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Cornberg M, Sandmann L, Jaroszewicz J, Kennedy P, Lampertico P, Lemoine M, Lens S, Testoni B, Lai-Hung Wong G, Russo FP. EASL Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2025:S0168-8278(25)00174-6. [PMID: 40348683 DOI: 10.1016/j.jhep.2025.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Accepted: 03/20/2025] [Indexed: 05/14/2025]
Abstract
The updated EASL Clinical Practice Guidelines on the management of hepatitis B virus (HBV) infection provide comprehensive, evidence-based recommendations for its management. Spanning ten thematic sections, the guidelines address diagnostics, treatment goals, treatment indications, therapeutic options, hepatocellular carcinoma surveillance, management of special populations, HBV reactivation prophylaxis, post-transplant care, HBV prevention strategies, and finally address open questions and future research directions. Chronic HBV remains a global health challenge, with over 250 million individuals affected and significant mortality due to cirrhosis and hepatocellular carcinoma. These guidelines emphasise the importance of early diagnosis, risk stratification based on viral and host factors, and tailored antiviral therapy. Attention is given to simplified algorithms, vaccination, and screening to support global HBV elimination targets. The guidelines also discuss emerging biomarkers and evolving definitions of functional and partial cure. Developed through literature review, expert consensus, and a Delphi process, the guidelines aim to equip healthcare providers across disciplines with practical tools to optimise HBV care and outcomes worldwide.
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Liu X, Lei X, Huang S, Yang X. Current Perspectives of Immunotherapy for Hepatocellular Carcinoma. Comb Chem High Throughput Screen 2025; 28:185-201. [PMID: 38031784 DOI: 10.2174/0113862073255266231025111125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 09/10/2023] [Accepted: 09/25/2023] [Indexed: 12/01/2023]
Abstract
Hepatocellular carcinoma is the sixth most common tumor and the third leading cause of cancer death worldwide. It ranks fourth in the spectrum of malignant tumor incidence and second in the order of death from major malignant tumors in China. Hepatocellular carcinoma is a complex ecosystem containing non-tumor cells (mainly immune-related cells), and its immunotherapy can stimulate the recognition of specific tumor antigens, inhibit the proliferation of cancer cells, and produce over-memory lymphocytes, which can prevent recurrence. So, immunotherapy of hepatocellular carcinoma is increasingly becoming a research hotspot in liver cancer treatment. With the intensive research in recent years, great progress has been made in immunotherapy for hepatocellular carcinoma, including immune checkpoint inhibitors, pericyte therapy, vaccination, and antiviral therapy. In addition, the study found that the therapeutic effect of combination therapy was enhanced compared to monotherapy. This review summarizes the most prominent immunotherapies currently available for the clinical treatment of patients with HCC and the main opportunities and challenges facing HCC research.
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Affiliation(s)
- Xiaoyi Liu
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, Hunan 421001, People's Republic of China
| | - Xiaoyong Lei
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, Hunan 421001, People's Republic of China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, 28 Western Changsheng Road, Hengyang, Hunan 421001, People's Republic of China
| | - Sheng Huang
- Jiuzhitang Co., Ltd, Changsha, Hunan 410007, People's Republic of China
| | - Xiaoyan Yang
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, Hunan 421001, People's Republic of China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, 28 Western Changsheng Road, Hengyang, Hunan 421001, People's Republic of China
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Alshimerry AF, Farhood RG. Concept of HBV and HCV as a risk factor and prevention of viral hepatitis-related hepatocellular carcinoma. MEDICAL JOURNAL OF BABYLON 2023; 20:657-660. [DOI: 10.4103/mjbl.mjbl_269_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 03/31/2023] [Indexed: 01/03/2025] Open
Abstract
Abstract
Hepatocellular carcinoma (HCC) represents one of the most common cancers worldwide, and it is a very important reason for cancer-related death. Infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) is considered the major leading cause of HCC. The pathophysiology of HB and HC viral-related HCC includes chronic inflammation, deorganization of cell signaling pathways, and oxidative stress. Contrary to HCV, HBV is oncogenic by itself, due to its integration into the DNA of cell. Six months of ultrasound monitoring is recommended for high-risk patients. Using antiviral drugs to manage viral hepatitis decreases the risk of evolution and reoccurrence of HCC. Also, effective preventive measures are very important in decreasing the risk of HCC. The prevention involves primary prevention which is based on HBV vaccination, treatment of acute infection, and eliminating the route of transmission, while secondary prevention is based on using antiviral drugs against HBV and HCV infection to prevent the progress of disease into carcinoma. However, tertiary prevention involves treating the carcinoma to prevent the reoccurrence of the cancer.
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Affiliation(s)
| | - Rawaa Ghalib Farhood
- Department of Pathology, College of Medicine, University of Babylon, Babylon, Iraq
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Hepatocellular Carcinoma in Hepatitis B Virus-Infected Patients and the Role of Hepatitis B Surface Antigen (HBsAg). J Clin Med 2022; 11:jcm11041126. [PMID: 35207397 PMCID: PMC8878376 DOI: 10.3390/jcm11041126] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 02/09/2022] [Accepted: 02/17/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related death worldwide. Hepatitis B virus (HBV) infection is among the main risk factors for HCC. The risk of HCC is not eliminated completely after viral suppression, due to HBV DNA integrated into human chromosomes. Cirrhosis, HBV viral DNA levels, age, male gender, the immune response of the host against HBV, and a combination of obesity and diabetes are among the main risk factors for HCC. Active viral replication and long-standing active disease with inflammation are associated with a higher risk of HCC. Treatment of HBV with nucleos(t)ide analogues (NAs) decreased HCC risk by effectively decreasing viral load and inflammation. Similar risk factors have been reported in hepatitis B patients after seroclearance. Studies have reported decreased risk of HCC after seroclearance, but there were also conflicting results from a few studies indicating no difference in risk of developing HCC. The difference in HCC rates could be because of other factors such as coinfection, occult HBV infection, family history, HBV genotype, and other comorbidities. Due to the persistent risk of HCC after seroclearance, HCC surveillance is critical for early detection, especially in high-risk patients. However, long-term studies might be needed to further validate the results.
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Mao QG, Liang HQ, Yin YL, Tang JM, Yang JE, Wu CC, Chen Y, Zhang MY, Liu YY, Zheng XT, Zhuang LY, Chen SD. Comparison of Interferon-α-based therapy and nucleos(t)ide analogs in preventing adverse outcomes in patients with chronic hepatitis B. Clin Res Hepatol Gastroenterol 2022; 46:101758. [PMID: 34303003 DOI: 10.1016/j.clinre.2021.101758] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 06/17/2021] [Accepted: 06/21/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Whether interferon (IFN)-α therapy is better than nucleos(t)ide analogs (NAs) in the prevention of adverse outcomes, including hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) is still uncertain or controversial. This study aimed to compare the cumulative incidence of adverse outcomes in patients with CHB on IFN-α- and NA-based therapies. METHODS This was a retrospective study of patients with CHB on antivirals. Patients treated with IFN-α (IFN-α or peginterferon-α) with or without NAs were defined as the IFN-α group, and those only receiving NAs were defined as the NAs group. Propensity score matching (PSM) was used to minimize baseline bias. Cox regression models were performed to select possible factors related to adverse outcomes development. RESULTS All 1247 patients were divided into the IFN-α (n = 877) and NAs (n = 370) groups. 26patients (20 and 6 in the NAs and IFN-α groups) developed adverse outcomes (decompensated cirrhosis, liver failure, HCC, liver transplantation and deaths) during a median follow-up of 5.2 years. The cumulative adverse outcomes occurrence at 10 years was significantly lower in the IFN-α group than in the NAs group in all (1.1% vs. 11.9%, P <0.001) and treatment-naïve (1.1% vs. 12.4%, P <0.001) patients. Similar trends were observed after PSM and differentiation of cirrhosis. Multivariate analysis before and after PSM showed that IFN-α-based treatment was independently associated with a lower adverse outcomes incidence (before/after PSM: P = 0.001/P = 0.002). HCC risk stratification analyses revealed that the superiority of IFN-α in preventing HCC was more significant in patients with high-risk HCC. CONCLUSIONS IFN-α-based therapy was superior to NAs in preventing adverse outcomes in patients with CHB regardless of cirrhosis, and in reducing HCC in those with a high risk of HCC.
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Affiliation(s)
- Qian-Guo Mao
- Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361009, China.
| | - Hui-Qing Liang
- Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361009, China.
| | - Ya-Lin Yin
- School of Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Jin-Mo Tang
- Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361009, China
| | - Jia-En Yang
- Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361009, China
| | - Chun-Cheng Wu
- Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361009, China
| | - Yue Chen
- Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361009, China
| | - Man-Ying Zhang
- Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361009, China
| | - Yao-Yu Liu
- College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 351012, China
| | - Xiao-Ting Zheng
- College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 351012, China
| | - Lin-Yi Zhuang
- College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 351012, China
| | - Shao-Dong Chen
- School of Medicine, Xiamen University, Xiamen, 361102, China.
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Alqahtani SA, Colombo M. Treatment for Viral Hepatitis as Secondary Prevention for Hepatocellular Carcinoma. Cells 2021; 10:3091. [PMID: 34831314 PMCID: PMC8619578 DOI: 10.3390/cells10113091] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/05/2021] [Accepted: 11/07/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic infections with either hepatitis B or C virus (HBV or HCV) are among the most common risk factors for developing hepatocellular carcinoma (HCC). The hepatocarcinogenic potential of these viruses is mediated through a wide range of mechanisms, including the induction of chronic inflammation and oxidative stress and the deregulation of cellular pathways by viral proteins. Over the last decade, effective anti-viral agents have made sustained viral suppression or cure a feasible treatment objective for most chronic HBV/HCV patients. Given the tumorigenic potential of HBV/HCV, it is no surprise that obtaining sustained viral suppression or eradication proves to be effective in preventing HCC. This review summarizes the mechanisms by which HCV and HBV exert their hepatocarcinogenic activity and describes in detail the efficacy of anti-HBV and anti-HCV therapies in terms of HCC prevention. Although these treatments significantly reduce the risk for HCC in patients with chronic viral hepatitis, this risk is not eliminated. Therefore, we evaluate potential strategies to improve these outcomes further and address some of the remaining controversies.
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Affiliation(s)
- Saleh A. Alqahtani
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD 21287, USA
- Liver Transplant Center, and Biostatistics, Epidemiology, and Scientific Computing Department, King Faisal Specialist Hospital & Research Center, Riyadh 11564, Saudi Arabia
| | - Massimo Colombo
- Liver Center, IRCCS San Raffaele Hospital, 20132 Milan, Italy;
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Abstract
Hepatocellular carcinoma (HCC) is one of the five leading causes of cancer death in human. Hepatitis B virus (HBV) is the most common etiologic agent of HCC in the world. Prevention is the best way to control cancer. There are three levels of liver cancer prevention, i.e., primary prevention by HBV vaccination targeting the general population starting from birth dose, secondary prevention by antiviral agent for high-risk subjects with chronic HBV infection, and tertiary prevention by antiviral agent to prevent recurrence for patients who have been successfully treated for liver cancer. Primary prevention by hepatitis B vaccination is most cost effective, the cancer preventive efficacy support it as the first successful example of cancer preventive vaccine in human. Addition of hepatitis B immunoglobulin immediately after birth and antiviral agent during the third trimester of pregnancy to block mother-to-infant transmission of HBV are existing or possible emerging strategies to enhance the prevention efficacy of HBV infection and its related liver cancer. Secondary prevention with current antiviral agents may reduce the risk or delay the onset of HCC development, but could not eradicate HBV infection and HCC. Better antiviral therapeutic agents are needed for better secondary prevention.
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Affiliation(s)
- Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
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8
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Abstract
Enhancing host immunity by vaccination to prevent hepatitis B virus (HBV) infection remains the most important strategy for global control of hepatitis B. Currently, 187 countries have in place infant hepatitis B vaccination programs. Hepatitis B surface antigen prevalence has decreased to less than 1% in children after successful implementation of universal HBV vaccination in newborns. The incidence of primary liver cancer in children, adolescents, and young adults has drastically decreased to near zero in birth cohorts receiving hepatitis B vaccination. Elimination of chronic hepatitis B by 2030 is not a mission impossible.
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Yuwaki K, Shimazu T, Yamagiwa Y, Inoue M, Goto A, Yamaji T, Iwasaki M, Sawada N, Tsugane S. Association between serum liver enzymes and all-cause mortality: The Japan Public Health Center-based Prospective Study. Liver Int 2019; 39:1566-1576. [PMID: 30566759 DOI: 10.1111/liv.14030] [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: 09/05/2018] [Revised: 11/28/2018] [Accepted: 12/11/2018] [Indexed: 01/23/2023]
Abstract
BACKGROUND & AIMS The association of serum liver enzyme levels with all-cause mortality in individuals without hepatitis B virus or hepatitis C virus infection is inconsistent. We aimed to investigate all-cause and non-liver disease mortality according to levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT) stratified by hepatitis virus infection status in a Japanese cohort. METHODS Participants were 7243 men and 13 513 women aged 40-69 years at the baseline survey in 1993-1994. Multivariate-adjusted hazard ratios of death from the baseline health check-up to December 2012 were calculated with a Cox proportional hazards model controlling for potential confounding factors. RESULTS During follow-up, 2235 deaths in men and 1901 deaths in women were identified. All serum liver enzymes were associated with all-cause mortality in each sex and hepatitis virus infection status. In participants without infection, those with more than twice the upper level of normal (ULN), which was defined as 30 IU/L for AST and ALT and 50 IU/L for GGT, had a higher risk of non-liver disease mortality compared to those below the ULN (HR 1.69; 95% confidence interval 1.13-2.53, 1.49; 1.02-2.18, 1.39; 1.11-1.73, 1.72; 1.08-2.74 and 1.72; 1.10-2.69 for AST, ALT, and GGT in men and AST and GGT in women, respectively), except for ALT in women. CONCLUSIONS In participants without hepatitis virus infection, serum liver enzyme levels were positively associated with all-cause mortality. Similar associations were also found for non-liver disease mortality.
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Affiliation(s)
- Keiichi Yuwaki
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.,Underwriting and Medical Department, The Dai-ichi Life Insurance Company, Limited, Tokyo, Japan
| | - Taichi Shimazu
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Yoko Yamagiwa
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Manami Inoue
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Atsushi Goto
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Taiki Yamaji
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Motoki Iwasaki
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Norie Sawada
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Shoichiro Tsugane
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
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10
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Lin CL, Kao JH. Review article: the prevention of hepatitis B-related hepatocellular carcinoma. Aliment Pharmacol Ther 2018; 48:5-14. [PMID: 29722445 DOI: 10.1111/apt.14683] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 02/08/2018] [Accepted: 04/03/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Ample evidence indicates an aetiological association of persistent hepatitis B virus (HBV) infection with hepatocellular carcinoma (HCC). Several viral, host and external risk factors for the development of HBV-related HCC have been documented. AIMS To summarise and discuss the risk stratification and the preventive strategies of HBV-related HCC. METHODS Recent published studies identified from PubMed were comprehensively reviewed. The key words included chronic hepatitis B, HBV, hepatocellular carcinoma, prevention and antiviral therapy. RESULTS The incidence of HCC is extremely high in HBV hyperendemic areas. For HBV patients left untreated, significant risk factors for HCC include male gender, aging, advanced hepatic fibrosis, persistent serum transaminase elevation, specific HBV entry receptor (NTCP) genotype, PM2.5 exposure, HBeAg positivity, HBV genotype C/D/F, high proportion of core promoter mutation, pre-S deletion, high serum levels of HBV DNA and HBsAg as well as co-infection with HCV, HDV and HIV. Primary prevention of HBV-related HCC can be achieved through universal HBV vaccination and anti-viral prophylaxis for high viraemic mothers. The goal of secondary prevention has been reached by effective anti-viral therapy to reduce the risk of HCC development in chronic hepatitis B patients. However, whether HCC is prevented or delayed deserves further examination. Finally, several studies confirmed the tertiary preventive effect of anti-viral therapy in reducing risk of HCC recurrence after curative therapies. CONCLUSIONS Through the strategies of three-level prevention, the global burden of HBV-related HCC should decline over time and even be eliminated in conjunction with HBV cure.
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Affiliation(s)
- C-L Lin
- Department of Gastroenterology, Taipei City Hospital, Taipei, Taiwan.,Department of Psychology, National Chengchi University, Taipei, Taiwan
| | - J-H Kao
- Graduate Institute of Clinical Medicine, National Taiwan University, College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Research, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan
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11
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Abstract
Great strides have been made in hepatitis B virus (HBV)-related fibrosis and cirrhosis. Available evidence indicates that HBV viral suppression causes regression of advanced fibrosis and even cirrhosis, and therefore should be attempted in all patients with advanced fibrosis and cirrhosis. The preferred agents in patients with cirrhosis are entecavir and tenofovir, primarily because the risk of breakthrough is low. HBV viral suppression leads to improved clinical outcomes even in patients with cirrhosis and complications. The risk of hepatocellular carcinoma is reduced, but not eliminated. Thus, patients with HBV cirrhosis should continue to have routine screening for hepatocellular carcinoma, even after viral suppression.
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Affiliation(s)
- Don C Rockey
- Department of Internal Medicine, The Medical University of South Carolina, 96 Jonathan Lucas Street, 803 CSB, Charleston, SC 29425, USA.
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12
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Varbobitis I, Papatheodoridis GV. The assessment of hepatocellular carcinoma risk in patients with chronic hepatitis B under antiviral therapy. Clin Mol Hepatol 2016; 22:319-326. [PMID: 27729632 PMCID: PMC5066383 DOI: 10.3350/cmh.2016.0045] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 07/21/2016] [Accepted: 08/11/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary concern for patients with chronic hepatitis B (CHB). Antiviral therapy has been reasonably the focus of interest for HCC prevention, with most studies reporting on the role of the chronologically preceding agents, interferon-alfa and lamivudine. The impact of interferon-alfa on the incidence of HCC is clearer in Asian patients and those with compensated cirrhosis, as several meta-analyses have consistently shown HCC risk reduction, compared to untreated patients. Nucleos(t)ide analogues also seem to have a favorable impact on the HCC incidence when data from randomized or matched controlled studies are considered. Given that the high-genetic barrier agents, entecavir and tenofovir, are mainly used in CHB because of their favorable effects on the overall long-term outcome of such patients, the most clinically important challenge is the identification of patients who require close HCC surveillance despite on-therapy virological remission. Several risk scores have been developed for HCC prediction in CHB patients. Most of them, such as GAG-HCC, CU-HCC and REACH-B, have been developed and validated in Asian untreated and treated CHB patients, but they do not seem to offer good predictability in Caucasian CHB patients for whom a newer score, PAGE-B, has been recently developed.
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Affiliation(s)
- Ioannis Varbobitis
- Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - George V. Papatheodoridis
- Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
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Takami T, Yamasaki T, Saeki I, Matsumoto T, Suehiro Y, Sakaida I. Supportive therapies for prevention of hepatocellular carcinoma recurrence and preservation of liver function. World J Gastroenterol 2016; 22:7252-7263. [PMID: 27621572 PMCID: PMC4997645 DOI: 10.3748/wjg.v22.i32.7252] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 06/07/2016] [Accepted: 07/21/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world and is associated with a high risk of recurrence. The development of a wide range of new therapies is therefore essential. In this study, from the perspective of supportive therapy for the prevention of HCC recurrence and preservation of liver function in HCC patients, we surveyed a variety of different therapeutic agents. We show that branched chain amino acids (BCAA) supplementation and late evening snack with BCAA, strategies that address issues of protein-energy malnutrition, are important for liver cirrhotic patients with HCC. For chemoprevention of HCC recurrence, we show that viral control after radical treatment is important. We also reviewed the therapeutic potential of antiviral drugs, sorafenib, peretinoin, iron chelators. Sorafenib is a kinase inhibitor and a standard therapy in the treatment of advanced HCC. Peretinoin is a vitamin A-like molecule that targets the retinoid nuclear receptor to induce apoptosis and inhibit tumor growth in HCC cells. Iron chelators, such as deferoxamine and deferasirox, act to prevent cancer cell growth. These chelators may have potential as combination therapies in conjunction with peretinoin. Finally, we review the potential inhibitory effect of bone marrow cells on hepatocarcinogenesis.
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14
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Tawada A, Kanda T, Imazeki F, Yokosuka O. Prevention of hepatitis B virus-associated liver diseases by antiviral therapy. Hepatol Int 2016; 10:574-593. [PMID: 27026375 DOI: 10.1007/s12072-016-9720-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Accepted: 02/28/2016] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) is a major cause of acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma, particularly in Asia-Pacific countries. The major complications in HBV carriers are hepatocellular carcinoma (HCC), liver failure and esophageal varices following the progression to cirrhosis, while some develop HCC without cirrhosis. The progression to liver fibrosis and these other complications could be prevented by treatment with nucleos(t)ide analogues (NUCs); however, NUCs must be continuously administered for a long time. Peginterferon could lead to HBV surface antigen loss. It is difficult to use peginterferon in HBV-infected patients with decompensated cirrhosis. Acute liver failure due to HBV infection and acute exacerbation of chronic hepatitis B could be treated by NUCs. Universal vaccination programs against HBV could prevent new HBV infections globally. Here, we review the currently available treatments for HBV infection.
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Affiliation(s)
- Akinobu Tawada
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
- Safety and Health Organization, Chiba University, Chiba, 263-8522, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
| | - Fumio Imazeki
- Safety and Health Organization, Chiba University, Chiba, 263-8522, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
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15
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Ferrarese A, Zanetto A, Gambato M, Bortoluzzi I, Nadal E, Germani G, Senzolo M, Burra P, Russo FP. Liver transplantation for viral hepatitis in 2015. World J Gastroenterol 2016; 22:1570-1581. [PMID: 26819523 PMCID: PMC4721989 DOI: 10.3748/wjg.v22.i4.1570] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 09/20/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) is a life-saving treatment for patients with end-stage liver disease and for patients with liver cell cancer related to liver disease. Acute and chronic liver diseases related to hepatitis viruses are between the main indications for liver transplantation. The risk of viral reinfection after transplantation is the main limiting factor in these indications. Before the availability of antiviral prophylaxis, hepatitis B virus (HBV) recurrence was universal in patients who were HBV DNA-positive before transplantation. The natural history of recurrent HBV was accelerated by immunosuppression, and it progressed rapidly to graft failure and death. Introduction of post-transplant prophylaxis with immunoglobulin alone first, and associated to antiviral drugs later, drastically reduced HBV recurrence, resulting in excellent long-term outcomes. On the contrary, recurrence of hepatitis C is the main cause of graft loss in most transplant programs. Overall, patient and graft survival after LT for hepatitis C virus (HCV)-associated cirrhosis is inferior compared with other indications. However, successful pretransplant or post transplant antiviral therapy has been associated with increased graft and overall survival. Until recently, the combination of pegylated interferon and ribavirin was the standard of care for the treatment of patients with chronic hepatitis C. Highly active antiviral compounds have been developed over the past decade, thanks to new in vitro systems to study HCV entry, replication, assembly, and release.
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Kim SK, Kim SR, Imoto S, Tohyama M, Otono Y, Tamura T, Kim KI, Kobayashi M, Ohtani A, Sugimoto K, Mizuguchi A, Hiramatsu Y, Kudo M. Recent Advances in the Management of Chronic Hepatitis B Including Suppression of Hepatocellular Carcinoma by Entecavir and Interferon. Oncology 2015; 89 Suppl 2:60-9. [PMID: 26584037 DOI: 10.1159/000440633] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
At present, for adults with chronic hepatitis B virus (HBV) infection, two new analogues, entecavir (ETV) and tenofovir, are recommended as the first-line therapy by the EASL (European Association for the Study of the Liver), AASLD (American Association for the Study of Liver Diseases), and APASL (Asian Pacific Association for the Study of the Liver) guidelines. The use of pegylated interferon-α (PEG IFN-α) is recommended as the first-line therapy instead of standard IFN-α according to the above 3 guidelines. In this paper, the aim was to assess: (1) the long-term efficacy and safety as well as the resistance to ETV and tenofovir disoproxil fumarate (TDF); (2) the efficacy of PEG IFN-α; (3) the role of combination therapy with IFN plus two analogues, such as lamivudine and ETV; (4) the efficacy and safety of two analogues with cirrhosis, and (5) suppression of hepatocellular carcinoma (HCC) by ETV and IFN treatment. The results are as follows: (1) both ETV and TDF showed long-term efficacy and safety; (2) PEG IFN-α resulted in a greater decline in HBV DNA levels and a higher rate of HBeAg seroconversion; (3) combination therapy with IFN plus two analogues did not elevate the rate of sustained responses; (4) both ETV and TDF showed efficacy and safety with cirrhosis (ETV especially displayed efficacy and safety with decompensated cirrhosis), and (5) suppression of HCC was observed by ETV and IFN.
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Affiliation(s)
- Soo Ki Kim
- Department of Gastroenterology and Hepatology, Kyoto University, Kyoto, Japan
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Ozaras R, Khodor H, Yetim N, Unal UK, Demirhan YE, Gultekin G, Isal B. Monotherapy for hepatitis B infection: a review of treatment options. Expert Rev Anti Infect Ther 2015; 13:1457-68. [PMID: 26414781 DOI: 10.1586/14787210.2015.1093934] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Chronic hepatitis B (CHB) is a global health problem, causing liver failure, cirrhosis and hepatocellular carcinoma. CHB treatment aims to prevent liver-related complication. The treatment of CHB infection includes monotherapy with either interferons (IFNs) or nucleos(t)ide (NUC) analogs. IFNs have moderate antiviral effects, and their use is limited by side effects. With the availability of NUCs, IFN-intolerant and decompensated cirrhotic patients began to be treated. Lamivudine and telbivudine, nucleoside analogs, have low genetic barrier to resistance. Adefovir, a nucleotide analog, has moderate potency and potential nephrotoxicity. Entecavir and tenofovir, with their high potency, high genetic barrier to resistance and favorable safety profile are the standard of care in CHB treatment. Long-term use of NUCs with maintained viral suppression results in a decrease in liver-related complications.
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Affiliation(s)
| | - Hawa'a Khodor
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Nergul Yetim
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Umut Kaan Unal
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Yunus Emre Demirhan
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Goknil Gultekin
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Burak Isal
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
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18
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Kubo S, Takemura S, Tanaka S, Shinkawa H, Nishioka T, Nozawa A, Kinoshita M, Hamano G, Ito T, Urata Y. Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol 2015; 21:8249-8255. [PMID: 26217076 PMCID: PMC4507094 DOI: 10.3748/wjg.v21.i27.8249] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 03/16/2015] [Accepted: 05/04/2015] [Indexed: 02/06/2023] Open
Abstract
Although liver resection is considered the most effective treatment for hepatocellular carcinoma (HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence. Since we reported hepatitis B e-antigen positivity and high serum hepatitis B virus (HBV) DNA concentrations are strong risk factors for HCC recurrence after curative resection of HBV-related HCC in the early 2000s, many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes. These findings suggest controlling viral status is important to prevent HCC recurrence and improve survival after curative treatment for HBV-related HCC. Antiviral therapy after curative treatment aims to improve prognosis by preventing HCC recurrence and maintaining liver function. Therapy with interferon and nucleos(t)ide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for HBV-related HCC. In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation. Nevertheless, further studies are required to establish treatment guidelines for patients with HBV-related HCC.
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19
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Takano T, Tajiri H, Etani Y, Miyoshi Y, Tanaka Y, Brooks S. Natural history of chronic hepatitis B virus infection in childhood and efficacy of interferon therapy. Scand J Gastroenterol 2015; 50:892-899. [PMID: 25861806 DOI: 10.3109/00365521.2014.962075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES In short-term observations, interferon (IFN) therapy has been shown to be effective in producing both biochemical and virological responses in children with chronic hepatitis B virus (HBV) infection. However, in long-term follow up, no studies have shown a clear advantage of IFN therapy during childhood. We conducted a retrospective study on the sustained effect of IFN therapy among a Japanese pediatric population. METHODS AND SUBJECTS A retrospective study was performed on 155 children with chronic HBV infection who were followed in two affiliated hospitals during the period from 1986 to 2013. RESULTS The 155 patients comprised 97 males and 58 female. Infection route was maternal transmission in 96/155 patients. HBV genotype was A in 17, B in 6, and C in 51 patients. IFN therapy was performed in 48 patients. One year after the completion of IFN therapy, normalization of alanine aminotransferase (ALT) and lower viral levels (<10(4) copies/ml) was observed in 43 and 29 patients, respectively. The sustained effects of IFN therapy were evaluated by comparison between 43 hepatitis B e-antigen (HBeAg)-positive patients treated with IFN and 67 patients with chronic hepatitis B observed without IFN therapy. A Cox's proportional hazard analysis showed a higher seroconversion rate in the IFN group than in the untreated group (p = 0.003). Similarly, there were higher rates of ALT normalization and lower viral levels in the IFN group than in the untreated group (p = 0.001 for both). CONCLUSION IFN therapy showed sustained effects for achieving ALT normalization and HBeAg seroconversion and for reducing the viral load in children with chronic hepatitis B.
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Affiliation(s)
- Tomoko Takano
- Department of Pediatrics, Osaka General Medical Center , Osaka , Japan
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20
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Abstract
About 80% of hepatocellular carcinoma (HCC) is caused by hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections especially in the setting of established cirrhosis or advanced fibrosis, making HCC prevention a major goal of antiviral therapy. HCC tumors are highly complex and heterogeneous resulting from the aberrant function of multiple molecular pathways. The roles of HCV or HBV in promoting HCC development are still either directly or indirectly are still speculative, but the evidence for both effects is compelling. In patients with chronic hepatitis viral infection, cirrhosis is not a prerequisite for tumorigenesis.
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Affiliation(s)
- Ziv Ben Ari
- Liver Disease Center, Sheba Medical Center, Derech Sheba No 1, Ramat Gan 52621, Israel; Liver Research Laboratory, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
| | - Ella Weitzman
- Liver Disease Center, Sheba Medical Center, Derech Sheba No 1, Ramat Gan 52621, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Michal Safran
- Liver Disease Center, Sheba Medical Center, Derech Sheba No 1, Ramat Gan 52621, Israel; Liver Research Laboratory, Sheba Medical Center, Ramat Gan, Israel
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21
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Abstract
INTRODUCTION Liver cancer is one of the most common cancers. Hepatocellular carcinoma (HCC) represents > 90% of primary liver cancers and is a major global health problem today. Chronic hepatitis B virus (HBV) infection is associated with more than half of HCCs. AREAS COVERED Long-term therapy with nucleos(t)ide analogues (NUCs) improves outcomes in HBV-infected patients by slowing the progression of liver disease. It is associated with improvements in histological and clinical outcomes, improved patient survival, reduced need for liver transplantation and improved liver function in patients with decompensated liver disease. This review highlights the results of previous studies conducted on HCC prevention with long-term NUC therapy. Studies include the use of all available drugs in different clinical scenarios, and the comparison between treated and untreated patients. EXPERT OPINION NUCs have been studied extensively in HCC prevention. A comprehensive review of the literature has shown that they can be safely and effectively used for this purpose. Despite some discrepancies between studies, most of the evidence favors using NUC therapy for HCC prevention.
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Affiliation(s)
- Ezequiel Ridruejo
- Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno "CEMIC", Hepatology Section, Department of Medicine , Ciudad Autónoma de Buenos Aires , Argentina +54 11 4809 1980 ; +54 11 4809 1992 ;
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22
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Abstract
Chronic hepatitis B virus (HBV) infection is a global health problem, leading to cirrhosis, hepatocellular carcinoma (HCC) and liver-related deaths. Universal hepatitis B vaccination is the most cost-effective way to eradicate HBV infection with the remarkable reduction of chronic carriage, neonatal fulminant hepatitis and childhood HCC. The introduction of highly effective antiviral agents, including lamivudine, adefovir dipivoxil, entecavir, telbivudine, tenofovir disoproxil fumarate and pegylated interferons further improve short-, medium- and long-term outcomes of chronic HBV infection, such as ALT normalization, HBV DNA suppression, HBeAg seroconversion, HBsAg seroclearance, fibrosis regression, reduction of cirrhosis, HCC, liver-related deaths and the need for liver transplantation. Above all, sustained and profound viral suppression is the key to improve the clinical outcomes of chronic hepatitis B.
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Affiliation(s)
- Tung-Hung Su
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te Street, Taipei 10002, Taiwan
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23
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Su CH, Lin Y, Cai L. Genetic factors, viral infection, other factors and liver cancer: an update on current progress. Asian Pac J Cancer Prev 2014; 14:4953-60. [PMID: 24175758 DOI: 10.7314/apjcp.2013.14.9.4953] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Primary liver cancer is one of the most common cancers at the global level, accounting for half of all cancers in some undeveloped countries. This disease tends to occur in livers damaged through alcohol abuse, or chronic infection with hepatitis B and C, on a background of cirrhosis. Various cancer-causing substances are associated with primary liver cancer, including certain pesticides and such chemicals as vinyl chloride and arsenic. The strong association between HBV infection and liver cancer is well documented in epidemiological studies. It is generally acknowledged that the virus is involved through long term chronic infection, frequently associated with cirrhosis, suggesting a nonspecific mechanism triggered by the immune response. Chronic inflammation of liver, continuous cell death, abnormal cell growth, would increase the occurrence rate of genetic alterations and risk of disease. However, the statistics indicated that only about one fifth of HBV carries would develop HCC in lifetime, suggesting that individual variation in genome would also influence the susceptibility of HCC. The goal of this review is to highlight present level of knowledge on the role of viral infection and genetic variation in the development of liver cancer.
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Affiliation(s)
- Cheng-Hao Su
- Department of Emergency Countermeasure and Information Management, Xiamen Center for Disease Control and Prevention, Xiamen, China E-mail :
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24
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Abstract
Chronic hepatitis B (CHB) infection is the major cause of hepatocellular carcinoma (HCC), accounting for approximately 50% of the underlying etiologies. We reviewed the primary, secondary, and tertiary measures for the prevention of hepatitis B virus (HBV)-related HCC. The most effective method for preventing HBV-related HCC is vaccination. Universal hepatitis B vaccination has been shown to reduce the rates of HBV infection and HCC significantly. Once chronic HBV infection is established, antiviral treatment using interferon or nucleos(t)ide analogs is used to prevent disease progression to cirrhosis, HCC, or both. Studies have found viral replication indicated by HBV DNA level to be a strong risk factor for development of HCC. Additionally, periodic surveillance using ultrasonography and serum α-fetoprotein for earlier detection of HCC is also important so that curative treatments with survival benefit can be possible. Finally, adjuvant antiviral treatment using interferon or nucleos(t)ide analogs is used to prevent tumor recurrence after curative resection. Adjuvant interferon treatment prevented early recurrence, not late recurrence, probably due to its antiangiogenetic and antiproliferative effects. Adjuvant nucleos(t)ide analogs demonstrated promising results for preventing late recurrence, probably due to effective suppression of viral replication. Further investigations are required to establish the optimal preventive plans for HBV-related HCC.
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Affiliation(s)
- Mi Na Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 Project for Medical Science, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 Project for Medical Science, Seoul, Korea
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25
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El-Serag HB, Kanwal F. Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology 2014; 60:1767-75. [PMID: 24839253 PMCID: PMC4211957 DOI: 10.1002/hep.27222] [Citation(s) in RCA: 486] [Impact Index Per Article: 44.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 04/09/2014] [Accepted: 05/12/2014] [Indexed: 12/13/2022]
Affiliation(s)
- Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, Houston, TX; Houston VA HSR&D Center of Excellence Houston, TX
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26
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Jeng WJ, Lin CC, Chen WT, Sheen IS, Lin CY, Lin SM. Adjuvant therapy for hepatocellular carcinoma after curative treatment. Dig Dis 2014; 32:747-54. [PMID: 25376293 DOI: 10.1159/000368017] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy in the world. Although resection and various locoregional therapies can achieve eradication or complete ablation of small HCC, HCC recurrence after these therapies is still common. Although candidates for medical ablation usually exhibit compensated hepatic functional status, the frequent recurrence of HCC after successful ablation contributes to short survival. Therefore, attempts to prevent HCC recurrence are essential to prolong survival. Efforts in preventing HCC recurrence after curative therapies include prevention of early recurrence by improving liver immunity and eliminating microscopic tumor foci or micrometastases, and prevention of late recurrence by reducing the hepatitis activity and using antiviral therapies based on viral suppression/eradication. In HCC with vascular invasion, adjuvant transcatheter arterial chemoembolization should be considered to provide better control. Whether the adjuvant use of sorafenib may suppress microscopic tumor foci or micrometastases may be unveiled in the near future. This review article will update the algorithms, novel medication or study drugs in the prevention of HCC after curative therapies.
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Affiliation(s)
- Wen-Juei Jeng
- Division of Hepatology, Liver Research Unit, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taipei, Taiwan, ROC
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27
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Seo Y, Yano Y. Short- and long-term outcome of interferon therapy for chronic hepatitis B infection. World J Gastroenterol 2014; 20:13284-13292. [PMID: 25309065 PMCID: PMC4188886 DOI: 10.3748/wjg.v20.i37.13284] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 01/25/2014] [Accepted: 06/26/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a serious clinical problem worldwide. Conventional interferon (IFN)-α has been approved for the treatment of chronic hepatitis B (CHB). Short-term studies have demonstrated that IFN-based therapy is moderately effective in inducing the loss of hepatitis e antigen (HBeAg) or seroconversion (30%-40%) in HBeAg-positive patients and also produces sustained HBV DNA suppression (20%-30%) in HBeAg-negative patients. Many studies have reported a correlation between the HBV genotype and response to IFN treatment. The highest response rate to IFN treatment was found in patients infected with HBV genotype A, followed by HBV genotypes B, C, and D. The long-term effect of IFN-α on CHB has not yet been elucidated. The ability of IFN-α treatment to prevent new cirrhosis, complications associated with cirrhosis, and development of hepatocellular carcinoma (HCC) is controversial. The beneficial effect of IFN-α treatment in reducing the development of HCC has mainly been observed in treatment responders who already have cirrhosis. These inconsistent findings may be attributed to the inevitable limitations of comparisons across studies, including differences in the baseline characteristics of the study and the moderate suppression of HBV replication by IFN-α relative to nucleoside/nucleos(t)ide analogs.
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28
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Calvaruso V, Craxì A. Regression of fibrosis after HBV antiviral therapy. Is cirrhosis reversible? Liver Int 2014; 34 Suppl 1:85-90. [PMID: 24373083 DOI: 10.1111/liv.12395] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Long-lasting HBV-DNA suppression is considered to be the best surrogate end-point of antiviral therapy in patients with hepatitis B virus (HBV) related chronic hepatitis or cirrhosis, and it is a prerequisite to prevent liver-related complications and improve survival. Treatment with oral antiviral drugs in patients with HBV cirrhosis is effective in restoring liver function and improving survival even in those with decompensated cirrhosis. These agents are generally well-tolerated for long-term treatment, and several evidences have demonstrated that they are able to reverse liver fibrosis and prevent the occurrence of HCC.
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Affiliation(s)
- Vincenza Calvaruso
- Gastroenterology and Hepatology Unit, University of Palermo, Palermo, Italy
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29
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Triolo M, Della Corte C, Colombo M. Impact of HBV therapy on the incidence of hepatocellular carcinoma. Liver Int 2014; 34 Suppl 1:139-45. [PMID: 24373091 DOI: 10.1111/liv.12394] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is a frequent, long term complication of chronic infection with hepatitis B virus (HBV) with an annual incidence ranging from 2 to 5%, often independent from the histological stage of underlying liver disease and serological status. Nevertheless, HCC is more often seen in older patients in whom HBV has been asserting its pro-oncogenic properties through both indirect and direct mechanisms. In Europe, HBV-related HCC is associated with cirrhosis in most patients, whereas this is not true in Asia and Africa where the tumour is also common among carriers with mild hepatic fibrosis, probably because of the coexistence of environmental co-carcinogens (aflatoxin) and long standing infection that is often acquired perinatally. Since hepatitis B-related carcinogenesis develops independently of the onset of cirrhosis, antiviral treatments such as nucleo(t)side analogues (NAs) that may result in the regression of fibrosis, prevent clinical decompensation and variceal bleeding, often fail to prevent HCC. Studies enrolling patients treated with lamivudine or rescued with adefovir, i.e. regimens characterized by limited potency and a low to moderate genetic barrier, have clearly been shown to help prevent HCC in patients with chronic hepatitis but not in those with cirrhosis, and in general not in patients that cannot achieve a sustained virological response. More potent anti-HBV drugs, such as entecavir and tenofovir, have been shown to improve the prevention of HCC in responders with cirrhosis, although HCC may still occur even in low risk patients. To attenuate HCC related outcomes, HBV replication must permanently be suppressed and HCC surveillance by abdominal ultrasound should be maintained even in responder patients.
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Affiliation(s)
- Michela Triolo
- 1st Division of Gastroenterology, Department of Liver, Kidney, Lung and Bone Marrow Units and Organ Transplant, A.M. & A. Migliavacca Center for Liver Disease, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milan, Italy
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30
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Drafting Committee for Hepatitis Management Guidelines and the Japan Society of Hepatology. JSH Guidelines for the Management of Hepatitis B Virus Infection. Hepatol Res 2014; 44 Suppl S1:1-58. [PMID: 24397839 DOI: 10.1111/hepr.12269] [Citation(s) in RCA: 133] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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31
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Vlachogiannakos J, Papatheodoridis G. Hepatocellular carcinoma in chronic hepatitis B patients under antiviral therapy. World J Gastroenterol 2013; 19:8822-30. [PMID: 24379605 PMCID: PMC3870533 DOI: 10.3748/wjg.v19.i47.8822] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Revised: 10/25/2013] [Accepted: 11/01/2013] [Indexed: 02/06/2023] Open
Abstract
Patients with chronic hepatitis B are at increased risk of hepatocellular carcinoma (HCC), while the inhibition of viral replication can represent a reasonable target for HCC prevention. Interferon-α therapy results in decreased HCC risk, which is more evident in patients with high baseline HCC risk. The majority of chronic hepatitis B patients are treated with a nucleos(t)ide analogue (NA) for several reasons including the non-sustained response after interferon-α. The effect of the first licensed and low genetic barrier NA, lamivudine, on HCC incidence, has been repeatedly evaluated. Lamivudine, compared to no treatment, reduces the HCC incidence, which may increase again in cases with lamivudine resistance. Emerging data with the currently first-line NAs, entecavir and tenofovir, suggest that they also reduce the HCC incidence. The treatment benefit in reduction of the HCC incidence is always greater in patients with high baseline HCC risk, particularly cirrhotics, and without virological remission under entecavir/tenofovir. However, the HCC risk is not eliminated even in the vast majority of patients who remain in virological remission under entecavir/tenofovir. Therefore, patients at increased baseline HCC risk should continue to undergo HCC surveillance even if they have achieved complete long-term inhibition of viral replication and improvements in liver histology.
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32
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Kusano H, Akiba J, Ogasawara S, Sanada S, Yasumoto M, Nakayama M, Ueda K, Ueda K, Kurita T, Todoroki K, Umeno Y, Nakashima O, Yano H. Pegylated interferon-α2a inhibits proliferation of human liver cancer cells in vitro and in vivo. PLoS One 2013; 8:e83195. [PMID: 24349459 PMCID: PMC3861497 DOI: 10.1371/journal.pone.0083195] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Accepted: 11/10/2013] [Indexed: 12/29/2022] Open
Abstract
Purpose We investigated the effects of pegylated interferon-α2a (PEG-IFN-α2a) on the growth of human liver cancer cells. Methods The effect of PEG-IFN-α2a on the proliferation of 13 liver cancer cell lines was investigated invitro. Cells were cultured with medium containing 0–4,194 ng/mL of PEG-IFN-α2a, and after 1, 2, 3, or 4 days of culture, morphologic observation and growth assay were performed. After hepatocellular carcinoma (HCC) cells (HAK-1B and KIM-1) were transplanted into nude mice, various doses of PEG-IFN-α2a were subcutaneously administered to the mice once a week for 2 weeks, and tumor volume, weight, and histology were examined. Results PEG-IFN-α2a inhibited the growth of 8 and 11 cell lines in a time- and dose-dependent manner, respectively, although the 50% growth inhibitory concentrations of 7 measurable cell lines on Day 4 were relatively high and ranged from 253 ng/mL to 4,431 ng/mL. Various levels of apoptosis induction were confirmed in 8 cell lines. PEG-IFN-α2a induced a dose-dependent decrease in tumor volume and weight, and a significant increase of apoptotic cells in the tumor. Subcutaneous administration of clinical dose for chronic hepatitis C (3 μg/kg, 0.06 μg/mouse) was effective and induced about 30-50% reduction in the tumor volume and weight as compared with the control. Conclusions Although invitro anti-proliferative effects of PEG-IFN-α2a were relatively weak, PEG-IFN-α2a induced strong anti-tumor effects on HCC cells invivo. The data suggest potential clinical application of PEG-IFN-α2a for the prevention and treatment of HCC.
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Affiliation(s)
- Hironori Kusano
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
- * E-mail:
| | - Jun Akiba
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Sachiko Ogasawara
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Sakiko Sanada
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Makiko Yasumoto
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Masamichi Nakayama
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Keiko Ueda
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Kosuke Ueda
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Takashi Kurita
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Keita Todoroki
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Yumi Umeno
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Osamu Nakashima
- Department of Clinical Laboratory Medicine, Kurume University Hospital, Kurume, Fukuoka, Japan
| | - Hirohisa Yano
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
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National Antiviral Treatment Program and the Incidence of Hepatocellular Carcinoma and Associated Mortality in Taiwan. Med Care 2013; 51:908-13. [DOI: 10.1097/mlr.0b013e3182a502ba] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Thiele M, Gluud LL, Dahl EK, Krag A. Antiviral therapy for prevention of hepatocellular carcinoma and mortality in chronic hepatitis B: systematic review and meta-analysis. BMJ Open 2013; 3:bmjopen-2013-003265. [PMID: 23945731 PMCID: PMC3752055 DOI: 10.1136/bmjopen-2013-003265] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES The effect of antiviral therapy on clinical outcomes in chronic hepatitis B virus (HBV) is not established. We aimed to assess the effects of interferon and/or nucleos(t)ide analogues versus placebo or no intervention on prevention of hepatocellular carcinoma (HCC) and mortality in chronic HBV. DESIGN Random-effects pairwise meta-analysis of randomised trials and observational studies. SETTING Electronic and manual searches were combined. Randomised controlled trials (RCTs) were included in the primary analyses. Observational studies were included in sensitivity analyses. PRIMARY AND SECONDARY OUTCOME MEASURES The primary outcome measures were HCC incidence and mortality. The secondary outcome measure was HCC mortality. RESULTS We included 8 RCTs, 8 prospective cohort studies and 19 case-control studies with a total of 3433 patients allocated to antiviral therapy and 4625 controls. The maximum duration of follow-up was 23 years. Randomised trials found no effect of antiviral therapy on HCC or mortality. Cohort studies found that antiviral therapy increased the risk of HCC (risk ratio 1.43; 95% CI 1.06 to 1.95), whereas case-control studies found a decreased risk of HCC in the intervention group (risk ratio 0.69; 95% CI 0.54 to 0.88). There was a clear difference between the results of RCTs and observational studies (test for subgroup differences, p<0.001). Antiviral therapy did not affect mortality in cohort studies, but reduced mortality in case-control studies (relative risk 0.71; 95% CI 0.54 to 0.93; test for subgroup differences, p=0.406). CONCLUSIONS The effect of antiviral therapy on clinical outcomes in HBV remains to be established. Although there was a positive effect in the sensitivity analyses, the strength of the evidence does not allow for extrapolation to clinical practice as research design plays an essential role in the overall assessment. TRIAL REGISTRATION NUMBER Prospero number CRD42013003881.
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Affiliation(s)
- Maja Thiele
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Lise L Gluud
- Department of Medicine, Copenhagen University Hospital of Gentofte, Hellerup, Denmark
| | - Emilie K Dahl
- Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
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Abstract
The hepatitis B virus (HBV) plays a dominant role in the 749,000 new cases and 692,000 deaths related to hepatocellular carcinoma (HCC) that are estimated to occur each year worldwide. Chronic infection with HBV is responsible for 60% of HCCs in Asia and Africa and at least 20% of the tumors in Europe, Japan, and the United States. This article discusses the pathogenic role of HBV and the risk of HCC. Tumors almost invariably develop in the context of chronic hepatitis or cirrhosis, which makes early diagnosis the only practical approach to improve prognosis. The treatment options are also discussed.
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Affiliation(s)
- Massimo Iavarone
- 1st Division of Gastroenterology, A.M. & A. Migliavacca Center for Liver Disease, Fondazione IRCCS Ca' Granda Maggiore Hospital, Università degli Studi di Milano, Via F. Sforza 35, Milan 20122, Italy
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36
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Abstract
Chronic hepatitis B virus (HBV) infection is a dynamic state of interactions between HBV, the hepatocytes, and the patient's immune system. HBV replication is the key driving force for the HBV-related immune clearance events that determine the outcomes. The extended immune clearance phase is associated with liver disease progression, including development of cirrhosis and hepatocellular carcinoma (HCC). Thus, the primary aim of therapy is to eliminate or permanently suppress HBV to reduce hepatitis activity and thereby reduce the risk or slow the progression of liver disease.
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Abstract
Chronic hepatitis B virus (HBV) infection is a dynamic state in which HBV replication is the key driving force of disease progression, resulting in the development of hepatic decompensation, cirrhosis and hepatocellular carcinoma (HCC). The primary aim of therapy is to eliminate or suppress HBV to reduce the activity of hepatitis thus reducing the risk of or slowing the progression of liver disease. Treatment with nucleos(t)ide analogues (Nuc) may result in rapid suppression of HBV replication with normalization of serum transaminases and restore liver function thus increasing survival in patients with hepatic decompensation. The long-term benefits of a finite course of interferon α (IFN) therapy include a sustained and cumulative response, as well as a reduction in the progression of fibrosis and in the development of cirrhosis and/or HCC. Long-term Nuc therapy may also result in histological improvement or reversal of advanced fibrosis and reduction in disease progression including the development of HCC. Hepatitis B surface antigen (HBsAg) seroclearance, a status close to a "cure", may also occur in patients with a sustained or maintained viral response, especially in those with IFN-based therapy. Pegylated IFN (PEG-IFN) and newer Nucs may have even better long-term outcomes because of improved efficacy and/or a low risk of drug resistance. However, treatment outcomes are still far from satisfactory. The development of more effective and safe but affordable anti-HBV agents/strategies is needed to further improve outcomes.
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Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
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38
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Lai CL, Yuen MF. Prevention of hepatitis B virus-related hepatocellular carcinoma with antiviral therapy. Hepatology 2013; 57:399-408. [PMID: 22806323 DOI: 10.1002/hep.25937] [Citation(s) in RCA: 165] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Accepted: 06/21/2012] [Indexed: 12/15/2022]
Abstract
Chronic hepatitis B (CHB) infection is the major cause of hepatocellular carcinoma (HCC). Primary prevention of hepatitis B infection by vaccination is effective in reducing the incidence of HCC. In persons with CHB infection, the two accepted treatment modalities are interferon alpha (IFN-α) given subcutaneously for a limited period and nucleoside/nucleotide analogs given orally on a long-term basis. These treatments are effective in suppressing viral activity and improving disease markers in short-term studies. The long-term effect on the development of liver cancers with these two forms of treatment appears to be different. However, there are no studies directly comparing IFN-α and nucleoside/nucleotide analogs. Comparisons across studies are inevitably limited by differences in the baseline characteristics of the study cohorts. Long-term follow-up studies of IFN-α therapy show inconsistent results. The beneficial effect in reducing the development of liver cancer is observed mainly in treatment responders who have preexisting cirrhosis of the liver. The long-term studies of lamivudine (and adefovir) show a consistent reduction in the development of liver cancers in patients with, and without, cirrhosis. This beneficial effect is blunted by the development of resistance. The effects of the newer nucleoside/nucleotide analogs, with higher potency and minimal risk of resistance development, are, as yet, unknown.
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Affiliation(s)
- Ching-Lung Lai
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
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39
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Asahina Y, Izumi N, Oketani M, Kumada H, Kurosaki M, Koike K, Suzuki F, Takikawa H, Tanaka A, Tanaka E, Tanaka Y, Tsubouchi H, Hayashi N, Hiramatsu N, Yotsuyanagi H. Guidelines for the management of hepatitis B virus infection. KANZO 2013; 54:402-472. [DOI: 10.2957/kanzo.54.402] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Shen YC, Hsu C, Cheng CC, Hu FC, Cheng AL. A critical evaluation of the preventive effect of antiviral therapy on the development of hepatocellular carcinoma in patients with chronic hepatitis C or B: a novel approach by using meta-regression. Oncology 2012; 82:275-89. [PMID: 22555181 DOI: 10.1159/000337293] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Accepted: 02/17/2012] [Indexed: 12/18/2022]
Abstract
BACKGROUND The extent of the effect of antiviral therapy and its predictors in preventing hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C (CHC) or B (CHB) remain unclear. METHODS We conducted a systemic review and meta-analysis of published randomized controlled trials (RCTs) and cohort studies (CSs) up to December 2010. Preventive efficacy was measured as absolute reduction in 3- and 5-year cumulative incidence of HCC with antiviral therapy. Predictors for efficacy were identified by using meta-regression. RESULTS Twenty-two studies (5 RCTs; 17 CSs) were included for analysis. Antiviral therapy reduced 5-year cumulative incidence of HCC by 7.8% (95% CI 4.6-11.1; p < 0.0001) in patients with CHC and by 7.1% (95% CI 4.1-10.2; p < 0.0001) in patients with CHB. The efficacy was significant as early as 3 years after antiviral therapy. While adjusting for available study-level, patient and virological factors, RCT and higher sustained virological response were identified as pertinent predictors of superior preventive efficacy in patients with CHC, whereas lower hepatitis B virus e antigen seropositivity was identified in patients with CHB. Antiviral therapy did not result in differential preventive efficacy between cirrhotic and noncirrhotic patients with CHC or CHB. CONCLUSION Antiviral therapy can reduce 3- and 5-year cumulative incidence of HCC in patients with CHC or CHB.
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Affiliation(s)
- Ying-Chun Shen
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC
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41
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Chan SL, Mo FKF, Wong VWS, Liem GS, Wong GLH, Chan VTC, Poon DMC, Loong HHF, Yeo W, Chan ATC, Mok TSK, Chan HLY. Use of antiviral therapy in surveillance: impact on outcome of hepatitis B-related hepatocellular carcinoma. Liver Int 2012; 32:271-278. [PMID: 22098536 DOI: 10.1111/j.1478-3231.2011.02634.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2011] [Accepted: 08/02/2011] [Indexed: 12/15/2022]
Abstract
BACKGROUND Antiviral therapy for hepatitis B virus (HBV) infection is frequently prescribed for patients with chronic HBV infection during surveillance for hepatocellular carcinoma (HCC). In patients who subsequently develop HCC, the impact of antiviral therapy on the outcome of HCC remains unclear. AIMS We aimed to study the impact of antiviral therapy on the survival of patients who developed HCC. METHODS From two prospective surveillance cohorts, the use of antiviral therapy for patients with HCC was retrospectively reviewed. We compared the overall survival, liver function and tumour characteristics between patients with and without antiviral therapy during surveillance. Multivariate analysis was conducted to determine the independent prognostication of antiviral therapy. RESULTS During a median follow-up of 10.1 years of 1429 patients, 148 cases of HCC were diagnosed and followed up for a median of 5.7 years. Twenty-nine patients were given antiviral therapy during surveillance and continued treatment after diagnosis of HCC. The median survival of this group of patients was better than the rest of cohorts (hazard ratio: 0.472; 95% CI: 0.25-0.89; P = 0.0191). Use of antiviral therapy remained an independent prognostic factor after adjustment for demographic factors and tumour staging on multivariate analysis. Exploratory analysis revealed that patients who commenced antiviral therapy during surveillance had lower HBV DNA, lower serum alanine transaminase, better hepatic reserves and higher rate of local treatment at diagnosis of HCC. CONCLUSION This study provides evidence that commencement of antiviral therapy during the surveillance period is associated with improvement in overall survival in HBV-related HCC.
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Affiliation(s)
- Stephen L Chan
- State Key Laboratory in Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.
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42
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Shimomura S, Nishiguchi S. Anticarcinogenic impact of interferon therapy on the progression of hepatocellular carcinoma in patients with chronic viral infection. Hepatol Res 2012; 42:22-32. [PMID: 21951512 DOI: 10.1111/j.1872-034x.2011.00889.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is mainly caused by a persistent infection due to the hepatitis B or hepatitis C virus. The number of HCC cases is increasing in Asian and African countries, as well as in European and American countries. Interferon (IFN) therapy, used for type B chronic liver diseases, inhibits hepatic carcinogenesis in patients with compensated cirrhosis. However, there is insufficient evidence that IFN therapy inhibits hepatic carcinogenesis in patients with chronic hepatitis B. There are few cases of HCC due to chronic hepatitis B, and long-term follow-up periods verifying the inhibitory effect of IFN on hepatic carcinogenesis have not been obtained. To improve the prognosis of type B chronic liver diseases, it is important that hepatitis treatment follows guidelines in which a patient's age and the extent of hepatic fibrosis are taken into account. As for chronic hepatitis C, since a sustained virological response (SVR) in IFN therapy inhibits hepatic carcinogenesis and improves prognosis, treatment that aims for an SVR while taking into consideration host-sided and virus-sided factors is recommended for patients with type C chronic liver diseases. In areas with low incidence of HCC (e.g. USA), a large number of cases and a long-term follow-up period are needed before it can be accepted that IFN therapy inhibits hepatic carcinogenesis. After locally curative treatment of HCC, IFN therapy suppresses recurrence and improves survival rates.
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Affiliation(s)
- Soji Shimomura
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
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43
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Jin H, Pan N, Mou Y, Wang B, Liu P. Long-term effect of interferon treatment on the progression of chronic hepatitis B: Bayesian meta-analysis and meta-regression. Hepatol Res 2011; 41:512-23. [PMID: 21501353 DOI: 10.1111/j.1872-034x.2011.00801.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
AIM The long-term effects of interferon treatment on the progression of chronic hepatitis B (CHB) have been studied extensively, but its true clinical benefits and the predictors of its efficacy remain unclear. METHODS A systematic published work search was undertaken. Eligible studies included those with interferon treatment and control groups, and with liver cirrhosis (LC), hepatocellular carcinoma (HCC) or death as main outcomes. Bayesian meta-analysis and meta-regression were performed to assess associations between interferon treatment and disease progression, and the impacts of potential covariates. RESULTS Eleven articles met the inclusion criteria. LC, HCC and death were end-points in four, nine and six studies, respectively. In all studies, interferon was associated with significant preventive effects on HCC according to the DerSimonian-Laird method (relative risk [RR] = 0.470, 95% confidence interval [CI] = 0.260-0.850) and Bayesian method adjusting underlying risk (RR = 0.249, 95% Bayesian credible intervals [BCI] = 0.049-0.961), but not according to Bayesian meta-analysis (RR = 0.274, 95% BCI = 0.059-1.031); and it showed similar effects in death but not in LC. However, most of the high-quality studies never revealed protective benefits in these end-points. Bayesian meta-regression identified Asian ethnicity in death, higher hepatitis B e-antigen (HBeAg) seroconversion rate or positivity rate, and length of follow up (≤5 years) in HCC as potentially protective against disease progression. Subgroup analysis confirmed similar effects from these factors in HCC and death. CONCLUSION Additional evidence is needed to support the role of interferon in delaying CHB progression.
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Affiliation(s)
- Hui Jin
- Department of Epidemiology and Health Statistics, School of Public Health Department of Medical Genetics, Southeast University, Nanjing City Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu City, China
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Miyake Y, Iwasaki Y, Yamamoto K. Meta-analysis: reduced incidence of hepatocellular carcinoma in patients not responding to interferon therapy of chronic hepatitis C. Int J Cancer 2010; 127:989-996. [PMID: 19957327 DOI: 10.1002/ijc.25090] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Interferon treatment for chronic hepatitis C reduces the incidence of hepatocellular carcinoma (HCC) in sustained responders. However, estimation of the effect of interferon treatment on HCC development in nonresponders is yet to be fully implemented. We conducted a meta-analysis of 3 randomized controlled trials and 6 prospective cohort studies, including 3,246 patients (1,922 patients received interferon treatment) to estimate the effect of single-course interferon treatment on HCC development in patients with chronic hepatitis C. Single-course interferon treatment prevented HCC development (RR 0.45; 95% CI 0.31-0.65). This preventive effect was shown even in nonresponders (RR 0.48; 95% CI 0.25-0.90). By subgroup analyses, single-course interferon treatment reduced HCC incidence in cirrhotic patients (RR 0.49; 95% CI 0.29-0.84), patients with annual HCC incidence less than 3% in control group (RR 0.42; 95% CI 0.26-0.66) and patients with annual HCC incidence of 3% or more in control group (RR 0.46; 95% CI 0.26-0.83). Furthermore, HCC incidence was reduced in 3 studies with follow-up period less than 5 years (RR 0.38; 95% CI 0.21-0.66) and in 6 studies with follow-up period of 5 years or more (RR 0.46; 95% CI 0.28-0.76). In conclusion, single-course interferon treatment was shown to prevent HCC development in chronic hepatitis C, even in nonresponders. This preventive effect may be speculated to be due to anti-inflammatory effect on persistent necro-inflammation and blocking progression of fibrosis in liver. Even if sustained virological response is not achieved, interferon may be worth administering in order to reduce HCC incidence in patients with chronic hepatitis C.
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Affiliation(s)
- Yasuhiro Miyake
- Department of Molecular Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
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Mizokami M, Tanaka E, Chayama K, Tanaka Y, Kurosaki M, Izumi N, Arase Y, Kumada H, Imazeki F, Yokosuka O, Kudo M. JSH Consensus Kobe 2009: Diagnosis and Treatment of Hepatitis B. KANZO 2010; 51:243-260. [DOI: 10.2957/kanzo.51.243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
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