. J Viral Hepat 2021; 28:95-104. [PMID: 33029863 DOI: 10.1111/jvh.13411] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/11/2020] [Accepted: 08/23/2020] [Indexed: 12/15/2022]
Abstract
Several prediction scores for the early detection of hepatocellular carcinoma (HCC) are available. We validated the predictive accuracy of age, albumin, sex, liver cirrhosis (AASL), RESCUE-B, PAGE-B and modified PAGE-B (mPAGE-B) scores in chronic hepatitis B (CHB) patients treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF). Between 2007 and 2014, 3171 patients were recruited (1645, ETV; 1517, TDF). The predictive accuracy of each prediction score was assessed. The mean age of the study population (1977 men; 1194 women) was 48.8 years. Liver cirrhosis was present in 1040 (32.8%) patients. During follow-up (median, 58.2 months), 280 (8.8%) patients developed HCC; these patients were significantly older; more likely to be male; had significantly higher proportions of liver cirrhosis, hypertension and diabetes; and had significantly higher values for the four risk scores than those who did not develop HCC (all P < .05). Older age (hazard ratio [HR] = 1.048), male sex (HR = 2.142), liver cirrhosis (HR = 3.144) and prolonged prothrombin time (HR = 2.589) were independently associated with an increased risk of HCC (all P < .05), whereas a higher platelet count (HR = 0.996) was independently associated with a decreased risk of HCC (P < .05). The predictive accuracy of AASL score was the highest for 3- and 5-year HCC predictions (areas under the curve [AUCs] = 0.818 and 0.816, respectively), followed by RESCUE-B, PAGE-B and mPAGE-B scores (AUC = 0.780-0.815 and 0.769-0.814, respectively). In conclusion, four HCC prediction scores were assessed in Korean CHB patients treated with ETV or TDF. The AASL score showed the highest predictive accuracy.
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Affiliation(s)
- Jin Won Chang
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Seung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Yeon Seok Seo
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Han Ah Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Mi Na Kim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Yu Rim Lee
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea
| | - Seong Gyu Hwang
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Kyu Sung Rim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Soon Ho Um
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Won Young Tak
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea
| | - Young Oh Kweon
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea
| | - Soo Young Park
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
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Papatheodoridis GV, Voulgaris T, Papatheodoridi M, Kim WR. Risk Scores for Hepatocellular Carcinoma in Chronic Hepatitis B: A Promise for Precision Medicine. Hepatology 2020; 72:2197-2205. [PMID: 32602980 DOI: 10.1002/hep.31440] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/13/2020] [Accepted: 06/15/2020] [Indexed: 02/06/2023]
Affiliation(s)
- George V Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greeces
| | - Thodoris Voulgaris
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greeces
| | - Margarita Papatheodoridi
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greeces
| | - W Ray Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA
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Frager SZ, Schwartz JM. Hepatocellular carcinoma: epidemiology, screening, and assessment of hepatic reserve. ACTA ACUST UNITED AC 2020; 27:S138-S143. [PMID: 33343207 DOI: 10.3747/co.27.7181] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma is a leading cause of cancer-related mortality worldwide. This review summarizes the epidemiology and causes of the disease, and the roles of screening and surveillance for early tumour detection. It also highlights the important role of assessment of hepatic reserve in consideration of appropriate staging and treatment.
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Affiliation(s)
- S Z Frager
- Division of Hepatology, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, U.S.A
| | - J M Schwartz
- Division of Hepatology, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, U.S.A
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Tseng CH, Tseng CM, Wu JL, Hsu YC, El-Serag HB. Magnitude of and prediction for risk of hepatocellular carcinoma in patients with chronic hepatitis B taking entecavir or tenofovir therapy: A systematic review. J Gastroenterol Hepatol 2020; 35:1684-1693. [PMID: 32343431 DOI: 10.1111/jgh.15078] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 04/01/2020] [Accepted: 04/23/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) have been shown to reduce incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This systematic review aims to evaluate the magnitude, change over time, and prediction of residual HCC risks in CHB patients treated with ETV/TDF therapy. METHODS Available literature was systematically reviewed through searches of PubMed and EMBASE databases from January 1, 2006 to September 1, 2019, to identify cohort studies that reported HCC incidence in CHB patients during ETV/TDF therapy. Studies were screened by title and abstract and then evaluated for eligibility in terms of full text. RESULTS We identified 141 studies for full-text review, and 34 were eligible for analysis. From 19 studies with data separated by cirrhosis status, the 5-year cumulative incidence of HCC was 0.5-6.9% in patients without cirrhosis, 4.5-21.6% in compensated cirrhosis, and 36.3-46.5% in decompensated cirrhosis. All four studies that addressed temporal changes in HCC risks consistently found the incidence rate decreased over time in patients with cirrhosis, although the findings were inconsistent in patients without cirrhosis. Six predictive scores were developed and validated to predict incident HCC during ETV/TDF therapy in CHB patients. Common scoring variables included age, sex, cirrhosis (fibrosis grade), and hepatic function. Conflicting results were reported in seven individual studies and two meta-analyses that compared ETV versus TDF. CONCLUSIONS The residual risk of HCC remains during ETV/TDF treatment in CHB patients with cirrhosis but declines over time. Risk stratification is attainable by validated predictive scores.
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Affiliation(s)
- Cheng-Hao Tseng
- Division of Gastroenterology and Hepatology, E-DA Cancer Hospital/I-Shou University, Kaohsiung, Taiwan.,Center for Liver Diseases and Division of Gastroenterology and Hepatology, E-DA Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Chao-Ming Tseng
- Division of Gastroenterology and Hepatology, E-DA Cancer Hospital/I-Shou University, Kaohsiung, Taiwan.,Center for Liver Diseases and Division of Gastroenterology and Hepatology, E-DA Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Jia-Ling Wu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, E-DA Cancer Hospital/I-Shou University, Kaohsiung, Taiwan.,Center for Liver Diseases and Division of Gastroenterology and Hepatology, E-DA Hospital/I-Shou University, Kaohsiung, Taiwan.,School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Hashem B El-Serag
- Michael E. DeBakey Veterans Affairs Medical Center and Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine Houston, Houston, Texas, USA
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Liang LY, Wong VWS, Toyoda H, Tse YK, Yip TCF, Yuen BWY, Tada T, Kumada T, Lee HW, Lui GCY, Chan HLY, Wong GLH. Serum hepatitis B core-related antigen predicts hepatocellular carcinoma in hepatitis B e antigen-negative patients. J Gastroenterol 2020; 55:899-908. [PMID: 32556643 DOI: 10.1007/s00535-020-01700-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 06/08/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hepatitis B core-related antigen (HBcrAg) is a novel serum viral marker. Recent studies showed that its level correlates with the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We aimed to evaluate the accuracy of serum HBsAg and HBcrAg levels at baseline to predict HCC. METHODS 1400 CHB patients who received nucleos(t)ide analogues (NA) treatment since December 2005 were included. Their stored serum samples at baseline were retrieved to measure HBsAg and HBcrAg levels. The primary endpoint was the cumulative incidence of HCC. RESULTS 85 (6.1%) patients developed HCC during a mean (± SD) follow-up duration of 45 ± 20 months. Serum HBcrAg level above 2.9 log10 U/mL at baseline was an independent factor for HCC in hepatitis B e antigen (HBeAg)-negative patients by multivariable analysis (adjusted hazard ratio 2.13, 95% CI 1.10-4.14, P = 0.025). HBcrAg above 2.9 log10 U/mL stratified the risk of HCC in HBeAg-negative patients with high PAGE-B score (P = 0.024 by Kaplan-Meier analysis), and possibly in cirrhotic patients (P = 0.08). Serum HBsAg level did not show any correlation with the risk of HCC in all patients or any subgroups. CONCLUSION Serum HBcrAg level predicts the risk of HCC accurately in NA-treated HBeAg-negative CHB patients.
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Affiliation(s)
- Lilian Yan Liang
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong
| | - Vincent Wai-Sun Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
| | | | - Yee-Kit Tse
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong
| | - Terry Cheuk-Fung Yip
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong
| | - Becky Wing-Yan Yuen
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong
| | | | | | - Hye-Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Grace Chung-Yan Lui
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong
| | - Henry Lik-Yuen Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
| | - Grace Lai-Hung Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR.
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong.
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR.
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Detectable HBV DNA during nucleos(t)ide analogues stratifies predictive hepatocellular carcinoma risk score. Sci Rep 2020; 10:13021. [PMID: 32747646 PMCID: PMC7400741 DOI: 10.1038/s41598-020-69522-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 06/05/2020] [Indexed: 02/08/2023] Open
Abstract
Nucleos(t)ide analogs (NA) suppress hepatitis B virus (HBV) replication and reduce the risk of hepatocellular carcinoma (HCC). However, NA cannot suppress carcinogenesis completely in patients with chronic hepatitis B. The aims of this study were to identify risk factors for HCC and develop a refined carcinogenesis prediction model. Patients receiving NA therapy (n = 1,183) were recruited retrospectively from the 16 hospitals. All patients had been receiving NA continuously for more than 1 year until the end of the follow-up. During a median follow-up of 4.9 (1.0–12.9) years, 52 (4.4%) patients developed HCC. A multivariate analysis revealed that male gender, older age, lower platelet counts at the baseline, and detectable HBV DNA during NA therapy were independent predictive factors of HCC development. The PAGE-B score was calculated by using these factors. 240 (20.3%), 661 (55.9%), and 282 (23.8%) patients were classified into low-, intermediate-, and high-risk groups, respectively. In the intermediate- and high-risk group, detectable HBV DNA was significantly associated with a higher risk of HCC development compared with continuously undetectable HBV DNA, respectively (HR 3.338; 95% CI 1.045–10.66/HR 3.191; 95% CI 1.543–6.597). PAGE-B–DNA, which is the combined PAGE-B and HBV DNA status, was valuable for a more refined stratification of PAGE-B.
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Wang HW, Lai HC, Hu TH, Su WP, Lu SN, Lin CH, Hung CH, Chuang PH, Wang JH, Lee MH, Chen CH, Peng CY. On-Treatment Changes in FIB-4 and 1-Year FIB-4 Values Help Identify Patients with Chronic Hepatitis B Receiving Entecavir Therapy Who Have the Lowest Risk of Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12051177. [PMID: 32392752 PMCID: PMC7281667 DOI: 10.3390/cancers12051177] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 05/05/2020] [Indexed: 02/08/2023] Open
Abstract
Noninvasive fibrosis indices can help stratify the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving nucleos(t)ide analogue (NA) therapy. We investigated the predictive performance of on-treatment changes in FIB-4 (△FIB-4) and 1-year FIB-4 values (FIB-4 12M) for HCC risk in patients with CHB receiving entecavir therapy. We included 1325 NA-naïve patients with CHB treated with entecavir, retrospectively, from January 2007 to August 2012. A combination of △FIB-4 and FIB-4 12M was used to stratify the cumulative risk of HCC into three subgroups each in the noncirrhotic and cirrhotic subgroups with p < 0.0001 by using the log-rank test (noncirrhotic: the highest risk (n = 88): FIB-4 12M ≥ 1.58/△FIB-4 ≥ 0 (hazard ratio (HR): 40.35; 95% confidence interval (CI): 5.107–318.7; p <0.0001) and cirrhotic: the highest risk (n = 89): FIB-4 12M ≥2.88/△FIB-4 ≥0 (HR: 9.576; 95% CI: 5.033–18.22; p < 0.0001)). Patients with noncirrhotic CHB treated with entecavir who had a FIB-4 12M < 1.58 or FIB-4 12M ≥ 1.58/△FIB-4 < 0 exhibited the lowest 5-year HCC risk (0.6%). A combination of on-treatment changes in FIB-4 and 1-year FIB-4 values may help identify patients with CHB receiving entecavir therapy with the lowest risk of HCC.
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Affiliation(s)
- Hung-Wei Wang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (H.-C.L.); (W.-P.S.); (C.-H.L.); (P.-H.C.)
| | - Hsueh-Chou Lai
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (H.-C.L.); (W.-P.S.); (C.-H.L.); (P.-H.C.)
- School of Chinese Medicine, China Medical University, Taichung 404, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; (T.-H.H.); (S.-N.L.); (C.-H.H.); (J.-H.W.)
| | - Wen-Pang Su
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (H.-C.L.); (W.-P.S.); (C.-H.L.); (P.-H.C.)
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; (T.-H.H.); (S.-N.L.); (C.-H.H.); (J.-H.W.)
| | - Chia-Hsin Lin
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (H.-C.L.); (W.-P.S.); (C.-H.L.); (P.-H.C.)
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; (T.-H.H.); (S.-N.L.); (C.-H.H.); (J.-H.W.)
| | - Po-Heng Chuang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (H.-C.L.); (W.-P.S.); (C.-H.L.); (P.-H.C.)
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; (T.-H.H.); (S.-N.L.); (C.-H.H.); (J.-H.W.)
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan;
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; (T.-H.H.); (S.-N.L.); (C.-H.H.); (J.-H.W.)
- Correspondence: (C.-H.C.); (C.-Y.P.); Tel.: +886-4-2205-2121 (ext. 2260) (C.-Y.P.)
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (H.-C.L.); (W.-P.S.); (C.-H.L.); (P.-H.C.)
- School of Medicine, China Medical University, Taichung 404, Taiwan
- Correspondence: (C.-H.C.); (C.-Y.P.); Tel.: +886-4-2205-2121 (ext. 2260) (C.-Y.P.)
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Incidence and predictors of hepatocellular carcinoma beyond year 5 of entecavir therapy in chronic hepatitis B patients. Hepatol Int 2020; 14:513-520. [PMID: 32319045 DOI: 10.1007/s12072-020-10031-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 03/06/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND PURPOSE: The study compared the incidence and predictors of hepatocellular carcinoma (HCC) within and beyond year 5 of entecavir (ETV) therapy. METHODS The study enrolled 1397 CHB patients who were naïve to nucleos(t)ide analogue (NA) treatment and had received ETV monotherapy for more than 12 months. RESULTS The cumulative incidences of HCC at 3, 5, and 10 years of ETV treatment were 4%, 9.1%, and 15.8%, respectively. In the entire cohort, the annual incidence rates of HCC were 2.28% within the first 5 years and 1.34% within 5-10 years of therapy. The incidences of HCC did not differ significantly within and beyond 5 years of ETV therapy (p = 0.53), including patients with cirrhosis (p = 0.85) and without cirrhosis (p = 0.47). At year 5 of treatment, the multivariate analysis showed that the fibrosis-4 (FIB-4) index and alpha-fetoprotein (AFP) levels were independent risk factors for HCC development beyond year 5. The 10-year cumulative incidences of HCC beyond year 5 in the high-risk group (FIB-4 > 2.20 and AFP > 3.21 ng/mL) and low-risk group (FIB-4 ≤ 2.20 and AFP ≤ 3.21 ng/mL) were 48.7% and 0%, respectively. APA-B score at 12 months and year 5 had a higher C-index for the prediction of HCC beyond year 5 than the PAGE-B at baseline and year 5 (p = 0.003 and p = 0.039, respectively) CONCLUSIONS: The HCC incidence tended to decrease but did not change significantly within and beyond 5 years of ETV therapy. The FIB-4 index and AFP levels at year 5 were predictive of HCC development beyond year 5 of ETV therapy.
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Tseng TC, Peng CY, Hsu YC, Su TH, Wang CC, Liu CJ, Yang HC, Yang WT, Lin CH, Yu ML, Lai HC, Tanaka Y, Nguyen MH, Liu CH, Chen PJ, Chen DS, Kao JH. Baseline Mac-2 Binding Protein Glycosylation Isomer Level Stratifies Risks of Hepatocellular Carcinoma in Chronic Hepatitis B Patients with Oral Antiviral Therapy. Liver Cancer 2020; 9:207-220. [PMID: 32399434 PMCID: PMC7206589 DOI: 10.1159/000504650] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 11/08/2019] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIMS Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel biomarker correlating with liver fibrosis stages. However, little is known about how it predicts risks of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients receiving long-term antiviral treatment. MATERIALS AND METHODS The study contained 2 parts. The first part was to explore whether M2BPGi could be an HCC predictor in 899 CHB patients receiving long-term entecavir therapy. The second part was to validate the findings in an independent cohort of 384 on-treatment CHB patients with more severe liver disease. RESULTS In the discovery cohort, there were 64 patients developing HCC within an average follow-up of 7.01 years. Our data showed that M2BPGi level was positively associated with HCC development. When stratifying the patients by an M2BPGi level of 1.73 (the third quartile), the high M2BPGi group was shown to have an increased HCC risk compared to the low M2BPGi group with hazard ratio of 5.80 (95% CI 3.50-9.60). Furthermore, we found that the M2BPGi level complements PAGE-B score, a well-validated HCC prediction model, to predict HCC development. Lastly, the cutoff was validated in the independent cohort, especially those with an intermediate PAGE-B score. CONCLUSIONS In CHB patients receiving long-term antiviral treatment, serum M2BPGi level not only serves as an independent HCC predictor but also complements PAGE-B in stratifying HCC risks.
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Affiliation(s)
- Tai-Chung Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Cheng-Yuan Peng
- School of Medicine, China Medical University, Taichung, Taiwan
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chia-Chi Wang
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hung-Chih Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Wan-Ting Yang
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chia-Hsin Lin
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsueh-Chou Lai
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Mindie H. Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
| | - Chen-Hua Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ding-Shinn Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Genomics Research Center Academia Sinica, Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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Voulgaris T, Papatheodoridi M, Lampertico P, Papatheodoridis GV. Clinical utility of hepatocellular carcinoma risk scores in chronic hepatitis B. Liver Int 2020; 40:484-495. [PMID: 31884726 DOI: 10.1111/liv.14334] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/28/2019] [Accepted: 12/15/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Several risk scores have been recently developed to predict hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. We systematically assessed the performance of the available HCC risk scores. METHODS Literature search was performed to identify all published studies reporting development or external validation of HCC risk scores in CHB patients. RESULTS Until March 2019, 12 scores were developed in untreated Asian and 7 scores in treated Asian (n = 6) or Caucasian (n = 1) patients. All scores provided significant predictions for HCC development in the derivation and validation cohorts of their original studies (c-statistic: 0.76-0.95) and usually classified patients into low, medium and high HCC risk groups. Eleven independent studies and three studies developing their own scores have validated externally some scores in Asian (GAG-HCC:5, CU-HCC:6, REACH-B:6, REACH-Bm:4, LSM-HCC:3, PAGE-B:5) or Caucasian/mixed origin patients (GAG-HCC:4, CU-HCC:4, REACH-B:4, PAGE-B:2). All scores offered acceptable predictability in almost all independent Asian cohorts (c-statistic: 0.70-0.86), but only PAGE-B and recently modified PAGE-B (mPAGE-B) offered good predictability in all independent Caucasian and/or Asian cohorts. Negative predictive values for 5-year HCC prediction were ≤99% (95%-99%) in most independent cohorts assessing Asian risk scores and 99%-100% in all independent cohorts (Caucasian/mixed origin:2; Asian:3) assessing PAGE-B and/or recently mPAGE-B. CONCLUSIONS Direct comparison of the newest HCC risk scores in independent patient cohorts of different origin remains intriguing, although statistical associations may not be directly transferable to clinical practice. PAGE-B and recently mPAGE-B score seem to offer persistently high predictability for Caucasian and/or Asian treated patients with low HCC risk who require no surveillance.
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Affiliation(s)
- Thodoris Voulgaris
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
| | - Margarita Papatheodoridi
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for the Study of Liver Disease, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - George V Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
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Su TH, Peng CY, Tseng TC, Yang HC, Liu CJ, Liu CH, Chen PJ, Chen DS, Kao JH. Serum Mac-2-Binding Protein Glycosylation Isomer at Virological Remission Predicts Hepatocellular Carcinoma and Death in Chronic Hepatitis B-Related Cirrhosis. J Infect Dis 2020; 221:589-597. [PMID: 31574141 DOI: 10.1093/infdis/jiz496] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 09/27/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND To investigate serum Mac-2-binding protein glycosylation isomer (M2BPGi) levels in predicting hepatocellular carcinoma (HCC) and mortality at virological remission (VR, HBV DNA <20 IU/mL) following antiviral therapy in chronic hepatitis B (CHB) patients with cirrhosis. METHODS This retrospective cohort study included patients with CHB-related Child-Pugh A cirrhosis undergoing long-term antiviral therapy. Serum M2BPGi levels were quantified and multivariable Cox proportional hazards regression models were used to identify risk predictors for HCC and death. RESULTS A total of 126 and 145 patients were included in the derivation and validation cohorts, respectively. The mean age was 56, and the mean M2BPGi level was 1.86 cut-off index (COI) in the derivation cohort. After adjustment for confounders, a higher M2BPGi level at VR significantly predicted HCC (hazard ratio [HR]: 1.58, 95% confidence interval [CI]: 1.19-2.10, P=0.002) and death (HR: 2.17, 95% CI: 1.02-4.62, P=0.044). The M2BPGi ≥3 COI significantly increased the risk of HCC and death in the derivation and validation cohorts. Serial M2BPGi levels declined significantly (P=0.0001) in non-HCC patients only, and remained significantly lower than those who developed HCC afterwards (P=0.039). CONCLUSIONS Serum M2BPGi levels at antiviral therapy-induced VR predict HCC development and death in patients with CHB-related Child-Pugh A cirrhosis.
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Affiliation(s)
- Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Cheng-Yuan Peng
- School of Medicine, China Medical University, Taichung, Taiwan
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Tai-Chung Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-Chih Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chen-Hua Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Ding-Shinn Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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Hsu YC, Wong GLH, Chen CH, Peng CY, Yeh ML, Cheung KS, Toyoda H, Huang CF, Trinh H, Xie Q, Enomoto M, Liu L, Yasuda S, Tanaka Y, Kozuka R, Tsai PC, Huang YT, Wong C, Huang R, Jang TY, Hoang J, Yang HI, Li J, Lee DH, Takahashi H, Zhang JQ, Ogawa E, Zhao C, Liu C, Furusyo N, Eguchi Y, Wong C, Wu C, Kumada T, Yuen MF, Yu ML, Nguyen MH. Tenofovir Versus Entecavir for Hepatocellular Carcinoma Prevention in an International Consortium of Chronic Hepatitis B. Am J Gastroenterol 2020; 115:271-280. [PMID: 31634265 DOI: 10.14309/ajg.0000000000000428] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION It is unclear whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) differ in their effectiveness for preventing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). METHODS This retrospective cohort study analyzed an international consortium that encompassed 19 centers from 6 countries or regions composed of previously untreated CHB patients then treated with either ETV or TDF monotherapy. Those who developed HCC before antiviral treatment or within 1 year of therapy were excluded. The association between antiviral regimen and HCC risk was evaluated using competing-risk survival regression. We also applied propensity score matching (PSM) to 1:1 balance the 2 treatment cohorts. A total of 5,537 patients were eligible (n = 4,837 received ETV and n = 700 received TDF) and observed for HCC occurrence until December 23, 2018. Before PSM, the TDF cohort was significantly younger and had generally less advanced diseases. RESULTS In the unadjusted analysis, TDF was associated with a lower risk of HCC (subdistribution hazard ratio [SHR], 0.45; 95% confidence interval [CI], 0.26-0.79; P = 0.005). The multivariable analysis, however, found that the association between TDF and HCC no longer existed (SHR, 0.81; 95% CI, 0.42-1.56; P = 0.52) after adjustment for age, sex, country, albumin, platelet, α-fetoprotein, cirrhosis, and diabetes mellitus. Furthermore, the PSM analysis (n = 1,040) found no between-cohort differences in HCC incidences (P = 0.51) and no association between regimens (TDF or ETV) and HCC risk in the multivariable-adjusted analysis (adjusted SHR, 0.89; 95% CI, 0.41-1.92; P = 0.77). DISCUSSION TDF and ETV did not significantly differ in the prevention of HCC in patients with CHB.
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Affiliation(s)
- Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung, Taiwan
- Division of Gastroenterology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan
- School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
- Department of Medicine and Therapeutics, the Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Department of Gastroenterology, China Medical University Hospital, Taichung, Taiwan
- Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medicine, the University of Hong Kong, Hong Kong SAR, China
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
- San Jose Gastroenterology, San Jose, California, USA
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
- Department of Infection Disease, the Third Hospital of Kumming City, Kumming, People's Republic of China
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
- Wong Clinics, San Francisco, California, USA
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, People's Republic of China
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, the United States of America
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Palo Alto Medical Foundation, Mountain View Division, Mountain View, California, USA
- Department of Gastroenterology, Good Gang-An Hospital, Busan, Sourth Korea
- Department of Internal Medicine, Saga University Hospital, Saga, Japan
- Chinese Hospital, San Francisco, California, USA
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
- Department of Cirrhosis, Institute of Liver Disease, Shuguang Hospital affiliated to Shanghai University of T.C.M., Shanghai, People's Republic of China
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, the Chinese University of Hong Kong, Hong Kong SAR, China
| | - Chien-Hung Chen
- Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Cheng-Yuan Peng
- Department of Gastroenterology, China Medical University Hospital, Taichung, Taiwan
| | - Ming-Lun Yeh
- Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ka-Shing Cheung
- Department of Medicine, the University of Hong Kong, Hong Kong SAR, China
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Chung-Feng Huang
- Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Huy Trinh
- San Jose Gastroenterology, San Jose, California, USA
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Li Liu
- Department of Infection Disease, the Third Hospital of Kumming City, Kumming, People's Republic of China
| | - Satoshi Yasuda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Ritsuzo Kozuka
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Pei-Chien Tsai
- Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yen-Tsung Huang
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | | | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, People's Republic of China
| | - Tyng-Yuan Jang
- Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Joseph Hoang
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, the United States of America
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Jiayi Li
- Palo Alto Medical Foundation, Mountain View Division, Mountain View, California, USA
| | - Dong-Hyun Lee
- Department of Gastroenterology, Good Gang-An Hospital, Busan, Sourth Korea
| | | | - Jian Q Zhang
- Chinese Hospital, San Francisco, California, USA
| | - Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Changqing Zhao
- Department of Cirrhosis, Institute of Liver Disease, Shuguang Hospital affiliated to Shanghai University of T.C.M., Shanghai, People's Republic of China
| | - Chenghai Liu
- Department of Cirrhosis, Institute of Liver Disease, Shuguang Hospital affiliated to Shanghai University of T.C.M., Shanghai, People's Republic of China
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Yuichiro Eguchi
- Department of Internal Medicine, Saga University Hospital, Saga, Japan
| | | | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, People's Republic of China
| | - Takashi Kumada
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Man-Fung Yuen
- Department of Medicine, the University of Hong Kong, Hong Kong SAR, China
| | - Ming-Lung Yu
- Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, the United States of America
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Yang HI, Yeh ML, Wong GL, Peng CY, Chen CH, Trinh HN, Cheung KS, Xie Q, Su TH, Kozuka R, Lee DH, Ogawa E, Zhao C, Ning HB, Huang R, Li J, Zhang JQ, Ide T, Xing H, Iwane S, Takahashi H, Wong C, Wong C, Lin CH, Hoang J, Le A, Henry L, Toyoda H, Ueno Y, Gane EJ, Eguchi Y, Kurosaki M, Wu C, Liu C, Shang J, Furusyo N, Enomoto M, Kao JH, Yuen MF, Yu ML, Nguyen MH. Real-World Effectiveness From the Asia Pacific Rim Liver Consortium for HBV Risk Score for the Prediction of Hepatocellular Carcinoma in Chronic Hepatitis B Patients Treated With Oral Antiviral Therapy. J Infect Dis 2020; 221:389-399. [PMID: 31550363 DOI: 10.1093/infdis/jiz477] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 09/13/2019] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Patients on oral antiviral (OAV) therapy remain at hepatocellular carcinoma (HCC) risk. Risk prediction tools distinguishing treated patients with residual HCC risk are limited. The aim of this study was to develop an accurate, precise, simple-to-use HCC risk score using routine clinical variables among a treated Asian cohort. METHODS Adult Asian chronic hepatitis B (CHB) patients on OAV were recruited from 25 centers in the United States and the Asia-Pacific region. Excluded persons were coinfected with hepatitis C, D, or human immunodeficiency virus, had HCC before or within 1 year of study entry, or their follow-up was <1 year. Patients were randomized to derivation and validation cohorts on a 2:1 ratio. Statistically significant predictors from multivariate modeling formed the Real-world Effectiveness from the Asia Pacific Rim Liver Consortium for HBV (REAL-B) score. RESULTS A total of 8048 patients were randomized to the derivation (n = 5365) or validation group (n = 2683). The REAL-B model included 7 variables (male gender, age, alcohol use, diabetes, baseline cirrhosis, platelet count, and alpha fetoprotein), and scores were categorized as follows: 0-3 low risk, 4-7 moderate risk, and 8-13 high risk. Area under receiver operating characteristics were >0.80 for HCC risk at 3, 5, and 10 years, and these were significantly higher than other risk models (p < .001). CONCLUSIONS The REAL-B score provides 3 distinct risk categories for HCC development in Asian CHB patients on OAV guiding HCC surveillance strategy.
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Affiliation(s)
- Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ming-Lun Yeh
- Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Grace L Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - Cheng-Yuan Peng
- Department of Gastroenterology, China Medical University Hospital, Taichung, Taiwan
| | - Chien-Hung Chen
- Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Huy N Trinh
- San Jose Gastroenterology, San Jose, California, USA
| | - Ka-Shing Cheung
- Department of Medicine, The University of Hong Kong, Hong Kong
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Peopole's Republic of China
| | - Tung-Hung Su
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Ritsuzo Kozuka
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Dong-Hyun Lee
- Department of Gastroenterology, Good Gang-An Hospital, Busan, South Korea
| | - Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Changqing Zhao
- Department of Cirrhosis, Institute of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, Peopole's Republic of China
| | - Hui-Bin Ning
- Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou, Peopole's Republic of China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, Peopole's Republic of China
| | - Jiayi Li
- Palo Alto Medical Foundation, Mountain View Division, Mountain View, California, USA
| | - Jian Q Zhang
- Chinese Hospital, San Francisco, California, USA
| | - Tatsuya Ide
- Department of Internal Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Huichun Xing
- Beijing Ditan Hospital, Capital Medical University, Beijing, Peopole's Republic of China
| | - Shinji Iwane
- Department of Internal Medicine, Saga University Hospital, Saga, Japan
| | | | | | | | - Chia-Hsin Lin
- Department of Gastroenterology, China Medical University Hospital, Taichung, Taiwan
| | - Joseph Hoang
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, USA
| | - An Le
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, USA
| | - Linda Henry
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, USA
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University, Yamagata, Japan
| | - Edward J Gane
- Liver Transplant Unit, University of Auckland, Auckland, New Zealand
| | - Yuichiro Eguchi
- Department of Internal Medicine, Saga University Hospital, Saga, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, Peopole's Republic of China
| | - Chenghai Liu
- Department of Cirrhosis, Institute of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, Peopole's Republic of China
| | - Jia Shang
- Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou, Peopole's Republic of China
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Jia-Horng Kao
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Hong Kong
| | - Ming-Lung Yu
- Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, USA
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Hsu YC, Yip TCF, Ho HJ, Wong VWS, Huang YT, El-Serag HB, Lee TY, Wu MS, Lin JT, Wong GLH, Wu CY. Development of a scoring system to predict hepatocellular carcinoma in Asians on antivirals for chronic hepatitis B. J Hepatol 2018; 69:278-285. [PMID: 29551708 DOI: 10.1016/j.jhep.2018.02.032] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 02/21/2018] [Accepted: 02/27/2018] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS The risk of hepatocellular carcinoma (HCC) during antiviral therapy in patients with chronic hepatitis B (CHB) is inadequately predicted by the scores built from untreated patients. We aimed at developing and validating a risk score to predict HCC in patients with CHB on entecavir or tenofovir treatment. METHODS This study analysed population-wide data from the healthcare databases in Taiwan and Hong Kong to identify patients with CHB continuously receiving entecavir or tenofovir. The development cohort included 23,851 patients from Taiwan; 596 (2.50%) of them developed HCC with a three-year cumulative incidence of 3.56% (95% CI 3.26-3.86%). The multivariable Cox proportional hazards model found that cirrhosis, age (cirrhosis and age interacted with each other), male sex, and diabetes mellitus were the risk determinants. These variables were weighted to develop the cirrhosis, age, male sex, and diabetes mellitus (CAMD) score ranging from 0 to 19 points. The score was externally validated in 19,321 patients from Hong Kong. RESULTS The c indices for HCC in the development cohort were 0.83 (95% CI 0.81-0.84), 0.82 (95% CI 0.81-0.84), and 0.82 (95% CI 0.80-0.83) at the first, second, and third years of therapy, respectively. In the validation cohort, the c indices were 0.74 (95% CI 0.71-0.77), 0.75 (95% CI 0.73-0.78), and 0.75 (95% CI 0.72-0.77) during the first three years, and 0.76 (95% CI 0.74-0.78) and 0.76 (95% CI 0.74-0.77) in the extrapolated fourth and fifth years, respectively. The predicted and observed probabilities of HCC were calibrated in both cohorts. A score <8 and >13 points identified patients at distinctly low and high risks. CONCLUSIONS The easily calculable CAMD score can predict HCC and may inform surveillance policy in patients with CHB during oral antiviral therapy. LAY SUMMARY This study analyses population-wide data from the healthcare systems in Taiwan and Hong Kong to develop and validate a risk score that predicts hepatocellular carcinoma during oral antiviral therapy in patients with chronic hepatitis B. The easily calculable CAMD score requires only simple information (i.e. cirrhosis, age, male sex, and diabetes mellitus) at the baseline of treatment initiation. With a scoring range from 0 to 19 points, the CAMD score discriminates the risk of hepatocellular carcinoma with a concordance rate of around 75-80% during the first three years on therapy. The risk prediction can be extrapolated to five years on treatment with similar accuracy. Patients with a score <8 and >13 points were exposed to distinctly lower and higher risks, respectively.
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Affiliation(s)
- Yao-Chun Hsu
- Big Data Research Center, School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan; Division of Gastroenterology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan; Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung, Taiwan; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
| | - Terry Cheuk-Fung Yip
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong; Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong; State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong
| | - Hsiu J Ho
- Division of Gastroenterology, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Vincent Wai-Sun Wong
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong; Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong; State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong
| | - Yen-Tsung Huang
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Department of Medicine, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA
| | - Teng-Yu Lee
- Division of Gastroenterology, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Jaw-Town Lin
- Big Data Research Center, School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan; Division of Gastroenterology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan
| | - Grace Lai-Hung Wong
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong; Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong; State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong.
| | - Chun-Ying Wu
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Division of Gastroenterology, Taichung Veterans General Hospital, Taichung, Taiwan; Faculty of Medicine and Graduate Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Public Health, China Medical University, Taichung, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
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Ultrasound-Based Liver Stiffness Surveillance in Patients Treated for Chronic Hepatitis B or C. APPLIED SCIENCES-BASEL 2018. [DOI: 10.3390/app8040626] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Effect of entecavir and adefovir dipivoxil on thyroid function and liver function in patients with decompensated hepatitis B cirrhosis. Shijie Huaren Xiaohua Zazhi 2018; 26:311-317. [DOI: 10.11569/wcjd.v26.i5.311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the effect of entecavir and adefovir dipivoxil on thyroid function and liver function in patients with decompensated hepatitis B cirrhosis.
METHODS One hundred and twenty patients with decompensated hepatitis B cirrhosis treated from September 2014 to September 2016 at our hospital were randomly divided into an observation group (n = 60) and a control group (n = 60). Both groups received conventional treatment. The control group was additionally given adefovir dipivoxil, and the observation group was given entecavir. At 3, 6, and 12 mo after treatment, hepatitis B virus (HBV) DNA negative rate, HBeAg negative rate, Child-Pugh score, liver function, thyroid function, the incidence of complications, mortality, and the incidence of adverse drug reactions were observed.
RESULTS At 3, 6, and 12 mo after treatment, HBV DNA negative rates were significantly higher in the observation group than in the control group (P < 0.05), although there was no significant difference in hepatitis B e antigen negative rates (P > 0.05); the Child-Pugh scores and serum levels of alanine transaminase, aspartate transaminase, and total bilirubin were significantly lower in the observation group than in the control group (P < 0.05). After treatment for 1 year, the levels of T3, T4, FT3, and FT4 were significantly higher and that of TSH was significantly lower in the observation group than in the control group (P < 0.05). There was no significant difference in the incidence of complications or mortality (P > 0.05), and no severe adverse reactions were observed in either group.
CONCLUSION Entecavir is significantly effective in patients with decompensated hepatitis B cirrhosis and can improve liver function and thyroid function with good safety.
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