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Yang J, Zheng L, Yang Z, Wei Z, Shao J, Zhang Y, Yao J, Li M, Wang X, Zheng M. 5-FU promotes HBV replication through oxidative stress-induced autophagy dysfunction. Free Radic Biol Med 2024; 213:233-247. [PMID: 38215891 DOI: 10.1016/j.freeradbiomed.2024.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 12/27/2023] [Accepted: 01/08/2024] [Indexed: 01/14/2024]
Abstract
BACKGROUND & AIMS Hepatitis B virus (HBV) reactivation is a major problem that must be overcome during chemotherapy for HBV-related hepatocellular carcinoma (HCC). However, the mechanism underlying chemotherapy-associated HBV reactivation is still not fully understood, hindering the development of improved HBV-related HCC treatments. METHODS A meta-analysis was performed to assess the HBV reactivation risk during transcatheter arterial chemoembolization (TACE). To investigate the regulatory effects and mechanisms of 5-FU on HBV replication, an HBV mouse model was established by pAAV-HBV1.2 hydrodynamic injection followed by intraperitoneal 5-FU injection, and different in vitro models (HepG2.2.15 or Huh7 cells) were established. Realtime RT‒qPCR, western blotting, luciferase assays, and immunofluorescence were used to determine viral parameters. We also explored the underlying mechanisms by RNA-seq, oxidative stress evaluation and autophagy assessment. RESULTS The pooled estimated rate of HBV reactivation in patients receiving TACE was 30.3 % (95 % CI, 23.1%-37.4 %). 5-FU, which is a chemotherapeutic agent commonly used in TACE, promoted HBV replication in vitro and in vivo. Mechanistically, 5-FU treatment obviously increased autophagosome formation, as shown by increased LC3-II levels. Additionally, 5-FU impaired autophagic degradation, as shown by marked p62 and mCherry-GFP-LC3 upregulation, ultimately promoting HBV replication and secretion. Autophagy inhibition by 3-methyladenine or chloroquine significantly altered 5-FU-induced HBV replication. Furthermore, 5-FU-induced autophagy and HBV replication were markedly attenuated with a reactive oxygen species (ROS) scavenger. CONCLUSIONS Together, our results indicate that ROS-induced autophagosome formation and autophagic degradation play a critical role in 5-FU-induced HBV reactivation.
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Affiliation(s)
- Jing Yang
- 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, College of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Luyan Zheng
- 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, College of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Zhenggang Yang
- 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, College of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Zhiqiang Wei
- 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, College of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Jiajia Shao
- 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, College of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Yina Zhang
- 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, College of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Jiping Yao
- 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, College of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Minwei Li
- 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, College of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Xueyu Wang
- 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, College of Medicine, Zhejiang University, Hangzhou, 310003, China.
| | - Min Zheng
- 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, College of Medicine, Zhejiang University, Hangzhou, 310003, China.
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Liu B, Wang Q, Mei T, Zheng J, Gao W, Yuan C, Li K, Zhang Y. Effect of HBsAg expression in liver tissue on prognosis of hepatocellular carcinoma after minimally invasive interventional therapy. Front Oncol 2023; 13:1106333. [PMID: 36969054 PMCID: PMC10033608 DOI: 10.3389/fonc.2023.1106333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 02/21/2023] [Indexed: 03/11/2023] Open
Abstract
BackgroundThe aim of this study was to investigate the association between pathologic markers and prognosis in patients with hepatocellular carcinoma who received transcatheter chemoembolization combined with locoregional ablation therapy.MethodsThis retrospective study included 111 hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). All patients underwent transcatheter arterial chemoembolization (TACE) combined with locoregional ablation therapy, and received core needle biopsy before therapy in Beijing You ‘an Hospital affiliated to Capital Medical University from January 1, 2013 to December 31, 2016. Demographic, pathological indicators and clinical laboratory data were collected. The cumulative recurrence-free survival (RFS) and overall survival (OS) were calculated and compared by Kaplan-Meier method and Log-rank test, and Cox proportional risk model was used to screen for independent predictors of recurrence and long-term prognosis in HCC patients.ResultsThere was a correlation between HBsAg expression in liver tissue and prognosis of HCC patients. Patients with negative HBsAg expression had longer 1-,3- and 5-year RFS rates than positive HBsAg expression (78.3%, 43.5%, 30.4% and 58.5%, 24.5%, 17.0%, P=0.018). Meanwhile,the postoperative 1-,3-and 5-year OS rates of HCC patients in the negative HBsAg expression group were significantly higher than those of HCC patients in the positive HBsAg expression group (100%, 89.1%, 80.4% and 100%, 75.5%, 58.5%, P=0.008).ConclusionsThe prognosis of patients with hepatocellular carcinoma with negative HBsAg expression was better than that with positive HBsAg expression. Accordingly, the expression of the liver HBsAg before combined therapy was a prognostic indicator for OS and RFS. For patients with liver HBsAg positive, follow-up should be strengthened and corresponding intervention measures should be taken to improve prognosis.
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Affiliation(s)
- Biyu Liu
- Research Center For Biomedical Resources, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Qi Wang
- Research Center For Biomedical Resources, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Tingting Mei
- Research Center For Biomedical Resources, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Jiasheng Zheng
- Interventional Therapy Center For Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Wenfeng Gao
- Interventional Therapy Center For Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Chunwang Yuan
- Interventional Therapy Center For Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Kang Li
- Research Center For Biomedical Resources, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Yonghong Zhang
- Interventional Therapy Center For Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, China
- *Correspondence: Yonghong Zhang,
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2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. JOURNAL OF LIVER CANCER 2023; 23:1-120. [PMID: 37384024 PMCID: PMC10202234 DOI: 10.17998/jlc.2022.11.07] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 11/07/2022] [Indexed: 06/30/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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Affiliation(s)
- Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea
- Corresponding author: KLCA-NCC Korea Practice Guideline Revision Committee (KPGRC) (Committee Chair: Joong-Won Park) Center for Liver and Pancreatobiliary Cancer, Division of Gastroenterology, Department of Internal Medicine, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea Tel. +82-31-920-1605, Fax: +82-31-920-1520, E-mail:
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Shen J, Wang X, Wang N, Wen S, Yang G, Li L, Fu J, Pan X. HBV reactivation and its effect on survival in HBV-related hepatocarcinoma patients undergoing transarterial chemoembolization combined with tyrosine kinase inhibitors plus immune checkpoint inhibitors. Front Cell Infect Microbiol 2023; 13:1179689. [PMID: 37197205 PMCID: PMC10183577 DOI: 10.3389/fcimb.2023.1179689] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 04/20/2023] [Indexed: 05/19/2023] Open
Abstract
Objective This study aimed to access hepatitis B virus (HBV) reactivation and its effect on survival in HBV-related hepatocarcinoma (HCC) patients who underwent transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs). Methods In this single-center retrospective study, we enrolled 119 HBV-related unresectable advanced HCC patients receiving TACE combined with TKIs plus ICIs. Risk factors for HBV reactivation were analyzed by logistic regression. Kaplan-Meier method was applied to draw the survival curve, and log-rank test was used to compare survival between patients with and without HBV reactivation. Results A total of 12 patients (10.1%) encountered HBV reactivation in our study, of which only 4 patients received antiviral prophylaxis. The incidence of HBV reactivation was 1.8% (1/57) in patients with detectable baseline HBV DNA and 4.2% (4/95) in patients with antiviral prophylaxis respectively. Lack of prophylactic antiviral treatment (OR=0.047, 95%CI 0.008-0.273, P=0.001) and undetectable HBV DNA (OR=0.073, 95%CI 0.007-0.727, P=0.026) were independent risk factors for HBV reactivation. The median survival time (MST) for all patients was 22.4 months. No survival difference was observed in patients with or without HBV reactivation. (MST: undefined vs 22.4 months, log-rank test: P=0.614). Conclusion HBV reactivation could occur in HBV-related HCC patients who treated with TACE in combination with TKIs plus ICIs. Before and during the combination treatment, it is necessary to routinely monitor HBV DNA and to take effective prophylactic antiviral therapy.
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2022 KLCA-NCC Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Korean J Radiol 2022; 23:1126-1240. [PMID: 36447411 PMCID: PMC9747269 DOI: 10.3348/kjr.2022.0822] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 10/28/2022] [Indexed: 11/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. Clin Mol Hepatol 2022; 28:583-705. [PMID: 36263666 PMCID: PMC9597235 DOI: 10.3350/cmh.2022.0294] [Citation(s) in RCA: 161] [Impact Index Per Article: 53.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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Clinical Outcomes of Hepatitis B Virus-Related Hepatocellular Carcinoma Patients with Undetectable Serum HBV DNA Levels. Dig Dis Sci 2022; 67:4565-4573. [PMID: 34800218 DOI: 10.1007/s10620-021-07312-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 11/01/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Some hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients show undetectable serum HBV DNA levels at HCC diagnosis. The risk of HBV reactivation and its impact on clinical outcomes are not well-unknown. METHODS This retrospective cohort study included a total of 985 HBV-related HCC patients with undetectable serum HBV DNA levels (< 12 IU/mL) at HCC diagnosis (112 were antiviral treatment (AVT)-naïve; 873 were receiving AVT). Incidence and risk factors for HBV reactivation (re-detection of HBV DNA in serum) during follow-up, as well as its association to overall survival, were assessed. RESULTS During a median of 33.4 months of follow-up (range: 0.2-124.2 months), HBV reactivation was observed in 279 patients. HBV reactivation rate was significantly lower for patients receiving AVT than AVT-naïve patients (three-year cumulative incidence rate: 27.3% versus 56.0%; P < 0.001). In multivariable-adjusted analysis, the risk of HBV reactivation was lower for those receiving AVT compared to AVT-naïve patients (adjusted hazard ratio: 0.39, 95% confidence interval: 0.29-0.54). Overall survival was significantly lower for those experiencing HBV reactivation than those who did not (71.5% and 85.7% at five-year) and was associated with higher risk of overall mortality (adjusted hazard ratio: 5.15, 95% confidence interval: 3.60-7.38). CONCLUSION More than half of AVT-naïve patients experienced HBV reactivation within three years, which was associated with increased risk of overall mortality. The risk of HBV reactivation was lower for those receiving AVT, suggesting that prompt AVT needs to be considered for AVT naïve HBV-related HCC patients with undetectable HBV DNA levels.
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Liu DM, Leung TW, Chow PK, Ng DC, Lee RC, Kim YH, Mao Y, Cheng YF, Teng GJ, Lau WY. Clinical consensus statement: Selective internal radiation therapy with yttrium 90 resin microspheres for hepatocellular carcinoma in Asia. Int J Surg 2022; 102:106094. [PMID: 35662438 DOI: 10.1016/j.ijsu.2021.106094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is subject to different management approaches and guidelines according to Eastern and Western therapeutic algorithms. Use of selective internal radiation therapy (SIRT) with resin yttrium 90 microspheres for HCC has increased in Asia in recent years, without clearly defined indications for its optimal application. The objective of this systematic review and expert consensus statement is to provide guidance and perspectives on the use of SIRT among patients with HCC in Asia. MATERIALS AND METHODS A systematic literature review identified current publications on HCC management and SIRT recommendations. A group of 10 experts, representing stakeholder specialties and countries, convened between August 2020 and March 2021 and implemented a modified Delphi consensus approach to develop guidelines and indications for use of SIRT for HCC in Asia. Final recommendations were organized and adjudicated based on the level of evidence and strength of recommendation, per approaches outlined by the American College of Cardiology/American Heart Association and Oxford Centre for Evidence-Based Medicine. RESULTS The experts acknowledged a general lack of evidence relating to use of SIRT in Asia and identified as an unmet need the lack of phase 3 randomized trials comparing clinical outcomes and survival following SIRT versus other therapies for HCC. Through an iterative process, the expert group explored areas of clinical relevance and generated 31 guidance statements and a patient management algorithm that achieved consensus. CONCLUSION These recommendations aim to support clinicians in their decision-making and to help them identify and treat patients with HCC using SIRT in Asia. The recommendations also highlight areas in which further clinical trials are needed to define the role of SIRT in management of HCC among Asian populations.
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Affiliation(s)
- David M Liu
- Department of Radiology, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Thomas Wt Leung
- Comprehensive Oncology Centre, Hong Kong Sanatorium & Hospital, Hong Kong
| | - Pierce Kh Chow
- National Cancer Centre Singapore, Singapore General Hospital, Duke-NUS Medical School, Singapore
| | - David Ce Ng
- Department of Nuclear Medicine and Molecular Imaging, Singapore General Hospital, Singapore, Duke-NUS Medical School, Singapore
| | - Rheun-Chuan Lee
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yun Hwan Kim
- Department of Radiology, Presbyterian Medical Center, Jeonju, South Korea
| | - Yilei Mao
- Department of Liver Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital, Beijing, China
| | - Yu-Fan Cheng
- Department of Diagnostic Radiology, Liver Transplantation Center, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Gao-Jun Teng
- Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China
| | - Wan Yee Lau
- Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong.
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Papatheodoridi M, Tampaki M, Lok AS, Papatheodoridis GV. Risk of HBV reactivation during therapies for HCC: A systematic review. Hepatology 2022; 75:1257-1274. [PMID: 34918361 DOI: 10.1002/hep.32241] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 11/05/2021] [Accepted: 11/09/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Treatment for HCC has evolved rapidly, but the risk of HBV reactivation to new therapies is unclear. We systematically reviewed data on HBV reactivation in patients receiving HCC therapy in relation to use of HBV antiviral prophylaxis. APPROACH AND RESULTS A literature search was performed to identify all published studies including HBsAg-positive patients with HCC providing data on HBV reactivation. Forty-one studies with 10,223 patients, all from Asia, were included. The pooled HBV reactivation rate was 5% in patients receiving no specific HCC therapy and was higher in patients undergoing surgical resection (16%), transarterial chemoembolization (19%), or radiotherapy (14%) and intermediate in patients treated with local ablation therapy (7%) or systemic agents (7%). HBV reactivation rates were higher in those without compared to those with HBV prophylaxis (ablation, 9% versus 0%; resection, 20% versus 3%; chemoembolization, 23% versus 1%; external radiotherapy alone, 18% versus 0%; systemic therapy, 9% versus 3%). HBV-related biochemical reactivation rates varied between 6%-11% and 2% in patients receiving HCC therapies with high and intermediate HBV reactivation risk, respectively. Liver decompensation and death were rarely reported (0%-3%) and only in patients receiving HCC treatment with high HBV reactivation risk. CONCLUSIONS HBsAg-positive patients with HCC are at high or intermediate risk of HBV reactivation depending on the type of HCC therapy. Nucleos(t)ide analogue prophylaxis reduces the risk of HBV reactivation, practically eliminates the risk of hepatitis flare, and should be administered regardless of HCC treatment.
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Affiliation(s)
| | - Maria Tampaki
- Department of Gastroenterology and Liver Transplantation UnitMedical School of National and Kapodistrian University of AthensGeneral Hospital of Athens "Laiko"AthensGreece
| | - Anna S Lok
- Division of Gastroenterology and HepatologyUniversity of MichiganAnn ArborMichiganUSA
| | - George V Papatheodoridis
- Department of Gastroenterology and Liver Transplantation UnitMedical School of National and Kapodistrian University of AthensGeneral Hospital of Athens "Laiko"AthensGreece
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2022; 28:276-331. [PMID: 35430783 PMCID: PMC9013624 DOI: 10.3350/cmh.2022.0084] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 01/10/2023] Open
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Abstract
Hepatitis B virus (HBV) can hide in the liver in the form of covalently closed circular DNA. When the body’s immunity changes, HBV reactivation (HBV-R) can occur. The risk of HBV-R is determined by the complex interaction among virological factors, medication factors and host factors. However, many patients do not know that they are infected with HBV, and doctors often do not invest enough time to systematically evaluate the patient’s HBV-R risk factors before immunosuppressive treatment. Therefore, HBV clinical screening should be vigorously promoted to achieve early detection and early prevention for patients with high risk of HBV-R. The mechanism, clinical features, risk factors, HBV-R under different disease etiologies, prevention and treatment of HBV-R were summarized to improve the in-depth understanding and awareness.
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Affiliation(s)
- Wei Huang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy & Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lingyao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy & Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy & Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
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Lau G, Yu ML, Wong G, Thompson A, Ghazinian H, Hou JL, Piratvisuth T, Jia JD, Mizokami M, Cheng G, Chen GF, Liu ZW, Baatarkhuu O, Cheng AL, Ng WL, Lau P, Mok T, Chang JM, Hamid S, Dokmeci AK, Gani RA, Payawal DA, Chow P, Park JW, Strasser SI, Mohamed R, Win KM, Tawesak T, Sarin SK, Omata M. APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy. Hepatol Int 2021; 15:1031-1048. [PMID: 34427860 PMCID: PMC8382940 DOI: 10.1007/s12072-021-10239-x] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIM Hepatitis B reactivation related to the use of immunosuppressive therapy remains a major cause of liver-related morbidity and mortality in hepatitis B endemic Asia-Pacific region. This clinical practice guidelines aim to assist clinicians in all disciplines involved in the use of immunosuppressive therapy to effectively prevent and manage hepatitis B reactivation. METHODS All publications related to hepatitis B reactivation with the use of immunosuppressive therapy since 1975 were reviewed. Advice from key opinion leaders in member countries/administrative regions of Asian-Pacific Association for the study of the liver was collected and synchronized. Immunosuppressive therapy was risk-stratified according to its reported rate of hepatitis B reactivation. RECOMMENDATIONS We recommend the necessity to screen all patients for hepatitis B prior to the initiation of immunosuppressive therapy and to administer pre-emptive nucleos(t)ide analogues to those patients with a substantial risk of hepatitis and acute-on-chronic liver failure due to hepatitis B reactivation.
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Affiliation(s)
- George Lau
- Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Hong Kong SAR, China.
- The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, 100039, China.
| | - Ming-Lung Yu
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100, Tz-You 1st Rd, Chinese Taipei, Kaohsiung, Taiwan.
| | - Grace Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | | | - Hasmik Ghazinian
- Department of Hepatology, Nork Clinical Hospital of Infectious Diseases, Yerevan, Armenia
| | - Jin-Lin Hou
- Department of Infectious Diseases, Institute of Hepatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Teerha Piratvisuth
- Department of Medicine, NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand
| | - Ji-Dong Jia
- Liver Research Center, Beijing Friendship Hospital, Beijing, China
| | - Masashi Mizokami
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Gregory Cheng
- The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, 100039, China
- Faculty of Health Science, Macau University, Macau SAR, China
| | - Guo-Feng Chen
- Department of Liver Diseases, Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Zhen-Wen Liu
- Research Center for Liver Transplantation, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Oidov Baatarkhuu
- Department of Infectious Diseases, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Ann Lii Cheng
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Woon Leung Ng
- Department of Medicine, United Christian Hospital, Hong Kong SAR, China
| | - Patrick Lau
- Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Hong Kong SAR, China
| | - Tony Mok
- Department of Clinical Oncology, State Key Laboratory of South China, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jer-Ming Chang
- Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Saeed Hamid
- Department of Medicine, Aga Khan University and Hospital, Stadium Road, Karachi, 74800, Pakistan
| | - A Kadir Dokmeci
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Rino A Gani
- Liver Transplantation Team, Ciptomangunkusumo Hospital, Jakarta, Indonesia
| | - Diana A Payawal
- Department of Medicine, Cardinal Santos Medical Center, Mandaluyong, Metro, Manila, Philippines
| | - Pierce Chow
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Joong-Won Park
- Center for Liver Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea
| | - Simone I Strasser
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia
| | - Rosmawaiti Mohamed
- Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Khin Maung Win
- Yangon Gastroenterology and Liver Centre, Yangon, Myanmar
| | - Tanwandee Tawesak
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Masao Omata
- Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu-shi, Yamanashi, 400-8506, Japan
- The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
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13
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Chi CT, Lee IC, Lee RC, Hung YW, Su CW, Hou MC, Chao Y, Huang YH. Effect of Transarterial Chemoembolization on ALBI Grade in Intermediate-Stage Hepatocellular Carcinoma: Criteria for Unsuitable Cases Selection. Cancers (Basel) 2021; 13:4325. [PMID: 34503135 PMCID: PMC8431519 DOI: 10.3390/cancers13174325] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/21/2021] [Accepted: 08/24/2021] [Indexed: 02/08/2023] Open
Abstract
Transarterial chemoembolization (TACE) is the standard of care for intermediate stage hepatocellular carcinoma (HCC). We aimed to identify unsuitable cases who were at risk of ALBI-grade migration by TACE. Consecutive 531 BCLC-B HCC patients undergoing TACE were reviewed, and factors associated with ALBI-grade migration were analyzed. There were 129 (24.3%) patients experienced acute ALBI-grade migration after TACE, and 85 (65.9%) out of the 129 patients had chronic ALBI-grade migration. Incidences of acute ALBI-grade migration were 13.9%, 29.0% for patients within or beyond up-to-7 criteria (p < 0.001) and 20.0%, 36.2% for patients within or beyond up-to-11 criteria (p < 0.001), respectively. HBV infection, tumor size plus tumor number criteria were risk factors associated with acute ALBI-grade migration. Bilobar tumor involvement was the risk factor of chronic ALBI-grade migration in patients with acute ALBI-grade migration. Up-to-eleven (p = 0.007) performed better than up-to-seven (p = 0.146) to differentiate risk of dynamic ALBI score changes. Moreover, ALBI-grade migration to grade 3 has adverse effect on survival. In conclusion, tumor burden beyond up-to-eleven was associated with ALBI-grade migration after TACE, indicating that up-to-eleven can select TACE-unsuitable HCC patients who are at risk of liver function deterioration.
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Affiliation(s)
- Chen-Ta Chi
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (C.-T.C.); (I.-C.L.); (Y.-W.H.); (C.-W.S.); (M.-C.H.)
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - I-Cheng Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (C.-T.C.); (I.-C.L.); (Y.-W.H.); (C.-W.S.); (M.-C.H.)
| | - Rheun-Chuan Lee
- Department of Radiology, Taipei Veterans General Hospital, Taipei 11217, Taiwan;
| | - Ya-Wen Hung
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (C.-T.C.); (I.-C.L.); (Y.-W.H.); (C.-W.S.); (M.-C.H.)
| | - Chien-Wei Su
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (C.-T.C.); (I.-C.L.); (Y.-W.H.); (C.-W.S.); (M.-C.H.)
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (C.-T.C.); (I.-C.L.); (Y.-W.H.); (C.-W.S.); (M.-C.H.)
| | - Yee Chao
- Department of Oncology, Taipei Veterans General Hospital, Taipei 11217, Taiwan;
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (C.-T.C.); (I.-C.L.); (Y.-W.H.); (C.-W.S.); (M.-C.H.)
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
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14
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Yang Y, Yan Y, Chen Z, Hu J, Wang K, Tang N, Li X, Zhou Z. Histone Deacetylase Inhibitors Romidepsin and Vorinostat Promote Hepatitis B Virus Replication by Inducing Cell Cycle Arrest. J Clin Transl Hepatol 2021; 9:160-168. [PMID: 34007797 PMCID: PMC8111102 DOI: 10.14218/jcth.2020.00105] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 01/29/2021] [Accepted: 02/24/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND AND AIMS Chronic hepatitis B virus (HBV) infection is a global public health challenge. HBV reactivation usually occurs in cancer patients after receiving cytotoxic chemotherapy or immunosuppressive therapies. Romidepsin (FK228) and vorinostat (SAHA) are histone deacetylase inhibitors (HDACi) approved by the Food and Drug Administration as novel antitumor agents. The aim of this study was to explore the effects and mechanisms of HDACi treatment on HBV replication. METHODS To assess these effects, human hepatoma cell lines were cultured and cell viability after FK228 or SAHA treatment was measured by the CCK-8 cell counting kit-8 assay. Then, HBV DNA and RNA were quantified by real-time PCR and Southern blotting. Furthermore, analysis by western blotting, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and flow cytometry was performed. RESULTS FK228/SAHA treatment significantly promoted HBV replication and biosynthesis in both HBV-replicating cells and HBV-transgenic mouse model. Flow cytometry assay indicated that FK228/SAHA enhanced HBV replication by inducing cell cycle arrest through modulating the expression of cell cycle regulatory proteins. In addition, simultaneous inhibition of HDAC1/2 by FK228 promoted HBV replication more effectively than the broad spectrum HDAC inhibitor SAHA. CONCLUSIONS Overall, our results demonstrate that cell cycle blockage plays an important role in FK228/SAHA-enhanced HBV replication, thus providing a potential avenue for rational use of HDACi in patients with chronic hepatitis B.
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Affiliation(s)
- Yang Yang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yu Yan
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Zhen Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Jie Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Kai Wang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ni Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Xiaosong Li
- Clinical Molecular Medicine Testing Center, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Correspondence to: Xiaosong Li, Clinical Molecular Medicine Testing Center, The First Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China. Tel: +86-23-68486780, E-mail: ; Zhi Zhou, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China. Tel: +86-23-62887067, E-mail:
| | - Zhi Zhou
- Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Correspondence to: Xiaosong Li, Clinical Molecular Medicine Testing Center, The First Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China. Tel: +86-23-68486780, E-mail: ; Zhi Zhou, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China. Tel: +86-23-62887067, E-mail:
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15
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Jang JW, Yoo SH, Nam HC, Jang BH, Sung Sung PS, Lee W, Kwon JH, Nam SW, Bae SH, Yoon SK, Choi JY. Association of Prophylactic Anti-Hepatitis B Virus Therapy With Improved Long-term Survival in Patients With Hepatocellular Carcinoma Undergoing Transarterial Therapy. Clin Infect Dis 2021; 71:546-555. [PMID: 31504352 DOI: 10.1093/cid/ciz860] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 08/30/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The effect of prophylactic antiviral therapy (AVT) on survival of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains unknown. This study aimed to determine whether prophylactic AVT could improve long-term survival in patients undergoing transarterial chemotherapy (TAC). METHODS Between 2002 and 2016, 2860 newly diagnosed HBV-related patients with HCC treated with TAC were screened to analyze 2 groups based on prophylactic use of antivirals. Treatment effects were analyzed using propensity score (PS) matching (1:1) separately for the entire cohort and each subgroup. The primary endpoint was overall survival. RESULTS A total of 1547 patients met the inclusion criteria and 1084 were PS matched for the 2 groups. Median follow-up duration was 16.55 months. In the entire unmatched cohort, patients receiving prophylactic AVT survived significantly longer than those who did not. Among AVT-untreated patients, baseline high viremia and HBV reactivation during treatment were significantly associated with shorter survival. Regarding types of antivirals, survival was significantly longer for patients receiving high-potency antivirals than those receiving low-potency antivirals. Survival differed with antiviral response. In the PS-matched cohort, the prophylactic AVT group survived significantly longer than the nonprophylactic group, irrespective of viral status or tumor stage. Prophylactic AVT remained an independent factor for survival. The association of prophylactic AVT with decreased risk of mortality persisted in patient subgroups after adjusting for baseline risk factors. Sensitivity analyses also confirmed estimated treatment effects. CONCLUSIONS Prophylactic AVT is associated with significantly improved long-term survival among patients undergoing TAC. High-potency antivirals are indicated for this approach.Hepatitis B virus-associated morbidity is a well-known complication during transarterial chemotherapy (TAC). Our large-scale study demonstrated that prophylactic therapy with high-potency antivirals provides a significantly better survival in TAC-treated patients, irrespective of baseline viremia status or tumor stage.
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Affiliation(s)
- Jeong Won Jang
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Sun Hong Yoo
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Hee Chul Nam
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Bo Hyun Jang
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Pil Soo Sung Sung
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Won Lee
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Jung Hyun Kwon
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Soon Woo Nam
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Si Hyun Bae
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Seung Kew Yoon
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Jong Young Choi
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
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16
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Liu S, Lai J, Lyu N, Xie Q, Cao H, Chen D, He M, Zhang B, Zhao M. Effects of Antiviral Therapy on HBV Reactivation and Survival in Hepatocellular Carcinoma Patients Undergoing Hepatic Artery Infusion Chemotherapy. Front Oncol 2021; 10:582504. [PMID: 33614477 PMCID: PMC7890701 DOI: 10.3389/fonc.2020.582504] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 12/16/2020] [Indexed: 01/27/2023] Open
Abstract
Background This study aimed to investigate the influence of hepatic artery infusion chemotherapy (HAIC) on hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg) positive patients with primary hepatocellular carcinoma (HCC) as well as evaluate the role of antiviral prophylaxis in these patients. Methods We enrolled 170 HBsAg-positive advanced HCC patients receiving HAIC using mFOLFOX regimen, of which 137 patients received antiviral prophylaxis. Risk factors for HBV reactivation were analyzed. The overall survival (OS) from the first application of HAIC were compared between antiviral and non-antiviral groups. Results A total of 25 patients (14.7%) developed HBV reactivation after HAIC, of which 16 patients received antiviral treatment and nine patients did not. The incidence of HBV reactivation was 11.7% (16/137) in antiviral group and 27.3% (9/33) in non-antiviral group respectively. No antiviral prophylactic was the only significant risk factor for HBV reactivation (OR=12.35, 95% confidence interval (CI) 4.35–33.33, p<0.001). Patients in antiviral group received more cycles of HAIC compared with non-antiviral group (3.11 ± 1.69 vs 1.75 ± 1.18, p<0.05) at the time of HBV reactivated. Seven of the 25 HBV reactivation patients developed hepatitis. OS in antiviral group was significantly longer than that of non-antiviral group (median 16.46 vs 10.68 months; HR=0.57; 95% CI, 0.36–0.91; p<0.05). Conclusions HBV reactivation is more prone to occur in the HBsAg-positive HCC patients undergoing HAIC without antiviral prophylaxis. Regular monitoring of HBV DNA and antiviral prophylaxis are suggested to prevent HBV reactivation as well as prolong the OS of these patients. Name of the Trial Register HAIC Using Oxaliplatin Plus Fluorouracil/Leucovorin for Patients with Locally Advanced HCC. Clinical Trial Registration https://www.clinicaltrials.gov/, identifier NCT 02436044
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Affiliation(s)
- Shousheng Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of the General Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jinfa Lai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Minimally Invasive Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ning Lyu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Minimally Invasive Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qiankun Xie
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Huijiao Cao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of the General Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Dabiao Chen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Meng He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Minimally Invasive Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Bei Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of the General Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ming Zhao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Minimally Invasive Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China
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17
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Yang K, Sung PS, You YK, Kim DG, Oh JS, Chun HJ, Jang JW, Bae SH, Choi JY, Yoon SK. Pathologic complete response to chemoembolization improves survival outcomes after curative surgery for hepatocellular carcinoma: predictive factors of response. HPB (Oxford) 2019; 21:1718-1726. [PMID: 31171489 DOI: 10.1016/j.hpb.2019.04.017] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 04/09/2019] [Accepted: 04/22/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND We identified the predictive factors and prognostic significance of transarterial chemoembolization (TACE) for achieving pathologic complete response (pCR) before curative surgery for hepatocellular carcinoma (HCC) in hepatitis B-endemic areas. METHODS Among 753 HCC patients treated with surgery, 124 patients underwent preoperative TACE before liver resection (LR), and 166 before liver transplantation (LT) between 2005 and 2016. Overall survival (OS) and recurrence-free survival (RFS) were analyzed. Pathologic response (PR) was defined as the mean percentage of necrotic area, and pCR was defined as the absence of viable tumor. RESULTS A total of 34 (27%) and 38 (23%) patients had pCR before LR and LT, respectively. Alpha-fetoprotein (AFP) < 100 ng/mL and single tumor were significant preoperative predictors of pCR. OS and RFS were significantly improved in patients with pCR or a PR ≥ 90%, but not in patients with PR ≥ 50% after LR and LT. On multivariate analyses, PR ≥ 90% remained an independent predictor of better OS and RFS in LR and LT groups. CONCLUSION Overall, our data clearly demonstrate that pCR predicts favorable prognosis after curative surgery for HCC, and predictors of pCR are AFP <100 ng/mL and single tumor.
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Affiliation(s)
- Keungmo Yang
- Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Pil S Sung
- Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Young K You
- Department of Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Dong G Kim
- Department of Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Jung S Oh
- Department of Radiology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Ho J Chun
- Department of Radiology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Jeong W Jang
- Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Si H Bae
- Department of Internal Medicine, St. Paul's Hospital, The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, 02559, Republic of Korea
| | - Jong Y Choi
- Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Seung K Yoon
- Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, 06591, Republic of Korea.
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18
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Kim TS, Sinn DH, Kang W, Gwak GY, Paik YH, Choi MS, Lee JH, Koh KC, Paik SW. Hepatitis B virus DNA levels and overall survival in hepatitis B-related hepatocellular carcinoma patients with low-level viremia. J Gastroenterol Hepatol 2019; 34:2028-2035. [PMID: 31157456 DOI: 10.1111/jgh.14750] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 05/23/2019] [Accepted: 05/27/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Clinical course of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients presenting with low-level viremia (LLV) is unclear. METHODS A total of 565 HBV-related HCC patients with LLV (detectable but HBV DNA ≤ 2000 IU/mL) at the time of HCC diagnosis were analyzed. Based on patterns of HBV DNA levels during follow-up, patients were categorized into three groups: maintained virologic remission (MVR), LLV, and flare. Overall survival was compared between those three groups. RESULTS During a median 4.5 years of follow-up, 33% showed MVR, 39% showed LLV, and 28% experienced flare. The overall survival differed between MVR, LLV, and flare groups (5-year overall survival: 74.3%, 67.3%, and 61.7%, respectively, 0.015). The patterns of HBV DNA levels were independent factors associated with overall survival, along with age, antiviral treatment, Barcelona clinic liver cancer stage, and initial treatment modality. Flare group showed increased risk of mortality (adjusted hazard ratio [HR] 1.71, 95% confidence interval [CI] 1.15-2.55) compared with MVR group, while the risk was statistically marginal for the LLV group (adjusted HR 1.39, 95% CI 0.95-2.04). During follow-up, 183 patients (32.4%) newly started antiviral therapy (AVT) at LLV. Flare risk was significantly lower among patients who started AVT at LLV compared with those who did not (adjusted HR 0.26, 95% CI 0.17-0.38). CONCLUSIONS Among HBV-related HCC patients with LLV, flare was frequent during follow-up and was associated with poorer overall survival compared with MVR group. Prospective studies that address whether inducing MVR by early AVT improves patient outcome are warranted.
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Affiliation(s)
- Tae-Se Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Wonseok Kang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yong-Han Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Moon Seok Choi
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Hyeok Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kwang Cheol Koh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Woon Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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19
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2018 Korean Liver Cancer Association-National Cancer Center Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Korean J Radiol 2019; 20:1042-1113. [PMID: 31270974 PMCID: PMC6609431 DOI: 10.3348/kjr.2019.0140] [Citation(s) in RCA: 191] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 02/24/2019] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and the fourth most common cancer in men in Korea, where the prevalence of chronic hepatitis B infection is high in middle-aged and elderly patients. These practice guidelines will provide useful and constructive advice for the clinical management of patients with HCC. A total of 44 experts in hepatology, oncology, surgery, radiology, and radiation oncology in the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2014 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions.
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20
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2019; 25:93-159. [PMID: 31185710 PMCID: PMC6589848 DOI: 10.3350/cmh.2019.1002] [Citation(s) in RCA: 161] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
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21
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2018 Korean Liver Cancer Association-National Cancer Center Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Gut Liver 2019; 13:227-299. [PMID: 31060120 PMCID: PMC6529163 DOI: 10.5009/gnl19024] [Citation(s) in RCA: 239] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 01/24/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and the fourth most common cancer in men in Korea, where the prevalence of chronic hepatitis B infection is high in middle-aged and elderly patients. These practice guidelines will provide useful and constructive advice for the clinical management of patients with HCC. A total of 44 experts in hepatology, oncology, surgery, radiology and radiation oncology in the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2014 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions.
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22
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Zhang SS, Liu JX, Zhu J, Xiao MB, Lu CH, Ni RZ, Qu LS. Effects of TACE and preventive antiviral therapy on HBV reactivation and subsequent hepatitis in hepatocellular carcinoma: a meta-analysis. Jpn J Clin Oncol 2019; 49:646-655. [PMID: 30968933 DOI: 10.1093/jjco/hyz046] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 03/02/2019] [Accepted: 03/09/2019] [Indexed: 02/06/2023] Open
Abstract
Abstract
Background and aim
The impact of transarterial chemoembolization (TACE) and preventive antiviral therapy on the occurrence of hepatitis B virus (HBV) reactivation and subsequent hepatitis remains controversial. This meta-analysis aimed to evaluate the effect of TACE and preventive antiviral therapy on the risk of HBV reactivation and subsequent hepatitis. Meanwhile, we explored the role of HBeAg status in HBV reactivation after TACE.
Methods
We performed this meta-analysis with 11 included studies to assess the effect of TACE and preventive antiviral therapy on predicting clinical outcomes in HBV-related hepatocellular carcinoma (HCC). The pooled odds ratios (OR) were calculated using a random or fixed effects model. PUBMED, MEDLINE, EMBASE and the Cochrane Central Register of Controlled were searched for the included articles (from 2000 to December 2017).
Results
Our results showed that TACE significantly increased the risk of HBV reactivation (OR: 3.70; 95% CI 1.45–9.42; P < 0.01) and subsequent hepatitis (OR: 4.30; 95% CI 2.28–8.13; P < 0.01) in HCC patients. There was no significant difference in HBV reactivation after TACE between HBeAg positive and negative patients (OR: 1.28; 95% CI 0.31–5.34; P = 0.73). Preventive antiviral therapy could statistically reduce the rate of HBV reactivation (OR: 0.08; 95% CI 0.02–0.32; P < 0.01) and hepatitis (OR: 0.22; 95% CI 0.06–0.80; P = 0.02) in those with TACE treatment.
Conclusions
The present study suggested that TACE was associated with a higher possibility of HBV reactivation and subsequent hepatitis. Preventive antiviral therapy is significantly in favor of a protective effect.
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Affiliation(s)
- Su-Su Zhang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu, China
| | - Jin-Xia Liu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu, China
| | - Jing Zhu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu, China
| | - Ming-Bing Xiao
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu, China
| | - Cui-Hua Lu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu, China
| | - Run-Zhou Ni
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu, China
| | - Li-Shuai Qu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu, China
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23
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Chen X, Hu Y, Zhang W, Chen K, Hu J, Li X, Liang L, Cai X, Hu J, Wang K, Huang A, Tang N. Cisplatin induces autophagy to enhance hepatitis B virus replication via activation of ROS/JNK and inhibition of the Akt/mTOR pathway. Free Radic Biol Med 2019; 131:225-236. [PMID: 30550853 DOI: 10.1016/j.freeradbiomed.2018.12.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 12/06/2018] [Accepted: 12/10/2018] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis B virus (HBV) infection remains a serious global health concern. Cisplatin is a chemotherapeutic agent commonly used to treat various cancers. However, HBV-infected patients receiving chemotherapy are at risk of HBV reactivation via unknown mechanisms, which we aimed to elucidate in this study. We found that autophagy plays a central role in cisplatin-induced HBV replication. Cisplatin treatment induced autophagy in both HBV-replicating cells and an HBV-transgenic mouse model as evident from marked upregulation of microtubule-associated protein 1 light chain 3 (LC3)-II and the accumulation of red fluorescent protein (RFP)-LC3 puncta. Cisplatin induced complete autophagic flux, which was detected via monitoring of p62 degradation and RFP-GFP-LC3 expression. Inhibition of autophagy by chloroquine, 3-methyladenine, or Atg5 knockdown significantly attenuated cisplatin-induced HBV replication. Additionally, cisplatin-induced autophagy could be significantly attenuated by using the ROS scavenger N-acetyl-l-cysteine. Mechanically, cisplatin promoted HBV replication and autophagy through ROS/JNK and AKT/mTOR signaling. Inhibition of JNK or activation of Akt/mTOR signaling reversed cisplatin-mediated autophagy and HBV replication promotion. In contrast, suppression of Akt/mTOR signaling further promoted cisplatin-induced HBV replication. Finally, pharmacotherapeutic inhibition of autophagy or ROS production impaired HBV production induced by cisplatin in vivo. Together, our results indicate that ROS/JNK and mTOR/AKT-mediated autophagy plays an important role in cisplatin-induced HBV reactivation.
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Affiliation(s)
- Xuemei Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yuan Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Wenlu Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ke Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Jie Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Xiaosong Li
- The First Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Li Liang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Xuefei Cai
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Jieli Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Kai Wang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Ailong Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Ni Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
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24
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Hayashi M, Abe K, Fujita M, Okai K, Takahashi A, Ohira H. Hepatitis B Virus Reactivation in a Patient with Nonalcoholic Steatohepatitis 41 Months after Rituximab-containing Chemotherapy. Intern Med 2019; 58:375-380. [PMID: 30210131 PMCID: PMC6395117 DOI: 10.2169/internalmedicine.1587-18] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Hepatitis B virus (HBV) reactivation occasionally occurs long after immunosuppressive therapy. The characteristics of late HBV reactivation remain unclear. We herein present a case of HBV reactivation in a patient with nonalcoholic steatohepatitis (NASH) more than 3 years after rituximab-containing chemotherapy for diffuse large B-cell lymphoma. Increased transaminase levels, which were induced by NASH, were observed after chemotherapy and were alleviated with statin treatment. HBV reactivation was identified incidentally. The patient developed hepatitis that improved with entecavir therapy. Our case might indicate that the presence of NASH is associated with HBV reactivation long after treatment and that statins, as immune-modulatory agents, affect HBV reactivation.
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Affiliation(s)
- Manabu Hayashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Kazumichi Abe
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Masashi Fujita
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Ken Okai
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
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25
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Jun BG, Kim YD, Kim SG, Kim YS, Jeong SW, Jang JY, Lee SH, Kim HS, Kang SH, Kim MY, Baik SK, Lee M, Kim TS, Choi DH, Choi SH, Suk KT, Kim DJ, Cheon GJ. Hepatitis B virus reactivation after radiotherapy for hepatocellular carcinoma and efficacy of antiviral treatment: A multicenter study. PLoS One 2018; 13:e0201316. [PMID: 30059513 PMCID: PMC6066246 DOI: 10.1371/journal.pone.0201316] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 07/12/2018] [Indexed: 02/06/2023] Open
Abstract
Convincing data that support routine use of preventive therapy against hepatitis B virus (HBV) reactivation in radiotherapy (RT) for hepatocellular carcinoma (HCC) are lacking. The aim of this study was to investigate the incidence, clinical significance, and risk factors of HBV reactivation after RT. Medical records of 133 HBsAg (+) HCC patients who received radiotherapy from March 2009 to February 2016 were reviewed. Patients were divided into two groups: 1) non-antiviral group, those who did not receive antiviral therapy before RT (n = 27); and antiviral group (those who underwent antiviral therapy before RT) (n = 106). Factors related to HBV reactivation in HCC patients were evaluated. 17 (12.7%) of 133 patients developed HBV reactivation after RT. Patients in the antiviral group had significantly lower rates of HBV reactivation than those in the non-antiviral group (7.5% vs. 33.3%, p<0.001). HBV related hepatitis was also lower in the antiviral group (3.8% vs. 14.8%, p = 0.031). In multivariate analysis, absence of antiviral treatment (OR: 8.339, 95% CI: 2.532-27.470, p<0.001) and combined treatment of RT with transarterial chemoembolizatoin (TACE) (OR: 5.313, 95% CI: 1.548-18.232, p = 0.008) were risk factors for HBV reactivation. HBV reactivation can occur after radiotherapy. Combination treatment of RT with TACE and non-antiviral treatment are major risk factors for HBV reactivation during or after RT. Therefore, preventive antiviral therapy should be recommended for patients with HCC who are scheduled to receive RT.
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Affiliation(s)
- Baek Gyu Jun
- Department of Internal Medicine, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung, South Korea
| | - Young Don Kim
- Department of Internal Medicine, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung, South Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine Bucheon Hospital, Bucheon, South Korea
| | - Young Seok Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine Bucheon Hospital, Bucheon, South Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Soonchunhyang University College of Medicine Seoul Hospital, Seoul, South Korea
| | - Jae Young Jang
- Department of Internal Medicine, Soonchunhyang University College of Medicine Seoul Hospital, Seoul, South Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine Cheonan Hospital, Cheonan, South Korea
| | - Hong Soo Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine Cheonan Hospital, Cheonan, South Korea
| | - Seong Hee Kang
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, South Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, South Korea
| | - Soon Koo Baik
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, South Korea
| | - Minjong Lee
- Department of Internal medicine, Kangwon National University Hospital, Chuncheon, South Korea
| | - Tae-Suk Kim
- Department of Internal medicine, Kangwon National University Hospital, Chuncheon, South Korea
| | - Dae Hee Choi
- Department of Internal medicine, Kangwon National University Hospital, Chuncheon, South Korea
| | - Sang-Hyeon Choi
- Department of Internal Medicine Hallym University College of Medicine, Chuncheon, South Korea
| | - Ki Tae Suk
- Department of Internal Medicine Hallym University College of Medicine, Chuncheon, South Korea
| | - Dong Joon Kim
- Department of Internal Medicine Hallym University College of Medicine, Chuncheon, South Korea
| | - Gab Jin Cheon
- Department of Internal Medicine, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung, South Korea
- * E-mail:
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26
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Wang K, Jiang G, Jia Z, Zhu X, Ni C. Effects of transarterial chemoembolization combined with antiviral therapy on HBV reactivation and liver function in HBV-related hepatocellular carcinoma patients with HBV-DNA negative. Medicine (Baltimore) 2018; 97:e10940. [PMID: 29851833 PMCID: PMC6392611 DOI: 10.1097/md.0000000000010940] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The aim of this study was to investigate the reactivation of the hepatitis B virus (HBV) following transarterial chemoembolization (TACE) in primary hepatocellular carcinoma (HCC) patients with HBV-DNA negative and to evaluate the effects of TACE combined with antiviral therapy. METHODS This prospective study involved 98 patients with HBV-related and HBV-DNA negative HCC (HBV DNA < 10 copies/mL) underwent TACE procedures with serial HBV DNA tests. Patients were divided into the antiviral treatment group and the no-antiviral group. The antiviral group received entecavir antiviral therapy, and the other group received no antiviral therapy. Two groups of patients were compared in rate of HBV reactivation and liver function before and after only 1 session of TACE in average 1-month follow-up after operation. P < .05 indicated differences with a statistical significance. RESULTS HBV reactivation occurred in 11 patients in the nonantiviral group (11/47, 23.4%) but only 3 patients in the antiviral group (3/51, 5.9%, P < .05). On multivariate analysis, HBeAg-positive status, number of tumors more than 3, and absence of antiviral therapy were the independent risk predictor of HBV reactivation. Liver function indicators did not differ significantly between the antiviral group and the nonantiviral group in 5 days after TACE. However, the level of alanine aminotransferase and bilirubin were raised and albumin was reduced at the HBV reactivation group compared with no HBV reactivation group (P < .05). At 1 month after TACE, liver function indicators did not differ significantly between the HBV reactivation group and without HBV reactivation group. CONCLUSION HCC patients with HBV DNA negative still remain associated with risk of HBV reactivation after TACE. HBeAg-positive, number of tumors more than 3, and absence of antiviral therapy in HCC patients after TACE have a higher risk of HBV reactivation. Antiviral therapy can reduce the risk of reactivation, helping improve liver function after TACE.
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Affiliation(s)
- Kai Wang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou
- Department of Interventional Radiology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, China
| | - Guomin Jiang
- Department of Interventional Radiology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, China
| | - Zhongzhi Jia
- Department of Interventional Radiology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, China
| | - Xiaoli Zhu
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou
| | - Caifang Ni
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou
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Toesca DAS, Ibragimov B, Koong AJ, Xing L, Koong AC, Chang DT. Strategies for prediction and mitigation of radiation-induced liver toxicity. JOURNAL OF RADIATION RESEARCH 2018; 59:i40-i49. [PMID: 29432550 PMCID: PMC5868188 DOI: 10.1093/jrr/rrx104] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 12/12/2017] [Indexed: 05/07/2023]
Abstract
Although well described in the 1960s, liver toxicity secondary to radiation therapy, commonly known as radiation-induced liver disease (RILD), remains a major challenge. RILD encompasses two distinct clinical entities, a 'classic' form, composed of anicteric hepatomegaly, ascites and elevated alkaline phosphatase; and a 'non-classic' form, with liver transaminases elevated to more than five times the reference value, or worsening of liver metabolic function represented as an increase of 2 or more points in the Child-Pugh score classification. The risk of occurrence of RILD has historically limited the applicability of radiation for the treatment of liver malignancies. With the development of 3D conformal radiation therapy, which allowed for partial organ irradiation based on computed tomography treatment planning, there has been a resurgence of interest in the use of liver irradiation. Since then, a large body of evidence regarding the liver tolerance to conventionally fractionated radiation has been produced, but severe liver toxicities has continued to be reported. More recently, improvements in diagnostic imaging, radiation treatment planning technology and delivery systems have prompted the development of stereotactic body radiotherapy (SBRT), by which high doses of radiation can be delivered with high target accuracy and a steep dose gradient at the tumor - normal tissue interface, offering an opportunity of decreasing toxicity rates while improving tumor control. Here, we present an overview of the role SBRT has played in the management of liver tumors, addressing the challenges and opportunities to reduce the incidence of RILD, such as adaptive approaches and machine-learning-based predictive models.
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Affiliation(s)
- Diego A S Toesca
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Bulat Ibragimov
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Amanda J Koong
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Lei Xing
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Albert C Koong
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Daniel T Chang
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
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28
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Li X, Pan E, Zhu J, Xu L, Chen X, Li J, Liang L, Hu Y, Xia J, Chen J, Chen W, Hu J, Wang K, Tang N, Huang A. Cisplatin Enhances Hepatitis B Virus Replication and PGC-1α Expression through Endoplasmic Reticulum Stress. Sci Rep 2018; 8:3496. [PMID: 29472690 PMCID: PMC5823916 DOI: 10.1038/s41598-018-21847-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 02/12/2018] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B infection remains a serious public health issue worldwide. Hepatitis B virus (HBV) reactivation is commonly reported in patients receiving anticancer therapy, immunosuppressive therapy, or organ and tissue transplantation. However, the precise mechanisms underlying chemotherapeutic agent-related HBV reactivation remain unclear. Here, we report that peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) plays a central role in cisplatin-induced HBV transcription and replication. First, cisplatin treatment upregulated the expression levels of PGC-1α and hepatocyte nuclear factor 4 alpha (HNF-4α) in both HBV-replicating cells and an HBV-transgenic mouse model. PGC-1α coactivates with HNF-4α, which interacts with a core promoter and enhancer II region of HBV genome, thereby promoting HBV production. In contrast, knockdown of PGC-1α and HNF-4α by RNA interference in hepatoma cells reversed HBV activation in response to cisplatin. Additionally, PGC-1α upregulation depended on cisplatin-mediated endoplasmic reticulum (ER) stress. We further observed that the recruitment of cyclic AMP-responsive element-binding protein plays a crucial role for PGC-1α transcriptional activation in cisplatin-treated cells. Finally, pharmacologic inhibition of ER stress impaired PGC-1α upregulation and HBV production induced by cisplatin treatment. These findings demonstrate novel molecular mechanisms indicating that ER stress-PGC1α signaling pathway plays a critical role in cisplatin-evoked HBV reactivation.
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Affiliation(s)
- Xiaosong Li
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - E Pan
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Junke Zhu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Lei Xu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Xuemei Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Jingjing Li
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Li Liang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yuan Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Jie Xia
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Juan Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Wannan Chen
- Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou Fujian, China
| | - Jieli Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Kai Wang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ni Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Ailong Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. .,The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (CCID), Zhejiang University, Hangzhou, China.
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29
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Pinato DJ, Arizumi T, Jang JW, Allara E, Suppiah PI, Smirne C, Tait P, Pai M, Grossi G, Kim YW, Pirisi M, Kudo M, Sharma R. Combined sequential use of HAP and ART scores to predict survival outcome and treatment failure following chemoembolization in hepatocellular carcinoma: a multi-center comparative study. Oncotarget 2018; 7:44705-44718. [PMID: 27244889 PMCID: PMC5190130 DOI: 10.18632/oncotarget.9604] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 04/26/2016] [Indexed: 02/07/2023] Open
Abstract
Background The prognosis of patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) is variable, despite a myriad of prognostic markers. We compared and integrated the established prognostic models, HAP and ART scores, for their accuracy of overall survival (OS) prediction. Results In both training and validation sets, HAP and ART scores emerged as independent predictors of OS (p<0.01) with HAP achieving better prognostic accuracy (c-index: 0.68) over ART (0.57). We tested both scores in combination to evaluate their combined ability to predict OS. Subgroup analysis of BCLC-C patients revealed favorable HAP stage (p<0.001) and radiological response after initial TACE (p<0.001) as positive prognostic factors. Patients and Methods Prognostic scores were studied using multivariable Cox regression and c-index analysis in 83 subjects with Barcelona Clinic Liver Cancer (BCLC) A/B stage from UK and Italy (training set), and 660 from Korea and Japan (validation set), all treated with conventional TACE. Scores were further validated in an separate analysis of patients with BCLC-C stage disease (n=63) receiving initial TACE. Conclusion ART and HAP scores are validated indices in patients with intermediate stage HCC undergoing TACE. The HAP score is best suited for screening patients prior to initial TACE, whilst sequential ART assessment improves early detection of chemoembolization failure. BCLC-C patients with low HAP stage may be a subgroup where TACE should be explored in clinical studies.
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Affiliation(s)
- David J Pinato
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Tadaaki Arizumi
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan
| | - Jeong Won Jang
- Department of Internal Medicine, The Catholic University of Korea Incheon St. Mary's Hospital, Seoul, Republic of Korea
| | - Elias Allara
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Novara, Italy.,School of Public Health, Università degli Studi di Torino, Torino, Italy
| | - Puvan I Suppiah
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Carlo Smirne
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Novara, Italy
| | - Paul Tait
- Department of Radiology, Imperial College NHS Trust, Hammersmith Hospital, London, UK
| | - Madhava Pai
- Department of Surgery, Imperial College NHS Trust, Hammersmith Hospital, London, UK
| | - Glenda Grossi
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Novara, Italy
| | - Young Woon Kim
- Department of Internal Medicine, The Catholic University of Korea Incheon St. Mary's Hospital, Seoul, Republic of Korea
| | - Mario Pirisi
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Novara, Italy.,Interdisciplinary Research Center of Autoimmune Diseases, Università degli Studi del Piemonte Orientale "A. Avogadro", Novara, Italy
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan
| | - Rohini Sharma
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
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30
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Xu Z, Dai W, Wu YT, Arshad B, Li X, Wu H, Chen HR, Wu KN, Kong LQ. Prophylactic effect of lamivudine on chemotherapy-induced hepatitis B virus reactivation in patients with solid tumour: A meta-analysis. Eur J Cancer Care (Engl) 2017; 27:e12799. [PMID: 29265535 DOI: 10.1111/ecc.12799] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/21/2017] [Indexed: 01/03/2023]
Abstract
Hepatitis B virus (HBV) reactivation is a remarkable risk during the chemotherapy for solid tumour patients. Nucleos(t)ide analogues (NAs) are recommended as prophylaxis for the reactivation of HBV infection in some cancer patients prior to systemic chemotherapy. Therefore, we performed a meta-analysis aiming to determine the efficacy of prophylactic lamivudine on prevention of HBV reactivation and its related negative outcomes among solid tumour patients with chronic HBV infection receiving systemic chemotherapy. The primary outcome was HBV reactivation, and the secondary outcomes were HBV-related hepatitis, chemotherapy disruption, mortality and tyrosine-methio-nine-aspartate-aspartate (YMDD) mutations. Twelve original researches involving 1,101 patients were analysed in this study. The relative risk of HBV reactivation in patients with lamivudine prophylaxis was significantly lower than that without prophylaxis (RR = 0.17, 95% CL: 0.10-0.29, p < .00001). Lamivudine prophylaxis reduced the relative risk of hepatitis (p < .00001), chemotherapy disruptions (p = .01) and mortality (p = .08) due to HBV reactivation. Lamivudine prophylaxis is effective in reducing HBV reactivation and its related negative outcomes, such as hepatitis and chemotherapy disruption and mortality among chemotherapeutic solid tumour patients with chronic HBV infection. Future studies should lay more emphasis on the early HBV screening, mode of treatment and duration of NAs prophylaxis among solid tumour patients receiving chemotherapy.
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Affiliation(s)
- Z Xu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - W Dai
- Department of Orthopaedics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Y-T Wu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - B Arshad
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - X Li
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - H Wu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - H-R Chen
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - K-N Wu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - L-Q Kong
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Gonzalez SA, Perrillo RP. Hepatitis B Virus Reactivation in the Setting of Cancer Chemotherapy and Other Immunosuppressive Drug Therapy. Clin Infect Dis 2017; 62 Suppl 4:S306-13. [PMID: 27190320 DOI: 10.1093/cid/ciw043] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus reactivation (HBVr) is an important complication of immunosuppressive drug therapy (ISDT). It can occur with active or resolved hepatitis B virus (HBV) infection with a clinical spectrum that ranges from mild elevations in liver tests to fulminant hepatic failure. The risk of it occurring is determined by the interplay between HBV serological status, level of viremia, and the immunosuppressive potency of the drug(s) used. Reactivation is most common during treatment of hematologic malignancies but also occurs with chemotherapy for breast cancer and numerous other solid organ malignancies, organ transplant, and immune suppression for nonmalignant conditions. The expansion of new biologic treatments for malignant and nonmalignant disorders has enlarged the population at risk. Increased awareness of HBVr among healthcare providers who prescribe ISDT, adoption of routine HBV screening, and linking the results of screening to antiviral prophylaxis are needed to reduce the incidence of this potentially fatal but preventable disorder.
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Affiliation(s)
- Stevan A Gonzalez
- Division of Hepatology, Annette C. and Harold C. Simmons Transplant Institute, Baylor All Saints Medical Center, Fort Worth
| | - Robert P Perrillo
- Division of Hepatology, Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas
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Voican C, Mir O, Loulergue P, Dhooge M, Brezault C, Dréanic J, Chaussade S, Pol S, Coriat R. Hepatitis B virus reactivation in patients with solid tumors receiving systemic anticancer treatment. Ann Oncol 2016; 27:2172-2184. [DOI: 10.1093/annonc/mdw414] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2014] [Revised: 05/11/2015] [Accepted: 08/23/2016] [Indexed: 02/06/2023] Open
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Li X, Zhong X, Chen ZH, Wang TT, Ma XK, Xing YF, Wu DH, Dong M, Chen J, Ruan DY, Lin ZX, Wen JY, Wei L, Wu XY, Lin Q. Efficacy of Prophylactic Entecavir for Hepatitis B Virus-Related Hepatocellular Carcinoma Receiving Transcatheter Arterial Chemoembolization. Asian Pac J Cancer Prev 2016; 16:8665-70. [PMID: 26745134 DOI: 10.7314/apjcp.2015.16.18.8665] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND AND AIMS Hepatitis B virus (HBV) reactivation was reported to be induced by transcatheter arterial chemoembolization (TACE) in HBV-related hepatocellular carcinonma (HCC) patients with a high incidence. The effective strategy to reduce hepatitis flares due to HBV reactivation in this specific group of patients was limited to lamivudine. This retrospective study was aimed to investigate the efficacy of prophylactic entecavir in HCC patients receiving TACE. METHODS A consecutive series of 191 HBV-related HCC patients receiving TACE were analyzed including 44 patients received prophylactic entecavir. Virologic events, defined as an increase in serum HBV DNA level to more than 1 log10 copies/ml higher than nadir the level, and hepatitis flares due to HBV reactivation were the main endpoints. RESULTS Patients with or without prophylactic were similar in host factors and the majorities of characteristics regarding to tumor factors, HBV status, liver function and LMR. Notably, cycles of TACE were parallel between the groups. Ten (22.7%) patients receiving prophylactic entecavir reached virologic response. The patients receiving prophylactic entecavir presented significantly reduced virologic events (6.8% vs 54.4%, p=0.000) and hepatitis flares due to HBV reactivation (0.0% vs 11.6%, p=0.039) compared with patients without prophylaxis. Kaplan-Meier analysis illustrated that the patients in the entecavir group presented significantly improved virologic events free survival (p=0.000) and hepatitis flare free survival (p=0.017). Female and Eastern Cooperative Oncology Group (ECOG) performance status 2 was the only significant predictors for virological events in patients without prophylactic antiviral. Rescue antiviral therapy did not reduce the incidence of hepatitis flares due to HBV reactivation. CONCLUSION Prophylactic entecavir presented promising efficacy in HBV-related cancer patients receiving TACE. Lower performance status and female gender might be the predictors for HBV reactivation in these patients.
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Affiliation(s)
- Xing Li
- Department of Medical Oncology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China E-mail : ;
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Lin XJ, Lao XM, Shi M, Li SP. Changes of HBV DNA After Chemoembolization for Hepatocellular Carcinoma and the Efficacy of Antiviral Treatment. Dig Dis Sci 2016; 61:2465-76. [PMID: 27105647 DOI: 10.1007/s10620-016-4167-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 04/13/2016] [Indexed: 02/07/2023]
Abstract
Unlike systemic chemotherapy for hematological malignancies with hepatitis B virus (HBV) infection, transarterial chemoembolization (TACE) for HBV-related hepatocellular carcinoma (HCC) has only recently been reported to cause HBV reactivation and subsequent hepatitis. Most patients with HBV-related HCC have an underlying disease with liver fibrosis or cirrhosis, and TACE may potentially induce HBV reactivation and liver decompensation. Currently, there are no clinical guidelines for managing TACE-caused HBV reactivation. In this review, we summarize the changes of HBV status and liver function after TACE and the effect of antiviral treatment before, during, or after TACE.
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Affiliation(s)
- Xiao-Jun Lin
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, 651, Dongfeng Road East, Guangzhou, 510060, Guangdong, People's Republic of China
- State Key Laboratory of Southern China, Guangzhou, 510060, Guangdong, People's Republic of China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Xiang-Ming Lao
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, 651, Dongfeng Road East, Guangzhou, 510060, Guangdong, People's Republic of China.
- State Key Laboratory of Southern China, Guangzhou, 510060, Guangdong, People's Republic of China.
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, People's Republic of China.
| | - Ming Shi
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, 651, Dongfeng Road East, Guangzhou, 510060, Guangdong, People's Republic of China
- State Key Laboratory of Southern China, Guangzhou, 510060, Guangdong, People's Republic of China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Sheng-Ping Li
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, 651, Dongfeng Road East, Guangzhou, 510060, Guangdong, People's Republic of China
- State Key Laboratory of Southern China, Guangzhou, 510060, Guangdong, People's Republic of China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, People's Republic of China
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Yu JI, Park HC. Radiotherapy as valid modality for hepatocellular carcinoma with portal vein tumor thrombosis. World J Gastroenterol 2016; 22:6851-6863. [PMID: 27570422 PMCID: PMC4974584 DOI: 10.3748/wjg.v22.i30.6851] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 06/01/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Although the current standard treatment for hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is sorafenib, many previous studies have established the need for a reliable local modality for PVTT control, which is a major cause of liver function deterioration and metastasis. Additionally, there is growing evidence for the prognostic significance of PVTT classification according to the location of tumor thrombosis. Favorable outcomes can be obtained by applying local modalities, including surgery or transarterial chemoembolization, especially in second-order or distal branch PVTT. Rapid control of PVTT could maintain or improve liver function and reduce intrahepatic as well as distant metastasis. Radiotherapy (RT) is one of the main locoregional treatment modalities in oncologic fields, but has rarely been used in HCC because of concerns regarding hepatic toxicity. However, with the development of advanced techniques, RT has been increasingly applied in HCC management. Randomized studies have yet to definitively prove the benefit of RT, but several comparative studies have justified the application of RT in HCC. The value of RT is especially noticeable in HCC with PVTT; several prospective and retrospective studies have reported favorable outcomes, including a 40% to 60% objective response rate and median overall survival of 15 mo to 20 mo in responders. In this review, we evaluate the role of RT as an alternative local modality in HCC with PVTT.
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Méndez Romero A, de Man RA. Stereotactic body radiation therapy for primary and metastatic liver tumors: From technological evolution to improved patient care. Best Pract Res Clin Gastroenterol 2016; 30:603-16. [PMID: 27644908 DOI: 10.1016/j.bpg.2016.06.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Revised: 05/08/2016] [Accepted: 06/18/2016] [Indexed: 01/31/2023]
Abstract
Technical developments allowed stereotactic body radiation therapy (SBRT) to deliver effective doses of irradiation with high precision in a small number of fractions. This paper reviews the role of SBRT for liver metastases, hepatocellular carcinoma and cholangiocarcinoma, paying special attention to patient eligibility and treatment outcomes regarding local control, toxicity and quality of life. As well as discussing specific issues of these different tumors, such as the presence of underlying liver cirrhosis and the impact on toxicity, it outlines the limitations of SBRT and future areas of development and research.
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Affiliation(s)
- Alejandra Méndez Romero
- Department of Radiation Oncology, Erasmus MC University Medical Center (Cancer Institute), Rotterdam, The Netherlands.
| | - Robert A de Man
- Department of Gastroenterology & Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
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Cheng J, Pei HH, Sun J, Xie QX, Li JB. Radiation-induced hepatitis B virus reactivation in hepatocellular carcinoma: A case report. Oncol Lett 2015; 10:3213-3215. [PMID: 26722314 DOI: 10.3892/ol.2015.3724] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Accepted: 06/02/2015] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) reactivation associated with radiotherapy is rare. The present study reports the case of a 46-year-old man that experienced fatal HBV reactivation. The patient suffered from hepatocellular carcinoma (HCC) with portal vein tumor thrombus, which was treated by radiotherapy at a daily fraction of 2 Gy over 5 weeks, up to a total radiation dose of ~50 Gy. The patient presented with fatigue, yellow sclera and abdominal distension ~8 weeks subsequent to the administration of radiotherapy. The liver function tests, including the level of total bilirubin and prothrombin time, suggested acute-on-chronic liver failure. The serum HBV-DNA level had also increased between undetectable levels and 7.2×104 copies/ml. Although the present patient with HCC was treated with 0.5 mg/day entecavir for 8 weeks, in addition to radiotherapy, radiation-induced HBV reactivation occurred. The condition of the patient worsened gradually. The present study emphasizes the importance of liver function and HBV-DNA screening and pre-emptive antiviral prophylaxis prior to radiotherapy in patients with HCC.
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Affiliation(s)
- Jun Cheng
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Huan-Huan Pei
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Juan Sun
- Department of Science and Technology, Anhui University of Chinese Medicine, Hefei, Anhui 230038, P.R. China
| | - Qin-Xiu Xie
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Jia-Bin Li
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
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Shao W, Zhang F, Cong N, Li J, Song J. The hepatitis B virus reactivation after transarterial chemoembolization in Chinese hepatocellular carcinoma patients with low serum hepatitis B virus DNA level. Ther Clin Risk Manag 2015; 11:1367-70. [PMID: 26379440 PMCID: PMC4567233 DOI: 10.2147/tcrm.s91618] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Objective To investigate the reactivation of the hepatitis B virus (HBV) following transarterial chemoembolization (TACE) in Chinese hepatocellular carcinoma (HCC) patients with low serum HBV DNA level, and to analyze the factors related to HBV reactivation in HCC patients with low serum HBV DNA level. Methods From November 2011 to January 2014, 109 patients newly diagnosed with HCC with an HBV DNA level less than 2,000 IU/mL were enrolled in the study. These patients underwent at least two TACE procedures and were followed-up for at least 3 months to assess the reactivation of HBV DNA. Ten variables were compared in patients with and without HBV reactivation to evaluate the factors related to HBV reactivation in HCC patients with low serum HBV DNA level. Results Of 109 HCC patients with low level HBV DNA, nine patients were HBeAg-positive, the other 100 patients were HBeAg-negative. Twenty-three of 109 (21.1%) patients developed HBV reactivation after TACE. Of nine HBeAg-positive patients, 55.6% (5/9) developed HBV reactivation, while in 100 HBeAg-negative patients, the rate of HBV reactivation was 18% (18/100) (P=0.019). Of ten variables of patients with low level HBV DNA, the levels of AFP and HBeAg status were found to be significantly correlated with HBV reactivation. Nevertheless, on binary logistic regression analysis, only HBeAg-positive status was the independent predictor of HBV reactivation in HCC patients with low serum HBV DNA level (odds ratio, 7.41; P=0.013). Conclusion HCC patients with low serum HBV DNA level still remain associated with risk of viral reactivation after TACE, and HBeAg-positive HCC patients have a higher risk than patients with HBeAg-negative status.
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Affiliation(s)
- Wenbo Shao
- Department of Surgical Oncology (Interventional Therapy), Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| | - Fengjuan Zhang
- Department of Surgical Oncology (Interventional Therapy), Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| | - Ning Cong
- Department of Surgical Oncology (Interventional Therapy), Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| | - Jinpeng Li
- Department of Surgical Oncology (Interventional Therapy), Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| | - Jinlong Song
- Department of Surgical Oncology (Interventional Therapy), Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, People's Republic of China
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40
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2014 KLCSG-NCC Korea Practice Guideline for the Management of Hepatocellular Carcinoma. Gut Liver 2015; 9:267-317. [PMID: 25918260 PMCID: PMC4413964 DOI: 10.5009/gnl14460] [Citation(s) in RCA: 101] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 03/09/2015] [Indexed: 12/23/2022] Open
Abstract
The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC.
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41
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2014 Korean Liver Cancer Study Group-National Cancer Center Korea practice guideline for the management of hepatocellular carcinoma. Korean J Radiol 2015; 16:465-522. [PMID: 25995680 PMCID: PMC4435981 DOI: 10.3348/kjr.2015.16.3.465] [Citation(s) in RCA: 143] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Accepted: 04/02/2015] [Indexed: 02/07/2023] Open
Abstract
The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC.
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42
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Jang JW, Kim YW, Lee SW, Kwon JH, Nam SW, Bae SH, Choi JY, Yoon SK, Chung KW. Reactivation of hepatitis B virus in HBsAg-negative patients with hepatocellular carcinoma. PLoS One 2015; 10:e0122041. [PMID: 25894607 PMCID: PMC4403914 DOI: 10.1371/journal.pone.0122041] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Accepted: 02/06/2015] [Indexed: 01/09/2023] Open
Abstract
Background & Aims Despite increasing attention to hepatitis B virus (HBV) reactivation in hematologic settings, information on reactivation in hepatitis B surface (HBsAg)-negative patients with hepatocellular carcinoma (HCC) remains unknown. This study aimed to determine the incidence and risk factors of HBV reactivation in HBsAg-negative patients undergoing transarterial chemoembolization (TACE). Methods A total of 109 HBsAg-negative patients with HCC were consecutively recruited for this study and treated with either mono- (n = 75), combination-drug TACE (n = 20), or combination-drug TACE plus radiotherapy (n = 14). With serial monitoring of virological markers every 2–3 months, patients were observed for HBV reactivation (defined as the reappearance of HBV DNA or sero-reversion of HBsAg) in comparison with control subjects with HBsAg-negative cirrhosis (n = 16) or HBsAg loss (n = 46). Results During the study period, HBV reactivation occurred in 12 (11.0%) and 1 (1.6%) patients in the TACE and control groups, respectively. The median level of HBV DNA at reactivation was 5,174 copies/ml (range: 216–116,058). Of the 12 patients with HBV reactivation, four (33.3%) developed clinical hepatitis, including one patient who suffered from decompensation. All antiviral-treated patients achieved undetectable HBV DNA or HBsAg loss after commencement of antiviral drugs. TACE was significantly correlated with a high incidence of HBV reactivation, with increasing risk of reactivation with intensive treatment. On multivariate analysis, treatment intensity and a prior history of chronic hepatitis B remained independently predictive of reactivation. Conclusions TACE can reactivate HBV replication in HBsAg-negative patients, with a dose-risk relationship between treatment intensity and reactivation. Patients with prior chronic HBV infection who are to undergo intensive TACE should be closely monitored, with an alternative approach of antiviral prophylaxis against HBV reactivation.
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Affiliation(s)
- Jeong Won Jang
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Young Woon Kim
- Department of Internal Medicine, The Catholic University of Korea Incheon St. Mary’s Hospital, Incheon, Korea
| | - Sung Won Lee
- Department of Internal Medicine, The Catholic University of Korea Incheon St. Mary’s Hospital, Incheon, Korea
| | - Jung Hyun Kwon
- Department of Internal Medicine, The Catholic University of Korea Incheon St. Mary’s Hospital, Incheon, Korea
| | - Soon Woo Nam
- Department of Internal Medicine, The Catholic University of Korea Incheon St. Mary’s Hospital, Incheon, Korea
- * E-mail:
| | - Si Hyun Bae
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jong Young Choi
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung Kew Yoon
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kyu Won Chung
- Department of Internal Medicine, The Catholic University of Korea Incheon St. Mary’s Hospital, Incheon, Korea
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Perrillo RP. Hepatitis B reactivation from immunosuppressive drug therapy: A global menace. Clin Liver Dis (Hoboken) 2015; 5:39-42. [PMID: 31040946 PMCID: PMC6490453 DOI: 10.1002/cld.448] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 12/28/2014] [Indexed: 02/04/2023] Open
Affiliation(s)
- Robert P. Perrillo
- Hepatology DivisionBaylor University Medical Center and University of Texas SouthwesternDallasTX
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Short Term Virologic Efficacies of Telbivudine versus Entecavir against Hepatitis B-Related Hepatocellular Carcinoma. Gastroenterol Res Pract 2015; 2015:181065. [PMID: 25878659 PMCID: PMC4387973 DOI: 10.1155/2015/181065] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2014] [Revised: 02/24/2015] [Accepted: 03/11/2015] [Indexed: 02/08/2023] Open
Abstract
Telbivudine has been reported to be more effective than lamivudine. However, because of the resistance rate to telbivudine (TLV), the current guidelines recommend entecavir (ETV) or tenofovir (TNV) as the first-line therapy for chronic hepatitis B. We investigated the short term virologic efficacy of TLV in comparison with ETV as the first-line agent of HBV suppression in HBV-related advanced HCC patients. A total of 86 consecutive patients with HBV-related HCC for whom antiviral treatment was initiated in Incheon St. Mary's Hospital between 2010 and 2013 were analyzed. Virologic responses were investigated on the 4th, 12th, and 24th weeks of the antiviral therapies. In patients with advanced TNM stage cancer (stage 3 or 4) and poor liver function (Child-Pugh class B or C), the virologic response rates at weeks 12 and 24 were 25% (1/4) and 42.8% (3/7) in the TLV group and 33.3% (1/3) and 33.3% (1/3) in the ETV group, respectively (P = 0.424, P = 0.800). The short term efficacy of TLV was similar to that of ETV. Since TLV is highly cost-effective, it should be considered as a first-line antiviral agent in patients with advanced HCC, poor liver function, and short life expectancies.
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Perrillo RP, Gish R, Falck-Ytter YT. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 2015; 148:221-244.e3. [PMID: 25447852 DOI: 10.1053/j.gastro.2014.10.038] [Citation(s) in RCA: 385] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Robert P Perrillo
- Hepatology Division, Baylor University Medical Center, Department of Medicine, University of Texas Southwestern, Dallas, Texas
| | - Robert Gish
- Division of Gastroenterology and Hepatology, Department of Medicine,Stanford University, Palo Alto, California; Hepatitis B Foundation, Doylestown, Pennsylvania
| | - Yngve T Falck-Ytter
- Division of Gastroenterology and Hepatology, Department of Medicine, Case and VA Medical Center, Case Western Reserve University, Cleveland, Ohio
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Liu WR, Tian MX, Jin L, Yang LX, Ding ZB, Shen YH, Peng YF, Zhou J, Qiu SJ, Dai Z, Fan J, Shi YH. High levels of hepatitis B surface antigen are associated with poorer survival and early recurrence of hepatocellular carcinoma in patients with low hepatitis B viral loads. Ann Surg Oncol 2014; 22:843-50. [PMID: 25269529 DOI: 10.1245/s10434-014-4043-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Indexed: 12/28/2022]
Abstract
PURPOSE Recurrence is a disastrous outcome in patients with hepatitis-related hepatocellular carcinoma (HCC) who have undergone curative resection, and little is known about whether high levels of hepatitis B surface antigen (HBsAg) increase the risk of HCC recurrence. PATIENTS AND METHODS This retrospective study included 1,360 HBsAg-positive postoperative HCC patients with hepatitis B viral (HBV) DNA levels < 2000 IU/mL, including 298 patients in a training cohort and 1,062 patients in a validation cohort. The prognostic value of the HBsAg level was evaluated using Cox regression and Kaplan-Meier analyses. RESULTS We demonstrated that 1,000 IU/mL, but not 10 or 100 IU/mL, was a meaningful cutoff level for significantly discriminating these patients into an HBsAg(Low) group and an HBsAg(High) group based on correlations between the HBsAg level and liver cirrhosis (p = 0.028), tumor size (p = 0.039), and hepatitis B e antigen level (p < 0.001). The postoperative 1-, 3-, and 5-year overall survival (OS) rates of HCC patients in the HBsAg(Low) group were significantly higher than those of HCC patients in the HBsAg(High) group. Accordingly, the 5-year recurrence-free survival (RFS) rates of patients in the HBsAg(Low) group were markedly higher than those of HCC patients in the HBsAg(High) group. The HBsAg level was a prognostic indicator for OS (p = 0.014) and RFS (p = 0.01). CONCLUSION HBsAg level is correlated with more aggressive tumor behavior and serves as a prognostic indicator in patients with surgically resected HCC with low HBV load.
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Affiliation(s)
- Wei-Ren Liu
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
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Jang JW. Hepatitis B virus reactivation in patients with hepatocellular carcinoma undergoing anti-cancer therapy. World J Gastroenterol 2014; 20:7675-7685. [PMID: 24976705 PMCID: PMC4069296 DOI: 10.3748/wjg.v20.i24.7675] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/02/2014] [Accepted: 03/13/2014] [Indexed: 02/06/2023] Open
Abstract
Patients with hepatocellular carcinoma (HCC) often experience hepatic morbidity. Hepatitis B virus (HBV) reactivation is well documented as a serious hepatic morbidity during anti-cancer therapy. Reported rates of HBV reactivation in chronic carriers with HCC undergoing chemotherapy range from 4%-67%. Apart from chemotherapy, HBV reactivation has been increasingly identified in settings of hepatectomy and local ablation therapies. The rates of HBV reactivation vary with different levels of immunosuppression and depend on treatment, viral factors, and patient characteristics. The principal concern relating to reactivation is that a substantial proportion of patients with reactivation suffer from liver dysfunction during therapy, which often leads to disruption of planned, potentially life-prolonging treatments, adversely affecting the patients’ final outcome. The first step in the management of HBV reactivation is identification of patients at risk of reactivation by testing for HBV serology prior to commencing anti-cancer therapy. Although it is a serious complication, HBV reactivation is preventable with prophylactic anti-HBV drugs. Multiple publications have shown the benefit of prophylactic or preemptive antiviral therapy in this setting and justified such an approach before the start of therapy. Given the tumors and underlying cirrhosis, long-term use of antivirals with high potency and low risk of resistance is recommended in patients with HCC. This topic review will summarize the epidemiology, pathogenesis, and clinical issues related to HBV reactivation in HCC patients, and will discuss proper management against HBV reactivation during anti-cancer therapy for HCC.
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Lee JI, Kim JK, Chang HY, Lee JW, Kim JM, Chung HJ, Kim YS, Lee KS. Impact of postoperative hepatitis B virus reactivation in hepatocellular carcinoma patients who formerly had naturally suppressed virus. J Gastroenterol Hepatol 2014; 29:1019-27. [PMID: 24325315 DOI: 10.1111/jgh.12472] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/27/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Hepatitis B virus (HBV) replication detected before the resection of hepatocellular carcinoma (HCC) is to be controlled by antiviral agents. However, management strategy for patients with preoperatively undetectable HBV DNA without antiviral therapy is not clearly delineated. This study investigated viral reactivation after the liver resection in non-replicating HBV DNA-related HCC patients and its impact on the surgical outcome. METHODS From 198 patients that underwent liver resection due to HBV-related HCC, 101 patients who had serially checked serum HBV DNA were analyzed. RESULTS From 101 patients, 33 patients had baseline undetectable HBV DNA. Eleven patients (11/33, 33.3%) had viral replication after the liver resection. The postoperative viral reactivation (HR: 2.144; 95% CI: 1.122-4.097; P = 0.021), along with the existence of satellite nodules (HR: 3.034; 95% CI: 1.1.376-6.689; P = 0.006), existence of microvascular invasion (HR: 2.479; 95% CI: 1.303-4.718; P = 0.006), and HBeAg positivity (HR: 2.059; 95% CI: 1.155-3.670; P = 0.014) predicted recurrence after the surgery. Quantification of intrahepatic total and covalently closed circular DNA (cccDNA) was done in 14 patients whose baseline serum HBV DNA was undetectable without the use of antiviral agent. Amount of intrahepatic cccDNA expressed as copies/hepatocyte in patients with postoperative viral reactivation showed significantly higher than those in patients with sustained negative serum HBV DNA (P = 0.010). CONCLUSIONS This study shows that naturally suppressed preoperative HBV without application of antiviral agent does not ensure undetectable serum HBV after the surgery, and postoperative viral reactivation might be associated with HCC recurrence.
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Affiliation(s)
- Jung Il Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Liver Cirrhosis Clinical Trial Center, Seoul, Republic of Korea
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Liu Y, Kong XJ, Jiang YJ, Wu J, Li XH, Tian ZB. Reactivation of hepatitis B virus and antiviral treatment in cancer patients receiving chemotherapy. Shijie Huaren Xiaohua Zazhi 2013; 21:1050-1054. [DOI: 10.11569/wcjd.v21.i11.1050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the reactivation of hepatitis B virus (HBV) and the effect of antiviral treatment in cancer patients receiving chemotherapy.
METHODS: Clinical data for 2 253 cancer patients undergoing chemotherapy were reviewed. Of 125 patients who were positive for HBV surface antigen, 37 received antiviral treatment (therapy group) and 88 did not (control group). These patients were followed for at least 6 mo after the completion of treatment. During the course of chemotherapy, liver function tests, viral load (HBV-DNA), and HBV reactivation rate were determined on days 1 and 10 of each cycle.
RESULTS: A total of 879 (39.0%) cancer patients were screened for HBV status. In 125 patients who were positive for HBV surface antigen, 47 (37.6%) developed hepatitis during chemotherapy. Of these 47 patients, 7 (18.9%) were included in the antiviral treatment group and 40 (45.5%) in the control group (P = 0.008). Two patients in the antiviral treatment group developed severe hepatitis [2 (5.4%) vs 19 (21.6%), P = 0.035]. In the antiviral treatment group, there was significantly less patients developing HBV reactivation [1 (2.7%) vs 16 (18.2%), P = 0.022] or discontinuing chemotherapy (8.1% vs 33.0%, P = 0.003).
CONCLUSION: Prophylactic antiviral treatment significantly reduces the incidence of HBV reactivation in cancer patients undergoing chemotherapy.
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Lao XM, Luo G, Ye LT, Luo C, Shi M, Wang D, Guo R, Chen M, Li S, Lin X, Yuan Y. Effects of antiviral therapy on hepatitis B virus reactivation and liver function after resection or chemoembolization for hepatocellular carcinoma. Liver Int 2013; 33:595-604. [PMID: 23402625 DOI: 10.1111/liv.12112] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Revised: 12/23/2012] [Accepted: 12/30/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND How hepatitis B virus (HBV) infection react to hepatocellular carcinoma (HCC) treatment remains unclear, and the roles of anti-HBV therapy were seldom reported in HCC. AIMS To evaluate changes of HBV replication and liver function after hepatectomy or transarterial chemoembolization (TACE) for HCC, also the short-term effects of anti-viral therapy were analyzed. METHODS Totally, 590 HBsAg (+) HCC patients were recruited into two groups: only surgical resection, and only TACE, and subgrouped according to anti-HBV therapy or none. Clinical data were analyzed for statistical significance and risk factors for adverse events. RESULTS In the no antiviral therapy groups, rates of HBV reactivation were 15.7% and 17.5% in patients who underwent hepatectomy and TACE, respectively, while the rates of deterioration of liver function were 4.1% and 8.1%, respectively. In contrast, in the antivirus group, the rates of reactivation were 0% and 1.5% after hepatectomy and TACE respectively, while the liver function deterioration rates were 2.4% and 1.5%, respectively. For patients who underwent hepatectomy, no antiviral therapy, and long hepatic inflow occlusion times increased the risk of HBV reactivation. For TACE, no antivirus and HBeAg negativity were the risk factors for reactivation. HBV reactivation was significantly correlated to liver function exacerbation after hepatectomy, while HBV reactivation, baseline ALT (alanine aminotransferase), and α-fetoprotein levels were significantly correlated to liver function exacerbation after TACE. CONCLUSIONS HBV reactivation can occur after hepatectomy or TACE. Anti-HBV therapy can reduce the risk of reactivation, thus reducing the risk of liver failure especially in patients undergoing TACE.
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Affiliation(s)
- Xiang-Ming Lao
- Department of Hepatobilliary Oncology, Sun Yat-sen University Cancer Center & State Key Laboratory of Oncology in Southern China, Guangzhou, China
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