1
|
Liu WJ, Wu WJ, Lin CL, Liu CJ, Huang YW, Hu JT, Yu MW. Impact of age at HBsAg seroclearance on hepatic outcomes and life expectancy in men with chronic HBV infection based on multi-state modeling of the natural history. J Gastroenterol 2025; 60:107-117. [PMID: 39438326 DOI: 10.1007/s00535-024-02162-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 10/13/2024] [Indexed: 10/25/2024]
Abstract
BACKGROUND The effects of age at HBsAg seroclearance on clinical outcomes and survival in chronic hepatitis B (CHB) have not been adequately assessed. We evaluated the impact of age at HBsAg seroclearance on long-term outcomes, along with how coexisting factors modified risks and life expectancy in CHB patients. METHODS We used multi-state modeling approach to examine transitions through the CHB continuum in a longitudinal cohort study of male civil servants recruited in 1989-1992. Hepatic outcomes and deaths were identified by clinical evaluation and linkage with national health databases. Four sets of risk factors (CHB-related, metabolic, lifestyle, and genetic factors) were assessed. RESULTS Of 2551 HBsAg carriers, with follow-up until 2021 or death, 695 achieved HBsAg seroclearance, 490 developed cirrhosis (88 decompensated), 252 developed hepatocellular carcinoma (HCC), and 652 died. The cumulative rates for HCC were 1.1% and 1.5% at 10 years after HBsAg seroclearance, respectively, for patients achieving seroclearance at age 50 and 60; correspondingly, the rates for cirrhosis were 2.3% and 3.0%. Developing HBsAg seroclearance was associated with a reduced risk of cirrhosis (HR = 0.37, 95% CI 0.15-0.92) but not HCC. Patients experiencing HBsAg seroclearance lived longer years free of major liver diseases than HBsAg-persistent patients, and achieving seroclearance at age 50 (vs 60) led to a greater increase in the disease-free life expectancy. However, obesity and smoking were associated with adverse hepatic outcomes and loss of the disease-free life expectancy following HBsAg seroclearance. CONCLUSIONS Our findings highlight the benefit of earlier HBsAg seroclearance for gains in disease-free life expectancy and the impact of obesity and smoking on loss of the life years free of major liver diseases following HBsAg seroclearance.
Collapse
Affiliation(s)
- Wen-Jie Liu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Room 522 No.17, Xuzhou Road, Zhongzheng, Taipei, 10055, Taiwan
| | - Wan-Jung Wu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Room 522 No.17, Xuzhou Road, Zhongzheng, Taipei, 10055, Taiwan
| | - Chih-Lin Lin
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Wen Huang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Jui-Ting Hu
- Liver Center, Cathay General Hospital Medical Center, School of Medicine, Fu-Jen Catholic University College of Medicine, Taipei, Taiwan
| | - Ming-Whei Yu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Room 522 No.17, Xuzhou Road, Zhongzheng, Taipei, 10055, Taiwan.
| |
Collapse
|
2
|
Huang SW, Long H, Huang JQ. Surveillance Following Hepatitis B Surface Antigen Loss: An Issue Requiring Attention. Pathogens 2024; 14:8. [PMID: 39860969 PMCID: PMC11768139 DOI: 10.3390/pathogens14010008] [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: 11/05/2024] [Revised: 12/25/2024] [Accepted: 12/27/2024] [Indexed: 01/27/2025] Open
Abstract
Due to the lack of agents that directly target covalently closed circular DNA and integrated HBV DNA in hepatocytes, achieving a complete cure for chronic hepatitis B (CHB) remains challenging. The latest guidelines recommend (hepatitis B surface antigen) HBsAg loss as the ideal treatment target for improving liver function, histopathology, and long-term prognosis. However, even after HBsAg loss, hepatitis B virus can persist, with a risk of recurrence, reactivation, cirrhosis, and hepatocellular carcinoma. Therefore, follow-up and surveillance are still necessary. With increasing treatment options available for achieving HBsAg loss in patients with CHB, developing effective surveillance strategies has become crucial. Recent studies on outcomes following HBsAg loss provide new insights for refining current surveillance strategies, though further improvement is needed through long-term observation and follow-up.
Collapse
Affiliation(s)
- Shuai-Wen Huang
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
- Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Hong Long
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
| | - Jia-Quan Huang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
| |
Collapse
|
3
|
Xu W, Gong H, Li B, Yin X. Hepatocellular carcinoma in HBsAg seroclearance: clinical features, recurrence, and prognosis following curative hepatectomy. Ther Adv Med Oncol 2024; 16:17588359241289202. [PMID: 39483138 PMCID: PMC11526261 DOI: 10.1177/17588359241289202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 09/18/2024] [Indexed: 11/03/2024] Open
Abstract
Aim To explore clinical features and prognosis of hepatocellular carcinoma (HCC) in hepatitis B virus surface antigen (HBsAg)-serocleared patients and identify risk factors associated with postoperative recurrence after curative hepatectomy. Methods Patients who had undergone initial hepatectomy for HCC from January 2010 through December 2022. Clinicopathological data were compared between HBsAg-seropositive and HBsAg-serocleared patients. Furthermore, risk factors associated with early and late postoperative HCC recurrence (early and late recurrences (ER and LR), respectively) were analyzed for HBsAg-serocleared HCC patients treated by curative hepatectomy. Results A total of 2184 consecutive patients undergoing initial hepatectomy for HCC were enrolled, including 339 (15.5%) HBsAg-serocleared and 1845 (84.5%) HBsAg-seropositive cases. Tumor characteristics were comparable between the two groups. After curative hepatectomy, the ER rate was lower in the HBsAg-serocleared group than in the HBsAg-seropositive group (16.2% vs 26.3%; p = 0.000). LR rates in the HBsAg-seropositive and HBsAg-serocleared groups were similar (8.3% vs 6.9%, respectively, p = 0.418). Multivariate analysis showed that among HBsAg-serocleared patients, Hong Kong Liver Cancer stage and microvascular invasion were risk factors associated with postoperative ER, while γ-glutamyl transferase level and neutrophil-to-lymphocyte ratio were associated with LR. Conclusion HBsAg-serocleared and HBsAg-seropositive HCC patients exhibited similar tumor characteristics. Curative hepatectomy-treated HBsAg-serocleared HCC patients experienced a lower ER rate and better short-term (⩽3 years) overall survival (OS) rates than their HBsAg-seropositive counterparts. LR, very late recurrence, and long-term (4-, and 5-year) OS rates were similar between the two groups.
Collapse
Affiliation(s)
- Wei Xu
- Department of Hepatobiliary Surgery, The First Hospital Affiliated with Hunan Normal University, Hunan Provincial People’s Hospital, No. 61 West Jiefang Road, Changsha 410005, China
| | - Huai Gong
- Department of Hepatobiliary Surgery, The First Hospital Affiliated with Hunan Normal University, Hunan Provincial People’s Hospital, Changsha, China
| | - Bolun Li
- Department of Hepatobiliary Surgery, The First Hospital Affiliated with Hunan Normal University, Hunan Provincial People’s Hospital, Changsha, China
| | - Xinmin Yin
- Department of Hepatobiliary Surgery, The First Hospital Affiliated with Hunan Normal University, Hunan Provincial People’s Hospital, No. 61 West Jiefang Road, Changsha 410005, China
| |
Collapse
|
4
|
Zhang M, Chen H, Liu H, Tang H. The impact of integrated hepatitis B virus DNA on oncogenesis and antiviral therapy. Biomark Res 2024; 12:84. [PMID: 39148134 PMCID: PMC11328401 DOI: 10.1186/s40364-024-00611-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 06/29/2024] [Indexed: 08/17/2024] Open
Abstract
The global burden of hepatitis B virus (HBV) infection remains high, with chronic hepatitis B (CHB) patients facing a significantly increased risk of developing cirrhosis and hepatocellular carcinoma (HCC). The ultimate objective of antiviral therapy is to achieve a sterilizing cure for HBV. This necessitates the elimination of intrahepatic covalently closed circular DNA (cccDNA) and the complete eradication of integrated HBV DNA. This review aims to summarize the oncogenetic role of HBV integration and the significance of clearing HBV integration in sterilizing cure. It specifically focuses on the molecular mechanisms through which HBV integration leads to HCC, including modulation of the expression of proto-oncogenes and tumor suppressor genes, induction of chromosomal instability, and expression of truncated mutant HBV proteins. The review also highlights the impact of antiviral therapy in reducing HBV integration and preventing HBV-related HCC. Additionally, the review offers insights into future objectives for the treatment of CHB. Current strategies for HBV DNA integration inhibition and elimination include mainly antiviral therapies, RNA interference and gene editing technologies. Overall, HBV integration deserves further investigation and can potentially serve as a biomarker for CHB and HBV-related HCC.
Collapse
Affiliation(s)
- Mingming Zhang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Han Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Huan Liu
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China.
- Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China.
| |
Collapse
|
5
|
Li J, Yang D, Zhong J, Liao Y. Letter: Determining optimal ALT cut-off values for predicting significant hepatic histological changes in chronic hepatitis B virus infection. Aliment Pharmacol Ther 2024; 59:1156-1157. [PMID: 38591800 DOI: 10.1111/apt.17939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/10/2024]
Abstract
LINKED CONTENTThis article is linked to Kang et al paper. To view this article, visit https://doi.org/10.1111/apt.17862
Collapse
Affiliation(s)
- Jianrong Li
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Dalong Yang
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jianhong Zhong
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, China
| | - Yingyang Liao
- Nutritional Department, Guangxi Medical University Cancer Hospital, Nanning, China
| |
Collapse
|
6
|
Liu YC, Jeng WJ. Should Indications for Antiviral Therapy for Hepatitis B Be Broadened to Include Immune-Tolerant Patients, Inactive Carriers, or Patients in the “Gray Zone”? CURRENT HEPATOLOGY REPORTS 2024; 23:11-21. [DOI: 10.1007/s11901-024-00635-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/04/2024] [Indexed: 01/04/2025]
|
7
|
Pan LX, Wang YY, Li ZH, Luo JX, Wu KJ, Liu ZX, Wu PS, Chen K, Ma L, Fan XH, Zhong JH. Entecavir versus tenofovir for prevention of hepatitis B virus-associated hepatocellular carcinoma after curative resection: study protocol for a randomized, open-label trial. Trials 2024; 25:25. [PMID: 38183137 PMCID: PMC10768195 DOI: 10.1186/s13063-023-07742-x] [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: 07/11/2023] [Accepted: 10/22/2023] [Indexed: 01/07/2024] Open
Abstract
BACKGROUND Entecavir and tenofovir disoproxil fumarate (TDF) are standard first-line treatments to prevent viral reactivation and hepatocellular carcinoma (HCC) in individuals chronically infected with the hepatitis B virus (HBV), but the long-term efficacy of the two drugs remains controversial. Also unclear is whether the drugs are effective at preventing viral reactivation or HCC recurrence after hepatectomy to treat HBV-associated HCC. This trial will compare recurrence-free survival, overall survival, viral indicators and adverse events in the long term between patients with HBV-associated HCC who receive entecavir or TDF after curative resection. METHODS This study is a randomized, open-label trial. A total of 240 participants will be randomized 1:1 into groups receiving TDF or entecavir monotherapy. The two groups will be compared in terms of recurrence-free and overall survival at 1, 3, and 5 years after surgery; adverse events; virological response; rate of alanine transaminase normalization; and seroreactivity at 24 and 48 weeks after surgery. DISCUSSION This study will compare long-term survival between patients with HBV-associated HCC who receive TDF or entecavir monotherapy. Numerous outcomes related to prognosis will be analyzed and compared in this study. TRIAL REGISTRATION ClinicalTrials.gov NCT02650271. Registered on January 7, 2016.
Collapse
Affiliation(s)
- Li-Xin Pan
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yi-Yang Wang
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Zhong-Hai Li
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jia-Xi Luo
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Kun-Jun Wu
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Zhen-Xiu Liu
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Pei-Sheng Wu
- Hepatobiliary Surgery Department, the First People's Hospital of Qinzhou, Qinzhou, China
| | - Kang Chen
- Hepatobiliary Surgery Department, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Liang Ma
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xiao-Hui Fan
- Department of Microbiology, School of Preclinical Medicine, Guangxi Medical University, Nanning, China.
| | - Jian-Hong Zhong
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China.
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumors (Guangxi Medical University), Ministry of Education, Nanning, China.
- Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumors, Nanning, China.
| |
Collapse
|
8
|
Kan K, Wong DKH, Hui RWH, Seto WK, Yuen MF, Mak LY. Anti-HBc: a significant host predictor of spontaneous HBsAg seroclearance in chronic hepatitis B patients - a retrospective longitudinal study. BMC Gastroenterol 2023; 23:348. [PMID: 37803352 PMCID: PMC10557289 DOI: 10.1186/s12876-023-02983-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 09/28/2023] [Indexed: 10/08/2023] Open
Abstract
BACKGROUND AND AIM In chronic hepatitis B infection (CHB), seroclearance of hepatitis B surface antigen (HBsAg) is associated with favourable clinical outcomes compared to those with persistent HBsAg seropositivity, and thus considered as a desired treatment endpoint. This current study explores the possibility of serum antibody to hepatitis B core antigen (anti-HBc) as a potential predictive factor of HBsAg seroclearance. METHODS This is a retrospective study that analyzed the plasma samples of CHB patients using the LUMIPULSE® G1200 analyzer. The longitudinal anti-HBc level between patients who subsequently achieved HBsAg seroclearance (S-losers) and those with persistent HBsAg-positivity (controls) were compared at multiple time points before the event. RESULTS A total of 240 subjects (120 S-losers and 120 controls; age- and gender-matched) were included (mean age 56.42 ± 10.81, 65% male). Compared to controls, S-losers had significantly lower plasma anti-HBc levels prior to HBsAg seroclearance, with a significant trend of declining plasma anti-HBc 8-5 years prior to HBsAg seroclearance (p < 0.01), while such trend was not observed in controls. ROC curve analysis revealed that plasma anti-HBc at multiple time points before HBsAg seroclearance return AUC greater than 0.7. Plasma anti-HBc level at the cut-off value of 82.50 COI was 68.3% sensitive and 90% specific for HBsAg seroclearance within 1 year. Combining with quantitative HBsAg < 100 IU/mL, anti-HBc < 82.5 COI identified 88.2% patients who would develop HBsAg seroclearance within 1 year. CONCLUSION Plasma anti-HBc level began to decline 10 years prior to HBsAg seroclearance and can serve as a potential predictor for subsequent HBsAg seroclearance.
Collapse
Affiliation(s)
- Karin Kan
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Danny Ka-Ho Wong
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Rex Wan-Hin Hui
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Wai Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China.
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
| | - Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China.
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
| |
Collapse
|
9
|
Broquetas T, Carrión JA. Past, present, and future of long-term treatment for hepatitis B virus. World J Gastroenterol 2023; 29:3964-3983. [PMID: 37476586 PMCID: PMC10354584 DOI: 10.3748/wjg.v29.i25.3964] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
The estimated world prevalence of hepatitis B virus (HBV) infection is 316 million. HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma (HCC) despite universal vaccination programs, and effective antiviral therapy. Long-term administration of nucleos(t)ide analogues (NA) has been the treatment of choice for chronic hepatitis B during the last decades. The NA has shown a good safety profile and high efficacy in controlling viral replication, improving histology, and decreasing the HCC incidence, decompensation, and mortality. However, the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment. The knowledge, in recent years, about the different phases of the viral cycle, and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches. Consequently, several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results. This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B, the present of NA treatment and withdrawal, and the future perspectives with combined molecules to achieve a functional cure.
Collapse
Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
- Universitat Pompeu Fabra, Facultat de Ciències de la Salut i de la Vida, Barcelona 08003, Spain
| |
Collapse
|
10
|
Forbes C, Lavoie L, Satram S, Shen L, Thanawala V, Arizpe A, Terrault N. Global importance of new treatment strategies to efforts to control hepatitis B virus. Expert Rev Anti Infect Ther 2023; 21:847-862. [PMID: 37322901 DOI: 10.1080/14787210.2023.2225771] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 06/09/2023] [Indexed: 06/17/2023]
Abstract
INTRODUCTION Hepatitis B Virus (HBV) infection can progress to chronic HBV (CHB) disease, thereby increasing the risk of severe forms of liver disease (i.e. liver cirrhosis and hepatocellular carcinoma) and resulting in a high global burden of morbidity, mortality, and health-care utilization. AREAS COVERED We discuss how future therapeutic strategies and treatment guidelines may address the large unmet medical needs among patients with CHB. EXPERT OPINION Complexity and a lack of consensus in current CHB treatment guidelines may limit their effective implementation. To minimize poor outcomes in patients not currently receiving treatment (including immune-tolerant and inactive carriers), a simplified harmonized treatment approach is needed across guidelines. Current treatment recommendations focus on nucleot(s)ide analogs (NAs) and pegylated interferon (Peg-IFN), both of which have limitations. NAs provide clinical benefits, but treatment is prolonged and has little impact on functional cure rates. Peg-IFN offers the potential for functional cure but has notable safety and tolerability issues. A shift toward finite treatments with acceptable safety and tolerability profiles is needed. CONCLUSION The key to achieving World Health Organization targets for the global eradication of HBV involves enhanced diagnosis with new treatments and/or combinations of existing treatments alongside globally aligned and simplified treatment guidelines for untreated/inadequately treated populations.
Collapse
Affiliation(s)
| | - Louis Lavoie
- Evidence Synthesis, Evidera Inc, Montreal, Canada
| | - Sacha Satram
- Evidence, Value & Access, Vir Biotechology Inc, San Francisco, CA, USA
| | - Ling Shen
- Biostatistics, Vir Biotechnology Inc, San Francisco, CA, USA
| | | | - Andre Arizpe
- Clinical Research, Vir Biotechnology Inc, San Francisco, CA, USA
| | - Norah Terrault
- Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| |
Collapse
|
11
|
Wang ZL, Zheng JR, Yang RF, Huang LX, Chen HS, Feng B. An Ideal Hallmark Closest to Complete Cure of Chronic Hepatitis B Patients: High-sensitivity Quantitative HBsAg Loss. J Clin Transl Hepatol 2023; 11:197-206. [PMID: 36406318 PMCID: PMC9647097 DOI: 10.14218/jcth.2022.00289] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/12/2022] [Accepted: 08/02/2022] [Indexed: 12/04/2022] Open
Abstract
In the era of antiviral therapy, the main goal of treatment has shifted from the persistent inhibition of hepatitis B virus (HBV) replication to the pursuit of serological clearance of HBs surface antigen (HBsAg). Based on the life cycle of HBV, HBsAg originates from covalently closed circular DNA (cccDNA) and integrated HBV DNA, thus reflecting their transcriptional activity. Complete HBsAg loss may mean elimination or persistent inactivity of the HBV genome including cccDNA and integrated HBV DNA. HBsAg loss improves the recovery of abnormal immune function, which in turn, may further promote the clearance of residual viruses. Combined with functional cure and the great improvement of clinical outcomes, the continuous seroclearance of high-sensitivity quantitative HBsAg may represent the complete cure of chronic hepatitis B (CHB). For many other risk factors besides HBV itself, patients with HBsAg loss still need regular monitoring. In this review, we summarized the evolution of CHB treatment, the origin of serum HBsAg, the pattern of HBsAg seroclearance, and the effect of HBsAg loss on immune function and disease outcomes. In addition, we discuss the significance of high-sensitivity HBsAg detection and its possibility as a surrogate of complete cure.
Collapse
Affiliation(s)
| | | | - Rui-Feng Yang
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Lin-Xiang Huang
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Hong-Song Chen
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Bo Feng
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| |
Collapse
|
12
|
Yeh SH, Li CL, Lin YY, Ho MC, Wang YC, Tseng ST, Chen PJ. Hepatitis B Virus DNA Integration Drives Carcinogenesis and Provides a New Biomarker for HBV-related HCC. Cell Mol Gastroenterol Hepatol 2023; 15:921-929. [PMID: 36690297 PMCID: PMC9972564 DOI: 10.1016/j.jcmgh.2023.01.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 12/24/2022] [Accepted: 01/02/2023] [Indexed: 01/25/2023]
Abstract
Hepatitis B virus (HBV) DNA integration is an incidental event in the virus replication cycle and occurs in less than 1% of infected hepatocytes during viral infection. However, HBV DNA is present in the genome of approximately 90% of HBV-related HCCs and is the most common somatic mutation. Whole genome sequencing of liver tissues from chronic hepatitis B patients showed integration occurring at random positions in human chromosomes; however, in the genomes of HBV-related HCC patients, there are integration hotspots. Both the enrichment of the HBV-integration proportion in HCC and the emergence of integration hotspots suggested a strong positive selection of HBV-integrated hepatocytes to progress to HCC. The activation of HBV integration hotspot genes, such as telomerase (TERT) or histone methyltransferase (MLL4/KMT2B), resembles insertional mutagenesis by oncogenic animal retroviruses. These candidate oncogenic genes might shed new light on HBV-related HCC biology and become targets for new cancer therapies. Finally, the HBV integrations in individual HCC contain unique sequences at the junctions, such as virus-host chimera DNA (vh-DNA) presumably being a signature molecule for individual HCC. HBV integration may thus provide a new cell-free tumor DNA biomarker to monitor residual HCC after curative therapies or to track the development of de novo HCC.
Collapse
Affiliation(s)
- Shiou-Hwei Yeh
- Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan; National Taiwan University Center for Genomic Medicine, National Taiwan University, Taipei, Taiwan
| | - Chiao-Ling Li
- Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - You-Yu Lin
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Genome and Systems Biology Degree Program, National Taiwan University College of Life Science, Taipei, Taiwan
| | - Ming-Chih Ho
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | | | | | - Pei-Jer Chen
- National Taiwan University Center for Genomic Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
| |
Collapse
|
13
|
Saab S, Pham N, Wu W, Dang L, Dang A, Yum J, Shim K, Wu S. Spontaneous Seroclearance Is Associated with Lower Liver Fibrosis in Treatment-Naïve Chronic Hepatitis B Patients. Dig Dis Sci 2022; 67:5309-5314. [PMID: 35244827 DOI: 10.1007/s10620-022-07402-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 01/15/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) is a major public health concern. Transient elastrography (TE) is a reliable method in assessing hepatic fibrosis in patients with liver disease. We assess the potential clinical associations between HBsAg seroclearance and the severity of liver fibrosis. METHODS We retrospectively performed a matched analysis of 23 consecutive HBsAg seroclearance patients who underwent TE between March 2008 and August 2021 from a community practice at a 1:3 ratio based on clinic visit date. Baseline laboratory and clinical data were collected. Fisher's exact test and Chi-square test for proportions, and Wilcoxon rank-sum test for median were performed. RESULTS Twenty-three cases and 69 controls were identified. Median follow up (interquartile range) for the cases and controls was 24,314 (1402) and 2332 (1587) days (p = 0.15), respectively. All patients were Asian. Median age of cases was higher than controls (64 vs 52, p < 0.01, respectively). While most comorbidities were similar, diabetes and hyperlipidemia were more prevalent in cases. Baseline HBV DNA was detectable in 78% of cases and 97% of controls (p < 0.01). More cases had baseline HBsAg titers below 1000 IU/mL than controls (81% vs 8.7%, p < 0.01). Other baseline laboratory values were similar. Few cases had a fibrosis score greater than 1, while control had over a quarter of patients with a fibrosis score of 2 or 3. CONCLUSION Spontaneous HBsAg seroclearance remains rare in patients with chronic HBV infection. It is associated with low baseline HBsAg, and lower level of liver fibrosis as detected by TE.
Collapse
Affiliation(s)
- Sammy Saab
- Departments of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. .,Departments of Surgery, University of California at Los Angeles, Los Angeles, CA, USA.
| | - Nguyen Pham
- Departments of Surgery, University of California at Los Angeles, Los Angeles, CA, USA
| | - William Wu
- Departments of Surgery, University of California at Los Angeles, Los Angeles, CA, USA.,Private Practice, Hacienda Heights, CA, 91745, USA
| | - Long Dang
- Departments of Surgery, University of California at Los Angeles, Los Angeles, CA, USA
| | - An Dang
- Departments of Surgery, University of California at Los Angeles, Los Angeles, CA, USA
| | - Jung Yum
- Departments of Surgery, University of California at Los Angeles, Los Angeles, CA, USA
| | - Kisub Shim
- Departments of Surgery, University of California at Los Angeles, Los Angeles, CA, USA
| | - Steven Wu
- Private Practice, Hacienda Heights, CA, 91745, USA
| |
Collapse
|
14
|
Hepatitis B Virus-Encoded HBsAg Contributes to Hepatocarcinogenesis by Inducing the Oncogenic Long Noncoding RNA LINC00665 through the NF-κB Pathway. Microbiol Spectr 2022; 10:e0273121. [PMID: 35993712 PMCID: PMC9603668 DOI: 10.1128/spectrum.02731-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Clinical and in vivo studies have demonstrated a role for hepatitis B virus (HBV)-encoded HBsAg (hepatitis B surface antigen) in HBV-related hepatocellular carcinoma (HCC); however, the underlying mechanisms remain largely unknown. Here, we investigated the role of HBsAg in regulating long noncoding RNAs (lncRNAs) involved in HCC progression. Our analysis of microarray data sets identified LINC00665 as an HBsAg-regulated lncRNA. Furthermore, LINC00665 is upregulated in liver samples from HBV-infected patients as well as in HCC, specifically in HBV-related HCC liver samples. These findings were supported by our in vitro data demonstrating that HBsAg, as well as HBV, positively regulates LINC00665 in multiple HBV cell culture models. Next, we evaluated the oncogenic potential of LINC00665 by its overexpression and CRISPR interference (CRISPRi)-based knockdown in various cell-based assays. LINC00665 promoted cell proliferation, migration, and colony formation but inhibited cell apoptosis in vitro. We then identified the underlying mechanism of HBsAg-mediated regulation of LINC00665. We used immunofluorescence assays to show that HBsAg enhanced the nuclear translocation of NF-κB factors in HepG2 cells, confirming that HBsAg activates NF-κB. Inhibition of NF-κB signaling nullified HBsAg-mediated LINC00665 upregulation, suggesting that HBsAg acts through NF-κB to regulate LINC00665. Furthermore, the LINC00665 promoter contains NF-κB binding sites, and their disruption abrogated HBsAg-induced LINC00665 upregulation. Finally, HBsAg facilitated the enrichment of the NF-κB factors NF-κB1, RelA, and c-Rel in the LINC00665 promoter. Taken together, this work shows that HBsAg can drive hepatocarcinogenesis by upregulating oncogenic LINC000665 through the NF-κB pathway, thereby identifying a novel mechanism in HBV-related HCC. IMPORTANCE Hepatitis B virus (HBV) is a major risk factor for hepatocellular carcinoma (HCC). Numerous reports indicate an oncogenic role for HBV-encoded HBsAg; however, the underlying mechanisms are not well understood. Here, we studied the role of HBsAg in regulating lncRNAs involved in hepatocarcinogenesis. We demonstrate that HBsAg, as well as HBV, positively regulates oncogenic lncRNA LINC00665. The clinical significance of this lncRNA is highlighted by our observation that LINC00665 is upregulated in liver samples during HBV infection and HBV-related HCC. Furthermore, we show LINC00665 can drive hepatocarcinogenesis by promoting cell proliferation, colony formation, and cell migration and inhibiting apoptosis. Taken together, this work identified LINC00665 as a novel gene through which HBsAg can drive hepatocarcinogenesis. Finally, we show that HBsAg enhances LINC00665 levels in hepatocytes by activating the NF-κB pathway, thereby identifying a novel mechanism by which HBV may contribute to HCC.
Collapse
|
15
|
Yang H, Bae SH, Nam H, Lee HL, Lee SW, Yoo SH, Song MJ, Kwon JH, Nam SW, Choi JY, Yoon SK, Jang JW. A risk prediction model for hepatocellular carcinoma after hepatitis B surface antigen seroclearance. J Hepatol 2022; 77:632-641. [PMID: 35398462 DOI: 10.1016/j.jhep.2022.03.032] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 03/13/2022] [Accepted: 03/18/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND & AIMS After hepatitis B surface antigen (HBsAg) seroclearance, the risk of hepatocellular carcinoma (HCC) remains, and the optimal surveillance strategy has yet to be determined. Herein, we aimed to evaluate incidence and risk factors for HCC and establish a novel prediction model for HCC development after HBsAg seroclearance. METHODS A total of 1,443 patients with chronic hepatitis B who achieved HBsAg seroclearance between 1991 and 2020 were retrospectively screened for study eligibility. The data from 831 of these patients were included in the final analysis. A prediction model was developed based on multivariable Cox models. Harrell's C-index and a time-dependent AUROC were used for discrimination. Bootstrap analysis was performed for internal validation. RESULTS Overall, 40 patients (4.8%) developed HCC after HBsAg seroclearance during a follow-up of 4,644 person-years (0.86%/year). Age at HBsAg seroclearance, presence of cirrhosis, family history of HCC, and more-than-moderate alcohol consumption were independently predictive of HCC, and these 4 independent variables were used to develop the prediction model. The C-index of the model was 0.804. The time-dependent AUROCs of the score for HCC prediction at 5, 10, and 15 years were 0.799, 0.835, and 0.817, respectively. The score also showed good discrimination in the internal validation and sensitivity analysis. CONCLUSIONS The novel prediction model based on age, cirrhosis, family history of HCC, and alcohol consumption enables reliable risk estimation of HCC after HBsAg seroclearance and may serve as a useful reference for decision-making in HCC surveillance for HBsAg-cleared patients. LAY SUMMARY After spontaneous hepatitis B surface antigen (HBsAg) seroclearance, the risk of hepatocellular carcinoma (HCC) remains. Age at HBsAg seroclearance, presence of cirrhosis, family history of HCC, and more-than-moderate alcohol consumption were independently associated with HCC development after HBsAg seroclearance. The novel prediction model using these 4 variables enables reliable risk estimation of HCC and serves as a useful reference for decision-making in HCC surveillance and management for HBsAg-cleared patients.
Collapse
Affiliation(s)
- Hyun Yang
- Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea; The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Si Hyun Bae
- Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea; The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Heechul Nam
- Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea; The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Hae Lim Lee
- Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea; The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Sung Won Lee
- Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea; The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Sun Hong Yoo
- Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea; The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Myeong Jun Song
- Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea; The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Jung Hyun Kwon
- Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea; The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Soon Woo Nam
- Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea; The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Jong Young Choi
- Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea; The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Seung Kew Yoon
- Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea; The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Jeong Won Jang
- Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea; The Catholic University Liver Research Center, Seoul, Republic of Korea.
| |
Collapse
|
16
|
Broquetas T, Carrión JA. Author's reply: Nucleo(s)tide analogue withdrawal in chronic hepatitis B virus infection. Beyond the HBsAg loss. Dig Liver Dis 2022; 54:1283-1284. [PMID: 35581131 DOI: 10.1016/j.dld.2022.04.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 04/21/2022] [Accepted: 04/26/2022] [Indexed: 01/27/2023]
Affiliation(s)
- Teresa Broquetas
- Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona, Spain
| | - Jose A Carrión
- Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona, Spain.
| |
Collapse
|
17
|
Gnyawali B, Pusateri A, Nickerson A, Jalil S, Mumtaz K. Epidemiologic and socioeconomic factors impacting hepatitis B virus and related hepatocellular carcinoma. World J Gastroenterol 2022; 28:3793-3802. [PMID: 36157533 PMCID: PMC9367226 DOI: 10.3748/wjg.v28.i29.3793] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 04/10/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
Chronic Hepatitis B is a highly prevalent disease worldwide and is estimated to cause more than 800000 annual deaths from complications such as cirrhosis and hepatocellular carcinoma (HCC). Although universal hepatitis B vaccination programs may have reduced the incidence and prevalence of chronic hepatitis B and related HCC, the disease still imposes a significant healthcare burden in many endemic regions such as Africa and the Asia-Pacific region. This is especially concerning given the global underdiagnosis of hepatitis B and the limited availability of vaccination, screening, and treatment in low-resource regions. Demographics including male gender, older age, ethnicity, and geographic location as well as low socioeconomic status are more heavily impacted by chronic hepatitis B and related HCC. Methods to mitigate this impact include increasing screening in high-risk groups according to national guidelines, increasing awareness and health literacy in vulnerable populations, and developing more robust vaccination programs in under-served regions.
Collapse
Affiliation(s)
- Bipul Gnyawali
- Department of Medicine, Kettering Medical Center, Dayton, OH 45342, United States
| | - Antoinette Pusateri
- Department of Medicine, The Ohio State University, Columbus, OH 43210, United States
| | - Ashley Nickerson
- Department of Medicine, The Ohio State University, Columbus, OH 43210, United States
| | - Sajid Jalil
- Department of Medicine, The Ohio State University, Columbus, OH 43210, United States
| | - Khalid Mumtaz
- Department of Medicine, The Ohio State University, Columbus, OH 43210, United States
| |
Collapse
|
18
|
Broquetas T, Carrión JA. Current Perspectives on Nucleos(t)ide Analogue Therapy for the Long-Term Treatment of Hepatitis B Virus. Hepat Med 2022; 14:87-100. [PMID: 35936810 PMCID: PMC9346298 DOI: 10.2147/hmer.s291976] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/12/2022] [Indexed: 01/27/2023] Open
Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| |
Collapse
|
19
|
Yuan BH, Li RH, Huo RR, Li MJ, Papatheodoridis G, Zhong JH. Lower risk of hepatocellular carcinoma with tenofovir than entecavir treatment in subsets of chronic hepatitis B patients: an updated meta-analysis. J Gastroenterol Hepatol 2022; 37:782-794. [PMID: 35080052 DOI: 10.1111/jgh.15783] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/26/2021] [Accepted: 01/05/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND AIM Previous smaller meta-analyses comparing the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with tenofovir disoproxil fumarate (TDF) versus entecavir (ETV) provided controversial results. This updated meta-analysis aimed to reliably identify any difference in the HCC incidence between TDF-treated or ETV-treated CHB patients in general or in specific subgroups. METHODS PubMed, EMBASE, Web of Science, and Cochrane Library were systematically searched for relevant studies with hazard ratios (HRs) for HCC between TDF-treated and ETV-treated CHB patients. Retrieved dates ranged from January 2009 to October 2021. HRs with or without adjustment were pooled with random-effects model. RESULTS Twenty-four comparative studies involving 37 771 CHB patients treated with TDF and 72 094 treated with ETV were included. TDF was associated with lower risk of HCC compared with ETV, with pooled unadjusted HR of 0.76 (95% confidence interval [CI]: 0.67-0.86) (24 studies) and adjusted HR of 0.81 (95% CI: 0.72-0.91) (21 studies). In propensity score matching cohorts, the TDF superiority was confirmed for unadjusted HR 0.83 (95% CI: 0.71-0.97) (14 studies) and was close to significance for adjusted HR (0.78, 95% CI: 0.58-1.04) (8 studies). Subgroup analyses showed that TDF was associated with lower HCC risk than ETV treatment in CHB patients who were from Asia (adjusted HR: 0.76, 95% CI: 0.66-0.87; 15 studies) or nucleos(t)ide naïve (adjusted HR:0.74, 95% CI: 0.65-0.84; 18 studies). CONCLUSION Current evidence from a sizable population suggests that TDF is associated with significantly lower HCC risk compared with ETV treatment in patients who are from Asia and/or nucleos(t)ide naïve.
Collapse
Affiliation(s)
- Bao-Hong Yuan
- Department of General Surgery, Yan'An Hospital Affiliated to Kunming Medical University, The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China
| | - Ru-Hong Li
- Department of General Surgery, Yan'An Hospital Affiliated to Kunming Medical University, The Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China
| | - Rong-Rui Huo
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Min-Jun Li
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - George Papatheodoridis
- Department of Gastroenterology, Medical School, National and Kapodistrian University of Athens, General Hospitalof Athens "Laiko", Athens, Greece
| | - Jian-Hong Zhong
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| |
Collapse
|
20
|
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.
Collapse
|
21
|
Schemmer P, Burra P, Hu R, Hüber CM, Loinaz C, Machida K, Vogel A, Samuel D. State of the art treatment of hepatitis B virus hepatocellular carcinoma and the role of hepatitis B surface antigen post-liver transplantation and resection. Liver Int 2022; 42:288-298. [PMID: 34846790 PMCID: PMC9300017 DOI: 10.1111/liv.15124] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 11/17/2021] [Accepted: 11/28/2021] [Indexed: 01/27/2023]
Abstract
Chronic hepatitis B virus (HBV) infection is the major aetiology of hepatocellular carcinoma (HCC). The optimal goal of therapy, hepatitis B surface antigen (HBsAg) loss and anti-HBs production, is achieved rarely and HBsAg-associated HCC risk is well recognized. Here we review the role of HBsAg in HCC, the link between HBsAg and HCC recurrence post-liver transplantation or resection, and the implications for therapy. HBV-associated carcinogenesis is a multifactorial process. The observation that HBV-related HCC can occur in the absence of cirrhosis is compatible with a direct oncogenic effect of the virus, which may occur via multiple mechanisms, including those mediated by both mutated and unmutated HBsAg. HCC recurrence in HBsAg-positive patients post-liver transplantation has been reported in 10%-15% of patients and is likely to be because of expansion of residual HCC tumour cell populations containing integrated HBV DNA, which expand and independently replicate HBV, leading to the recurrence of both HCC and HBV. The direct role of HBsAg in HCC recurrence post-liver resection is less clear. Cirrhosis is the most important risk factor for HCC development, and precancerous cirrhotic liver remains after resection, with the potential to undergo malignant transformation regardless of the existence of HBV-derived oncogenic drivers. The role of HBsAg in the development of HCC and its recurrence post-surgical intervention has multiple implications for therapy and suggests a potential role for immunotherapy in the future management of HCC, in particular post-liver transplantation. Use of hepatitis B immunoglobulins that target HBsAg directly, alongside immune-oncology therapies, may be relevant in this setting.
Collapse
Affiliation(s)
- Peter Schemmer
- General, Visceral and Transplant SurgeryDepartment of SurgeryMedical University of GrazGrazAustria
| | - Patrizia Burra
- Department of Surgery, Oncology, and GastroenterologyPadua University HospitalPaduaItaly
| | - Rey‐Heng Hu
- Department of SurgeryNational Taiwan University HospitalTaipeiTaiwan
| | | | - Carmelo Loinaz
- Department of General and Digestive SurgeryUniversity Hospital 12 de OctubreMadridSpain
| | - Keigo Machida
- Keck Hospital of University of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and EndocrinologyMedizinische Hochschule HannoverHannoverGermany
| | - Didier Samuel
- Centre HepatobiliaireUniversity Hospital Paul BrousseUniversity Paris‐Saclay and Inserm‐Paris Saclay Research Unit 1193VillejuifFrance
| |
Collapse
|
22
|
Wang L, Wu L, Li X, Zhang Y, Lai J, Zhu X, Xie C, Peng L. Tenofovir alafenamide fumarate therapy in subjects with positive HBV-DNA and normal levels of alanine transaminase: a study protocol for a randomised controlled trial. BMJ Open 2021; 11:e048410. [PMID: 34408049 PMCID: PMC8375735 DOI: 10.1136/bmjopen-2020-048410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
INTRODUCTION The current clinical guidelines do not recommend antiviral therapy for subjects with positive hepatitis B virus (HBV)-DNA and normal alanine transaminase (ALT). In this study, we will assess the safety and efficacy of tenofovir alafenamide fumarate (TAF) in the treatment of adults with positive HBV-DNA and normal ALT, including long-term prognosis. METHODS AND ANALYSIS This study is a non-double-blind randomised controlled trial. Study participants will be randomised into the treatment group and the control group. In the treatment group, subjects will receive TAF monotherapy, while those in the control group will receive no antiviral treatment. Subjects will be followed up at the beginning of the study and every 12 or 24 weeks thereafter for review of laboratory findings and to record adverse events. The primary endpoint is the proportion of patients with serum hepatitis B surface antigen loss. ETHICS AND DISSEMINATION This study protocol was approved by the Ethics Committee of the Third Affiliated Hospital of Sun Yat-Sen University for Human Study (reference number [2019]02-599-01). The results of this study will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER NCT04231565.
Collapse
Affiliation(s)
- Lu Wang
- Department of Infectious Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Lina Wu
- Department of Infectious Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xuejun Li
- Department of Infectious Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Ying Zhang
- Department of Infectious Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jing Lai
- Department of Infectious Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xiang Zhu
- Department of Infectious Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Chan Xie
- Department of Infectious Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Liang Peng
- Department of Infectious Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| |
Collapse
|
23
|
Song A, Lin X, Chen X. Functional cure for chronic hepatitis B: accessibility, durability, and prognosis. Virol J 2021; 18:114. [PMID: 34082765 PMCID: PMC8176700 DOI: 10.1186/s12985-021-01589-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 05/28/2021] [Indexed: 01/27/2023] Open
Abstract
Hepatitis B surface antigen (HBsAg) clearance is regarded as the ideal endpoint for antiviral treatment in terms of drug withdrawal safety and improvements in prognosis. However, the overall rate of HBsAg clearance is low and differs based on treatment method and course. The recent application of combined and extended treatment strategies have improved the HBsAg clearance rate, and several patients achieved HBsAg clearance in clinical treatment. In addition, the durability of and clinical outcomes after HBsAg clearance have become the focus of both researchers and clinicians. This article reviews HBsAg clearance in terms of accessibility, durability, improvements in prognosis and relevant advances.
Collapse
Affiliation(s)
- Aixin Song
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xiao Lin
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xinyue Chen
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing, China.
| |
Collapse
|
24
|
Li J, Xu J, Li Z. Obatoclax, the pan-Bcl-2 inhibitor sensitizes hepatocellular carcinoma cells to promote the anti-tumor efficacy in combination with immune checkpoint blockade. Transl Oncol 2021; 14:101116. [PMID: 33975180 PMCID: PMC8131730 DOI: 10.1016/j.tranon.2021.101116] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/07/2021] [Accepted: 04/26/2021] [Indexed: 01/27/2023] Open
Abstract
Obatoclax, the Bcl-2 inhibitor directly impaired HCC cell growth. Obatoclax suppressed HCC development in vivo. Obatoclax sensitized HCC cells to T cell-mediated killing. Combination therapy of obatoclax and anti-PD-1 antibody synergically reduced HCC growth. Bcl-2 family proteins play critical roles in regulating lymphocyte development and maintain homeostasis, and have also been proved to be involved in various cancer types development. However, the role of Bcl-2 in hepatocellular carcinoma (HCC) development has not been clearly studied. Here, we reported the pan-Bcl-2 inhibitor, obatoclax could directly inhibit HCC growth in vitro. We further demonstrated in murine HCC model that obatoclax also suppressed HCC development in vivo. We also proved that although obatoclax inhibited T cells expansion, it had no influence on T cells activation in vivo. Mechanism study revealed that obatoclax sensitized HCC cells to T cell-mediated killing. Combination therapy of obatoclax with anti-PD-1 antibody synergistically suppressed HCC development and prolonged the survival rate of tumor-bearing mice. The combination therapy promoted T cells activation and effector cytokines expression both in spleen and tumor. In summary, our results proved that obatoclax sensitized HCC cells to T cell -mediated killing. Combination of obatoclax with immune checkpoint blockade served as a promising therapeutic strategy for HCC treatment.
Collapse
Affiliation(s)
- Jingye Li
- Department of Medical oncology, Linyi Central Hospital, Shandong 276400, China
| | - Jinrong Xu
- Department of Cardiology, Linyi Central Hospital, Shandong 276400, China
| | - Zhibing Li
- Department of anesthesiology, Linyi Central Hospital, Shandong 276400, China.
| |
Collapse
|
25
|
Song A, Wang X, Lu J, Jin Y, Ma L, Hu Z, Zheng Y, Shen C, Chen X. Durability of hepatitis B surface antigen seroclearance and subsequent risk for hepatocellular carcinoma: A meta-analysis. J Viral Hepat 2021; 28:601-612. [PMID: 33455067 PMCID: PMC7986681 DOI: 10.1111/jvh.13471] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 12/21/2020] [Indexed: 02/07/2023]
Abstract
Hepatitis B surface antigen (HBsAg) seroclearance is regarded as the ideal endpoint for antiviral treatment. However, reports on the durability of and outcomes after HBsAg seroclearance are few, which has become a focus in clinical practice. This meta-analysis was performed to evaluate the durability and hepatocellular carcinoma (HCC) incidence after HBsAg seroclearance after treatment cessation. We searched PubMed, Embase, Medline and Web of Science for studies that reported the durability and HCC incidence after HBsAg seroclearance published between 1 January 2000 and 31 January 2020. Data were analysed by a random-effects model. Thirty-eight studies and 43,924 patients were finally included. The results showed that HBsAg seroclearance was durable, with a pooled recurrence rate of 6.19% (95% CI: 4.10%-8.68%). There was no significant difference in recurrence rates after different seroclearance methods or among recurrence types and different regions. Anti-HBs seroconversion resulted in a significantly reduced recurrence rate (RR = 0.25, p < .001). Patients who experienced HBsAg seroclearance had significantly lower HCC incidence than HBsAg-positive (RR = 0.41, p < .001). The pooled HCC incidence after HBsAg seroclearance was 1.88%; this rate was reduced to 0.76% among patients without baseline cirrhosis. In conclusion, the analysis during an average follow-up of 4.74 years suggested that in patients who experienced sustained HBsAg seroclearance and anti-HBs seroconversion, this was associated with low HCC incidence. Patients without baseline cirrhosis benefited even more. We emphasize the importance of gaining HBsAg seroclearance while highlighting the benefits of achieving this as early as possible.
Collapse
Affiliation(s)
- Aixin Song
- First Department of Liver Disease CenterBeijing Youan HospitalCapital Medical UniversityBeijingChina
| | - Xiaoxiao Wang
- First Department of Liver Disease CenterBeijing Youan HospitalCapital Medical UniversityBeijingChina
| | - Junfeng Lu
- First Department of Liver Disease CenterBeijing Youan HospitalCapital Medical UniversityBeijingChina
| | - Yi Jin
- First Department of Liver Disease CenterBeijing Youan HospitalCapital Medical UniversityBeijingChina
| | - Lina Ma
- First Department of Liver Disease CenterBeijing Youan HospitalCapital Medical UniversityBeijingChina
| | - Zhongjie Hu
- First Department of Liver Disease CenterBeijing Youan HospitalCapital Medical UniversityBeijingChina
| | - Yanhong Zheng
- First Department of Liver Disease CenterBeijing Youan HospitalCapital Medical UniversityBeijingChina
| | - Chengli Shen
- Division of Surgical OncologyJames Cancer HospitalThe Ohio State University Wexner Medical CenterColumbusOHUSA
| | - Xinyue Chen
- First Department of Liver Disease CenterBeijing Youan HospitalCapital Medical UniversityBeijingChina
| |
Collapse
|
26
|
Characteristics and etiologies of hepatocellular carcinoma in patients without cirrhosis: When East meets West. PLoS One 2021; 16:e0244939. [PMID: 33439893 PMCID: PMC7806135 DOI: 10.1371/journal.pone.0244939] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 12/18/2020] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND/AIMS A recent study from the United States reported that nearly 12% of hepatocellular carcinomas (HCCs) occurred in patients without cirrhosis. Non-alcoholic fatty liver disease (NAFLD) was the most common liver disease in these patients. We aim to evaluate the characteristics, etiologies, and outcomes of cases of non-cirrhotic HCC in East Asia, where there is a higher prevalence of hepatitis B virus (HBV)-associated non-cirrhotic HCC. METHODS This retrospective study consecutively enrolled de novo HCC patients managed at our institution from 2011 to 2017. The presence of cirrhosis was assessed by histology; if histology was not available, it was assessed by image study. RESULTS 2055 patients with HCC were enrolled in this study. Among them, 529 (25.7%) were non-cirrhotic. The non-cirrhotic patients were younger (60.9 vs. 62.5 years, p = 0.006), included a greater proportion of males (78.1% vs. 71.3%, p = 0.002), and had a lower body mass index (24.3 vs. 25.3 kg/m2, p<0.001) than the cirrhotic patients. Among the non-cirrhotic patients, HBV was the most common liver disease (49.0%). The patients with non-cirrhotic HCC had larger tumors (5.9 vs. 4.7 cm, p<0.001), underwent liver resection at a higher rate (66.0% vs. 17.4%, p<0.001), and had better overall survival than the cirrhotic HCC patients (median 5.67 vs. 2.83 years, p<0.001). CONCLUSIONS Nearly 26% of the HCCs occurred in patients without cirrhosis. HBV was the most common liver disease in these patients, and the survival was better in the non-cirrhotic patients than the cirrhotic patients.
Collapse
|
27
|
Huang DQ, Lim SG. Life After s Loss: Impact of Hepatitis B s Antigen Loss on Future Patient Outcomes. Clin Liver Dis (Hoboken) 2021; 16:262-265. [PMID: 33489099 PMCID: PMC7805298 DOI: 10.1002/cld.983] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 04/27/2020] [Accepted: 05/16/2020] [Indexed: 02/04/2023] Open
Affiliation(s)
- Daniel Q. Huang
- Division of Gastroenterology and HepatologyDepartment of MedicineNational University HospitalSingapore,Department of MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Seng Gee Lim
- Division of Gastroenterology and HepatologyDepartment of MedicineNational University HospitalSingapore,Department of MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore
| |
Collapse
|
28
|
Park Y, Lee JH, Sinn DH, Park JY, Kim MA, Kim YJ, Yoon JH, Kim DY, Ahn SH, Kang W, Gwak GY, Paik YH, Choi MS, Lee JH, Koh KC, Paik SW. Risk and Risk Score Performance of Hepatocellular Carcinoma Development in Patients With Hepatitis B Surface Antigen Seroclearance. Clin Transl Gastroenterol 2021; 12:e00290. [PMID: 33433118 PMCID: PMC7803670 DOI: 10.14309/ctg.0000000000000290] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 11/10/2020] [Indexed: 01/27/2023] Open
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) can develop among chronic hepatitis B patients after hepatitis B surface antigen (HBsAg) seroclearance. However, whether HCC risk after HBsAg seroclearance differs between antiviral therapy (AVT)-induced or spontaneous seroclearance cases and ways to identify at-risk populations remain unclear. METHODS A retrospective cohort of 1,200 adult chronic hepatitis B patients who achieved HBsAg seroclearance (median age: 56 years; 824 men; 165 with cirrhosis; 216 AVT-induced cases) were analyzed. The risk of HCC after HBsAg seroclearance and the performance of 6 HCC prediction models were assessed. RESULTS During a median of 4.8 years of follow-up (range: 0.5-17.8 years), HCC developed in 23 patients (1.9%). The HCC incidence rate was higher in the AVT-induced cases than that in the spontaneous cases (3.9% vs 0.9% at 5 years). AVT and cirrhosis were independent factors associated with HCC, with HCC incidence rates of 0.5%, 1.2%, 4.0%, and 10.5% at 5 years for spontaneous/no-cirrhosis, AVT-induced/no-cirrhosis, spontaneous/cirrhosis, and AVT-induced/cirrhosis patients, respectively. Among the 6 predictive HCC models tested, Chinese University-HCC score (0.82) showed the highest C-statistics, which was followed by guide with age, gender, HBV DNA, core promoter mutations and cirrhosis (0.81). DISCUSSION AVT-induced HBsAg seroclearance was associated with higher HCC risk, especially for patients with cirrhosis, indicating that they need careful monitoring for HCC risk. The HCC risk models were able to stratify the HCC risk in patients with HBsAg seroclearance.
Collapse
Affiliation(s)
- Yewan Park
- Department of Medicine, Samsung Medical Center, Seoul, Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Minseok Albert Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Wonseok Kang
- Department of Medicine, Samsung Medical Center, Seoul, Korea
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Seoul, Korea
| | - Yong-Han Paik
- Department of Medicine, Samsung Medical Center, Seoul, Korea
| | - Moon Seok Choi
- Department of Medicine, Samsung Medical Center, Seoul, Korea
| | - Joon Hyeok Lee
- Department of Medicine, Samsung Medical Center, Seoul, Korea
| | - Kwang Cheol Koh
- Department of Medicine, Samsung Medical Center, Seoul, Korea
| | - Seung Woon Paik
- Department of Medicine, Samsung Medical Center, Seoul, Korea
| |
Collapse
|
29
|
Lee HW. [Long Term Efficacy of Antiviral Therapy: Mortality and Incidence of Hepatocellular Carcinoma]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2020; 74:251-257. [PMID: 31765553 DOI: 10.4166/kjg.2019.74.5.251] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 11/14/2019] [Accepted: 11/15/2019] [Indexed: 01/27/2023]
Abstract
Multiple studies have shown that oral antiviral therapies reduced the incidence of hepatocellular carcinoma (HCC) and improved the survival of patients with chronic hepatitis B when compared with that of untreated patients. In particular, entecavir and tenofovir share the qualities of high efficacy in reducing the HBV DNA levels, and they have excellent tolerability and safety. These drugs modified the natural history of liver fibrosis, improve liver function, decrease the incidence of HCC, decrease the need for liver transplantation, and improve survival. Many studies have suggested that long-term antiviral therapy reduces the risk of HCC and liver cirrhosis in patients with chronic hepatitis. The mechanism of these drugs in reducing the risk of HCC is not clear. This article reviews the mechanisms of carcinogenic HBV by conducting a review of the literature on the efficacy of therapy for reducing the risk of HCC. A few recent articles have suggested that tenofovir offers advantages over entecavir in terms of HCC prevention, but these articles have the inherent limitations of observational data. No other head-to-head randomized trials exist. Further randomized studies would help provide stronger evidence of the association between the type of antiviral agent and the HCC outcomes. Only achieving complete viral eradication from the liver will truly decrease the mortality and incidence of HCC.
Collapse
Affiliation(s)
- Hyun Woong Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| |
Collapse
|
30
|
Lu SD, Li L, Liang XM, Chen W, Chen FL, Fan LL, Ahir BK, Zhang WG, Zhong JH. Updates and advancements in the management of hepatocellular carcinoma patients after hepatectomy. Expert Rev Gastroenterol Hepatol 2019; 13:1077-1088. [PMID: 31648568 DOI: 10.1080/17474124.2019.1684898] [Citation(s) in RCA: 7] [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: 07/12/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023]
Abstract
Introduction: The 5-year recurrence rate of hepatocellular carcinoma (HCC) after hepatic resection or local ablation is up to 70%. Adjuvant therapies to prevent HCC recurrence have been reported but are not currently recommended by EASL or AASLD guidelines. This review examined evidence from randomized controlled trials, meta-analyses and systematic reviews on the safety and efficacy of adjuvant therapies and chemotherapies in HCC patients after resection or local ablation.Areas covered: PubMed was searched through 15 June 2019. Available evidence was assessed based on the GRADE system.Expert commentary: Transarterial chemoembolization is the best adjuvant therapy for HCC patients at high risk of recurrence, antiviral therapy with nucleoside analogs is effective for preventing recurrence of HBV-related HCC, and interferon-α is effective for preventing recurrence of HCV-related HCC. Further studies are needed to clarify the efficacy of adjuvant immune checkpoint inhibitors. Adjuvant sorafenib appears to offer negligible clinical benefit and high risk of adverse effects.
Collapse
Affiliation(s)
- Shi-Dong Lu
- Department of Hepatobiliary Surgery, the Third Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lin Li
- Department of Hepatobiliary Surgery, the Third Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xin-Min Liang
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Wu Chen
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Fu-Li Chen
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Lang-Lin Fan
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Bhavesh K Ahir
- Section of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Wan-Guang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian-Hong Zhong
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| |
Collapse
|
31
|
Zhu SL, Li YQ, Hu H, Ma L. Letter: hepatocellular carcinoma surveillance determines survival in patients at risk. Aliment Pharmacol Ther 2019; 50:839-840. [PMID: 31532553 DOI: 10.1111/apt.15461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Affiliation(s)
- Shao-Liang Zhu
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital
| | - Yuan-Qi Li
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital
| | - Hui Hu
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital
| | - Liang Ma
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital
| |
Collapse
|
32
|
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: 165] [Impact Index Per Article: 27.5] [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
|
33
|
Abstract
PURPOSE OF REVIEW In prior decades, liver cancer was viewed as a neoplasm that almost exclusively arose among high-risk populations in low- and middle-income countries. Incidence rates in some high-risk populations, however, have been declining, while rates in low-risk populations have been increasing, reflecting changes in underlying etiology. In this review, we highlight the evolving epidemiology of liver cancer, focusing on recent research and advances. RECENT FINDINGS Efforts to reduce or eliminate the risk associated with major risk factors such as hepatitis B virus (HBV), hepatitis C virus (HCV) and aflatoxin B1 (AFB1) have met with some success. As opposed to these favorable trends, the joint epidemics of obesity and diabetes have begun to affect liver cancer rates around the world. SUMMARY While there has been progress in combating the effects of some risk factors, the increasing prevalence of others poses a major threat to attempts to tackle the rising incidence of liver cancer globally.
Collapse
Affiliation(s)
- Jessica L. Petrick
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Katherine A. McGlynn
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| |
Collapse
|