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Lee HA, Lee HW, Seo YS, Sinn DH, Ahn SH, Kim BK, Kim SU. Risk of Hepatocellular Carcinoma Decreases After Antiviral Therapy-Induced HBsAg Seroclearance. J Gastroenterol Hepatol 2025. [PMID: 40273951 DOI: 10.1111/jgh.16973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 03/30/2025] [Accepted: 04/03/2025] [Indexed: 04/26/2025]
Abstract
BACKGROUND Antiviral therapy (AVT) reduces the risk of hepatitis B virus-related hepatocellular carcinoma (HCC). AIMS The difference in risk of HCC after hepatitis B surface antigen (HBsAg) seroclearance to the AVT status was explored. METHODS Patients with chronic hepatitis B who achieved HBsAg seroclearance were retrospectively evaluated. The primary outcome was the development of HCC after HBsAg seroclearance. RESULTS Of the study population, 1280 (84.2%) and 241 (15.8%) patients achieved HBsAg seroclearance without (spontaneous clearance group) and with AVT (AVT-induced clearance group), respectively. HCC cumulative incidence was comparable between the two groups (hazard ratio [HR] = 0.461; log-rank test, p = 0.197), whereas it was significantly lower in the AVT-induced HBsAg clearance group than in the spontaneous HBsAg clearance group in inverse probability of treatment weighting analysis (HR = 0.442; log-rank test, p = 0.004). In multivariate analysis, spontaneous HBsAg clearance, albumin-bilirubin (ALBI) grade ≥ 2, cirrhosis, and platelet count < 50 × 109/L were independently associated with the increased risk of HCC. The newly established antiviral therapy, cirrhosis, ALBI, and platelet count (ACAP) scores had a C-index of 0.765, and the time-dependent areas under the curve of HCC prediction at 5 and 8 years were 0774 and 0.823, respectively. CONCLUSION The risk of HCC differed according to the AVT status after HBsAg seroclearance.
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Affiliation(s)
- Han Ah Lee
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Hyun Woong Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Yeon Seok Seo
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Dong Hyun Sinn
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
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Shrilall C, Arbuthnot P, Ely A. In Vitro Transcribed Artificial Primary MicroRNA for the Inhibition of Hepatitis B Virus Gene Expression in Cultured Cells. Microorganisms 2025; 13:604. [PMID: 40142497 PMCID: PMC11946339 DOI: 10.3390/microorganisms13030604] [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: 12/17/2024] [Revised: 02/07/2025] [Accepted: 02/26/2025] [Indexed: 03/28/2025] Open
Abstract
Available interventions for the management of chronic hepatitis B (hepB) exhibit limited efficacy and barriers to vaccination against the hepatitis B virus (HBV) have hampered prophylaxis programmes. Development of potent therapeutics capable of functional cure of chronic hepB thus remains a relevant medical objective. RNA interference (RNAi) can be exploited to effect potent and specific silencing of target genes through the introduction of RNA sequences that mimic the natural activators of the pathway. To achieve a therapeutic effect, artificial primary microRNAs (pri-miRNAs) have been used extensively to target various viruses, including HBV. To date artificial pri-miRNAs have exclusively been produced from DNA expression cassettes. Although this achieves impressive silencing, eventual translation of this platform to the clinic is complicated by the requirement for viral vectors to deliver DNA. Consequently, clinical translation has been slow. Recently, the use of in vitro transcribed RNA, specifically to produce mRNA vaccines at industrial scale, has gained significant interest. We therefore sought to evaluate the feasibility of using in vitro transcribed artificial pri-miRNAs for the inhibition of HBV gene expression. Artificial HBV-targeting pri-miR-31 sequences, which are highly effective when expressed in cells from a DNA template, demonstrated modest silencing of viral replication when incorporated into mRNA that was transcribed in vitro. Off-target effects were also observed. Characterisation revealed that intracellular processing of the artificial pri-miRNAs was inefficient and non-specific effects were caused by stimulation of the interferon response. Nevertheless, optimised nuclear delivery of the artificial pri-miRNAs should improve their processing and achieve better anti-hepB efficacy.
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Affiliation(s)
| | | | - Abdullah Ely
- Wits/SAMRC Antiviral Gene Therapy Research Unit, Infectious Diseases and Oncology Research Institute (IDORI), Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa; (C.S.); (P.A.)
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Xiao G, Ren H. A machine learning model to predict liver-related outcomes after the functional cure of chronic hepatitis B: Is cirrhosis driving the performance? J Hepatol 2025; 82:e141-e142. [PMID: 39306283 DOI: 10.1016/j.jhep.2024.09.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 09/13/2024] [Indexed: 12/13/2024]
Affiliation(s)
- Guanglin Xiao
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Hong Ren
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
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Hur MH, Yip TCF, Kim SU, Lee HW, Lee HA, Lee HC, Wong GLH, Wong VWS, Park JY, Ahn SH, Kim BK, Kim HY, Seo YS, Shin H, Park J, Ko Y, Park Y, Lee YB, Yu SJ, Lee SH, Kim YJ, Yoon JH, Lee JH. A machine learning model to predict liver-related outcomes after the functional cure of chronic hepatitis B. J Hepatol 2025; 82:235-244. [PMID: 39218223 DOI: 10.1016/j.jhep.2024.08.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 07/29/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND & AIMS The risk of hepatocellular carcinoma (HCC) and hepatic decompensation persists after hepatitis B surface antigen (HBsAg) seroclearance. This study aimed to develop and validate a machine learning model to predict the risk of liver-related outcomes (LROs) following HBsAg seroclearance. METHODS A total of 4,787 consecutive patients who achieved HBsAg seroclearance between 2000 and 2022 were enrolled from six centers in South Korea and a territory-wide database in Hong Kong, comprising the training (n = 944), internal validation (n = 1,102), and external validation (n = 2,741) cohorts. Three machine learning-based models were developed and compared in each cohort. The primary outcome was the development of any LRO, including HCC, decompensation, and liver-related death. RESULTS During a median follow-up of 55.2 (IQR 30.1-92.3) months, 123 LROs were confirmed (1.1%/person-year) in the Korean cohort. The model with the best predictive performance in the training cohort was selected as the final model (designated as PLAN-B-CURE), which was constructed using a gradient boosting algorithm and seven variables (age, sex, diabetes, alcohol consumption, cirrhosis, albumin, and platelet count). Compared to previous HCC prediction models, PLAN-B-CURE showed significantly superior accuracy in the training cohort (c-index: 0.82 vs. 0.63-0.70, all p <0.001; area under the receiver-operating characteristic curve: 0.86 vs. 0.62-0.72, all p <0.01; area under the precision-recall curve: 0.53 vs. 0.13-0.29, all p <0.01). PLAN-B-CURE showed a reliable calibration function (Hosmer-Lemeshow test p >0.05) and these results were reproduced in the internal and external validation cohorts. CONCLUSION This novel machine learning model consisting of seven variables provides reliable risk prediction of LROs after HBsAg seroclearance that can be used for personalized surveillance. IMPACT AND IMPLICATIONS Using large-scale multinational data, we developed a machine learning model to predict the risk of liver-related outcomes (i.e., hepatocellular carcinoma, decompensation, and liver-related death) after the functional cure of chronic hepatitis B (CHB). The new model named PLAN-B-CURE was constructed using seven variables (age, sex, alcohol consumption, diabetes, cirrhosis, serum albumin, and platelet count) and a gradient boosting machine algorithm, and it demonstrated significantly better predictive accuracy than previous models in both the training and validation cohorts. The inclusion of diabetes and significant alcohol intake as model inputs suggests the importance of metabolic risk factor management after the functional cure of CHB. Using seven readily available clinical factors, PLAN-B-CURE, the first machine learning-based model for risk prediction after the functional cure of CHB, may serve as a basis for individualized risk stratification.
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Affiliation(s)
- Moon Haeng Hur
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Terry Cheuk-Fung Yip
- Medical Data Analytics Centre, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Hyun Woong Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Han Ah Lee
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
| | - Hyung-Chul Lee
- Department of Anesthesiology, Seoul National University College of Medicine, Seoul, Korea
| | - Grace Lai-Hung Wong
- Medical Data Analytics Centre, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Vincent Wai-Sun Wong
- Medical Data Analytics Centre, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yong Park
- 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
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Hwi Young Kim
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
| | - Yeon Seok Seo
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hyunjae Shin
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jeayeon Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yunmi Ko
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Youngsu Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yun Bin Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Sang Hyub Lee
- 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
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea; Inocras Inc., San Diego, CA, USA.
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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.
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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.
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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.
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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;
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Wooddell CI, Sanders D, Xu Z, Mak LY, Schluep T, Seto WK, Given BD, Yuen MF. Characterization of Hepatitis B Virus Transcripts in Chronically HBV-Infected Chimpanzees and Patients Treated with ARC-520 siRNA Demonstrates Transcriptional Silencing of cccDNA. Viruses 2024; 16:1943. [PMID: 39772249 PMCID: PMC11680220 DOI: 10.3390/v16121943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/07/2024] [Accepted: 12/15/2024] [Indexed: 01/11/2025] Open
Abstract
Full-length hepatitis B virus (HBV) transcripts of chimpanzees and patients treated with multidose (MD) HBV siRNA ARC-520 and entecavir (ETV) were characterized by single-molecule real-time (SMRT) sequencing, identifying multiple types of transcripts with the potential to encode HBx, HBsAg, HBeAg, core, and polymerase, as well as transcripts likely to be derived from dimers of dslDNA, and these differed between HBeAg-positive (HBeAg+) and HBeAg-negative (HBeAg-) individuals. HBV transcripts from the last follow-up ~30 months post-ARC-520 treatment were categorized from one HBeAg+ (one of two previously highly viremic patients that became HBeAg- upon treatment and had greatly reduced cccDNA products) and four HBeAg- patients. The previously HBeAg+ patient received a biopsy that revealed that he had 3.4 copies/cell cccDNA (two to three orders of magnitude more cccDNA than HBeAg- chimpanzees) but expressed primarily truncated X and HBsAg from iDNA, like two patients that were HBeAg- at the start of the study and had one copy/cell cccDNA. No HBV transcripts were detected in two other HBeAg- patients that had ~0.3 copies/cell cccDNA, one of which had seroconverted for HBsAg. The paucity of cccDNA-derived transcripts in the presence of high cccDNA demonstrates the transcriptional silencing of HBV following MD siRNA treatment with ETV.
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Affiliation(s)
| | - Dean Sanders
- Arrowhead Pharmaceuticals Inc., 502 S. Rosa Road, Madison, WI 53719, USA;
| | - Zhao Xu
- Arrowhead Pharmaceuticals Inc., 10102 Hoyt Park Drive, San Diego, CA 92131, USA;
| | - Lung-Yi Mak
- Department of Medicine & State Key Laboratory of Liver Research, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China; (L.-Y.M.); (W.-K.S.); (M.-F.Y.)
| | - Thomas Schluep
- Arrowhead Pharmaceuticals Inc., 177 E. Colorado Boulevard, Suite 700, Pasadena, CA 91105, USA; (T.S.); (B.D.G.)
| | - Wai-Kay Seto
- Department of Medicine & State Key Laboratory of Liver Research, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China; (L.-Y.M.); (W.-K.S.); (M.-F.Y.)
| | - Bruce D. Given
- Arrowhead Pharmaceuticals Inc., 177 E. Colorado Boulevard, Suite 700, Pasadena, CA 91105, USA; (T.S.); (B.D.G.)
| | - Man-Fung Yuen
- Department of Medicine & State Key Laboratory of Liver Research, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China; (L.-Y.M.); (W.-K.S.); (M.-F.Y.)
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Hume SJ, Wong DK, Yuen MF, Jackson K, Bonanzinga S, Vogrin S, Hall SAL, Burns GS, Desmond PV, Sundararajan V, Ratnam D, Levy MT, Lubel JS, Nicoll AJ, Strasser SI, Sievert W, Ngu MC, Sinclair M, Meredith C, Matthews G, Revill PA, Littlejohn M, Bowden S, Visvanathan K, Holmes JA, Thompson AJ. High end-of-treatment hepatitis B core-related antigen levels predict hepatitis flare after stopping nucleot(s)ide analogue therapy. Liver Int 2024; 44:2605-2614. [PMID: 39007640 DOI: 10.1111/liv.16029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 05/17/2024] [Accepted: 06/26/2024] [Indexed: 07/16/2024]
Abstract
BACKGROUND AND AIMS Accurate biomarkers to predict outcomes following discontinuation of nucleos(t)ide analogue (NA) therapy are needed. We evaluated serum hepatitis B core-related antigen (HBcrAg) level as a biomarker for predicting outcomes after NA discontinuation. METHODS Patients with HBeAg-negative chronic hepatitis B (CHB) without cirrhosis were enrolled in a prospective trial evaluating clinical outcomes until 96 weeks after NA discontinuation. End of treatment (EOT) and off-treatment levels of serum HBcrAg, HBsAg, HBV RNA and HBV DNA were used to predict key clinical outcomes including hepatitis flare (ALT ≥5 × ULN and HBV DNA > 2000 IU/mL). The SCALE-B score was calculated for the purposes of model validation. RESULTS HBcrAg was tested amongst 65 participants. The median age was 54 years, 54% were male and 83% were Asian. HBcrAg was detectable in 86% patients. HBcrAg level ≥4 log U/mL at EOT was predictive of hepatitis flare [8/10 (80%) vs. 17/55 (31%), p = .001]. The presence of either HBcrAg ≥4 log U/mL or detectable HBV RNA at EOT predicted for both biochemical relapse and hepatitis flare. The SCALE-B model at EOT predicted for virological relapse, biochemical relapse, hepatitis flare and HBsAg loss in this cohort. An increase in the serum HBcrAg level off-treatment was also associated with hepatitis flare. No participant with EOT HBcrAg level ≥4 log U/mL achieved HBsAg loss. CONCLUSIONS High levels of serum HBcrAg predict for hepatitis flare after stopping NA therapy and low likelihood of HBsAg loss at week 96. People with high levels of serum HBcrAg are not suitable candidates for NA discontinuation.
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Affiliation(s)
- Simon J Hume
- St Vincent's Hospital Melbourne, Fitrozy, Victoria, Australia
- Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
- Victorian Infectious Diseases Reference Laboratory, Department of Infectious Diseases, Royal Melbourne Hospital, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Danny K Wong
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Kathy Jackson
- Victorian Infectious Diseases Reference Laboratory, Department of Infectious Diseases, Royal Melbourne Hospital, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Sara Bonanzinga
- Victorian Infectious Diseases Reference Laboratory, Department of Infectious Diseases, Royal Melbourne Hospital, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Sara Vogrin
- Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
| | - Samuel A L Hall
- St Vincent's Hospital Melbourne, Fitrozy, Victoria, Australia
- Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
| | | | - Paul V Desmond
- St Vincent's Hospital Melbourne, Fitrozy, Victoria, Australia
| | - Vijaya Sundararajan
- St Vincent's Hospital Melbourne, Fitrozy, Victoria, Australia
- Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
| | | | - Miriam T Levy
- Liverpool Hospital, Sydney, New South Wales, Australia
| | | | | | | | | | - Meng C Ngu
- Concord Hospital, Sydney, New South Wales, Australia
| | | | | | - Gail Matthews
- St Vincent's Hospital Sydney, Sydney, New South Wales, Australia
| | - Peter A Revill
- Victorian Infectious Diseases Reference Laboratory, Department of Infectious Diseases, Royal Melbourne Hospital, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Margaret Littlejohn
- Victorian Infectious Diseases Reference Laboratory, Department of Infectious Diseases, Royal Melbourne Hospital, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Scott Bowden
- Victorian Infectious Diseases Reference Laboratory, Department of Infectious Diseases, Royal Melbourne Hospital, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Kumar Visvanathan
- St Vincent's Hospital Melbourne, Fitrozy, Victoria, Australia
- Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
| | - Jacinta A Holmes
- St Vincent's Hospital Melbourne, Fitrozy, Victoria, Australia
- Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
| | - Alexander J Thompson
- St Vincent's Hospital Melbourne, Fitrozy, Victoria, Australia
- Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
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Cao QH, Liu H, Yan LJ, Wang HC, Ding ZN, Mao XC, Li RZ, Pan GQ, Zhang X, Tian BW, Han CL, Dong ZR, Tan SY, Wang DX, Yan YC, Li T. Role of hepatitis B core-related antigen in predicting the occurrence and recurrence of hepatocellular carcinoma in patients with chronic hepatitis B: A systemic review and meta-analysis. J Gastroenterol Hepatol 2024; 39:1464-1475. [PMID: 38686439 DOI: 10.1111/jgh.16558] [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: 10/26/2023] [Revised: 03/08/2024] [Accepted: 03/25/2024] [Indexed: 05/02/2024]
Abstract
BACKGROUND AND AIM The purpose of the current study was to investigate the predictive value of hepatitis B core-related antigen (HBcrAg) on the occurrence and recurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). METHODS We searched PubMed, Embase, Scopus, and Web of Science from database inception to April 6, 2023. Pooled hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) was calculated for the occurrence and recurrence of HCC. RESULTS Of the 464 articles considered, 18 articles recruiting 10 320 patients were included. The pooled results showed that high serum HBcrAg level was an independent risk factor for the occurrence of HCC in CHB patients (adjusted HR = 3.12, 95% CI: 2.40-4.06, P < 0.001, I2 = 43.2%, P = 0.043; OR = 5.65, 95% CI: 3.44-5.82, P < 0.001, I2 = 0.00%, P = 0.42). Further subgroup analysis demonstrated that the predictive ability of HBcrAg for the occurrence of HCC is not influenced by the hepatitis B e antigen (HBeAg) status or the use of nucleoside/nucleotide analogs (NAs). In addition, our meta-analysis also suggests that HBcrAg is a predictor of HCC recurrence (adjusted HR = 1.71, 95% CI: 1.26-2.32, P < 0.001, I2 = 7.89%, P = 0.031). CONCLUSIONS For patients with CHB, serum HBcrAg may be a potential predictive factor for the occurrence of HCC, regardless of HBeAg status or NA treatment. It may also serve as a novel prognostic biomarker for the recurrence of HCC. More studies are needed to confirm our conclusions.
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Affiliation(s)
- Qi-Hang Cao
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Hui Liu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Lun-Jie Yan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Han-Chao Wang
- Institute for Financial Studies, Shandong University, Jinan, China
| | - Zi-Niu Ding
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Xin-Cheng Mao
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Rui-Zhe Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Guo-Qiang Pan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Xiao Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Bao-Wen Tian
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Cheng-Long Han
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Si-Yu Tan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Dong-Xu Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yu-Chuan Yan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
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10
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Li YM, Shaw CS, Chen TC, Lin DSC. Beyond Occam's Razor: Concurrent Non-functional Pituitary Macroadenoma and Metastatic Hepatocellular Carcinoma in a Patient With Functional Cure of Hepatitis B. Cureus 2024; 16:e62339. [PMID: 39006628 PMCID: PMC11246244 DOI: 10.7759/cureus.62339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/13/2024] [Indexed: 07/16/2024] Open
Abstract
Occam's razor, the principle of parsimony, is frequently employed in medicine to derive a single diagnosis from a patient's myriad symptoms. Conversely, Hickam's dictum, which embraces the principle of plenitude by considering multiple diagnoses for a patient's presentation, is often underutilized or not as widely recognized as Occam's razor. The application of Hickam's dictum is particularly crucial when evaluating nonspecific symptoms such as fatigue, which can manifest in various diseases. This report describes the case of a 72-year-old man with a history of functional cure for hepatitis B who presented with chronic fatigue and hyponatremia. Initially, he was diagnosed with non-functional pituitary macroadenoma and panhypopituitarism. Two months following pituitary surgery, the onset of dyspepsia and the recurrence of fatigue revealed metastatic tumors in the liver, stomach, pancreas, left adrenal gland, and peri-pancreatic lymph nodes. A liver biopsy confirmed the diagnosis of hepatocellular carcinoma. This case highlights the importance of considering multiple, potentially co-existing conditions based on the patient's symptoms and risk factors to complete the thorough diagnoses. Additionally, it emphasizes the need to remain vigilant regarding the risk of liver cancer in patients with a history of chronic hepatitis B infection, irrespective of a functional cure.
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Affiliation(s)
- Yu-Ming Li
- Department of Integrative Immunobiology, Duke University School of Medicine, Durham, USA
| | - Ching-Shiang Shaw
- Department of Medicine, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, TWN
| | - Tse-Ching Chen
- Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, TWN
| | - Diego Shih-Chieh Lin
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, TWN
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11
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Yang H, Jang JW. Reply to: 'A risk prediction model for hepatocellular carcinoma after hepatitis B surface antigen seroclearance: Need a closer look!'. J Hepatol 2024; 80:e269-e270. [PMID: 38346580 DOI: 10.1016/j.jhep.2024.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 01/23/2024] [Accepted: 02/06/2024] [Indexed: 03/22/2024]
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
| | - 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.
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12
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Lee HW, Yip TCF, Wong VWS, Lim YS, Chan HLY, Ahn SH, Wong GLH, Choi J. CAMP-B score predicts the risk of hepatocellular carcinoma in patients with chronic hepatitis B after HBsAg seroclearance. Aliment Pharmacol Ther 2024; 59:1223-1235. [PMID: 38425096 DOI: 10.1111/apt.17933] [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] [Received: 12/10/2023] [Revised: 01/15/2024] [Accepted: 02/20/2024] [Indexed: 03/02/2024]
Abstract
BACKGROUND Risk of hepatocellular carcinoma (HCC) persists after hepatitis B surface antigen (HBsAg) seroclearance in patients with chronic hepatitis B (CHB). AIMS To identify risk factors and construct a predictive model for HCC development. METHODS We retrospectively analysed patients with CHB with HBsAg seroclearance. Primary outcome was HCC development. Factors identified from a multivariate Cox model in the training cohort, consisting of 3476 patients from two Korean hospitals, were used to construct the prediction model. External validation was performed using data from 5255 patients in Hong Kong. RESULTS In the training cohort, HCC occurred in 102 patients during 24,019 person-years of observation (0.43%/year). Risk scores were assigned to cirrhosis (C:3), age ≥50 years (A:2), male sex (M:3) and platelet count <150,000/mm3 (P:1); all were independently associated with an increased risk of HCC in multivariate analysis The time-dependent area under receiver operating characteristic curves for 5, 10 and 15 years in the training and validation cohorts were 0.782, 0.817 and 0.825 and 0.785, 0.771 and 0.796, respectively. In the validation cohort, 85 patients developed HCC (0.24%/year). The corresponding incidence of HCC in the low-, intermediate- and high-risk groups were 0.07%, 0.37% and 0.90%, respectively. CONCLUSIONS The CAMP-B score (cirrhosis, age ≥50 years, male sex and platelet count <150,000/mm3/L) was significantly associated with HCC development after HBsAg seroclearance. CAMP-B score can be easily implemented in real-world clinical practice and helps stratify HCC risk in patients with CHB following HBsAg seroclearance.
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Affiliation(s)
- Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Terry Cheuk-Fung Yip
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong, China
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong, China
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | | | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong, China
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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13
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Liu X, Wen X, Lu F. For long-term outcomes, is the impact of cirrhosis more important than HBsAg seroclearance? J Hepatol 2024; 80:e31-e32. [PMID: 37302581 DOI: 10.1016/j.jhep.2023.05.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 04/28/2023] [Accepted: 05/17/2023] [Indexed: 06/13/2023]
Affiliation(s)
- Xin Liu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xiajie Wen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Fengmin Lu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Hepatology Institute, Peking University People's Hospital, Beijing, China.
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14
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Zheng F, Tan Z, Liang Z, Xiang W. Efficacy and Safety of Antiviral Therapy for Immune-tolerant Hepatitis B Viral Infection in Children: A Systematic Review and Meta-analysis. Pediatr Infect Dis J 2023; 42:942-948. [PMID: 37523508 DOI: 10.1097/inf.0000000000004057] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/02/2023]
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection burden in children remains a pressing public health concern. Whether antiviral therapy should be administered to children with HBV in the immune-tolerant phase remains controversial. We performed a meta-analysis to evaluate antiviral therapy efficacy and safety in children with immune-tolerant hepatitis B (ITHB). METHODS A search was conducted in multiple databases (PubMed, Embase, Cochrane, Web of Science, CBM, CNKI and Wanfang Data) to identify clinical trials examining antiviral therapy efficacy and safety in children (1-18 years) with ITHB viral infection from inception to February 2023. Outcomes were calculated separately for controlled and single-arm studies. RESULTS Nine trials (442 patients), including 2 randomized controlled trials (RCTs), 3 non-RCTs and 4 single-arm studies, were included in this meta-analysis. In the RCTs, antiviral therapy group exhibited greater rates of HBsAg loss [risk ratio (RR) = 6.11, 95% confidence interval (CI): 1.67-22.31, P Z-test = 0.006], HBsAg serologic response (RR = 5.29, 95% CI: 1.47-19.07, P Z-test = 0.011) and HBeAg loss (RR = 3.00, 95% CI: 1.35-6.66, P Z-test = 0.007) compared with the control group at the end of follow-up. In single-arm studies, the pooled incidences of HBsAg loss, HBeAg loss and HBsAg seroconversion were 24% (95% CI: -0.1% to 48%), 24% (95% CI: -0.1% to 48%) and 24% (95% CI: -5% to 52%), respectively. CONCLUSION Current evidence suggests the effectiveness of antiviral therapy in children with HBV infection in the immune-tolerant stage, with few serious adverse events. Due to the limited quality and number of included studies, more high-quality studies are required to validate our findings.
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Affiliation(s)
- Fengli Zheng
- From the Department of Pediatrics, The People's Hospital of Guigang, Guigang, Guangxi, China
| | - Zhijun Tan
- Department of Infectious Diseases, The People's Hospital of Guigang, Guigang, Guangxi, China
| | - Zhou Liang
- Department of Infectious Diseases, The People's Hospital of Guigang, Guigang, Guangxi, China
| | - Wenyao Xiang
- Department of Infectious Diseases, The People's Hospital of Guigang, Guigang, Guangxi, China
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15
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Cho Y, Park S, Park S, Choi W, Kim B, Han H. Real-World Epidemiology, Treatment Patterns, and Disease Burden of Chronic Hepatitis B and HDV Co-Infection in South Korea. Infect Dis Ther 2023; 12:2387-2403. [PMID: 37768482 PMCID: PMC10600088 DOI: 10.1007/s40121-023-00860-8] [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: 06/27/2023] [Accepted: 08/16/2023] [Indexed: 09/29/2023] Open
Abstract
INTRODUCTION Long-term complications of chronic hepatitis B (CHB) viral infection, such as cirrhosis, hepatocellular carcinoma (HCC), and liver failure, cause a large disease burden. This study aimed to describe the epidemiology, clinical outcomes, and treatment patterns of CHB infection and co-infection with hepatitis D virus (HDV) in South Korea. METHODS The retrospective, observational study used existing data from the Health Insurance Review and Assessment Service (HIRA) database. Confirmed cases of (CHB) and HBV/HDV co-infection were identified between 2013 and 2019. Hepatitis C virus co-infections and acute HBV infections were excluded. Incident cases diagnosed between 2015 and 2018 with no prior disease history up to 2 years were included. Patient characteristics, clinical outcomes, economic burden, and healthcare-resource utilization were described. RESULTS The estimated 7-year prevalence of CHB and HBV/HDV co-infection were 0.9% and 0.0024%, respectively. The prevalence was higher among 45-54 years old (CHB: 1.6%, HBV/HDV: 0.0049%) and males (1.1%, 0.0035%). The 5-year cumulative incidences of compensated cirrhosis, decompensated cirrhosis, HCC, and liver transplantation were 13.3%, 7.1%, 8.4%, and 0.7%, respectively. Hyperlipidemia (40.6%), hypertension (23.5%), and peptic ulcer (23.7%) were the more prevalent comorbidities. Among CHB patients, 48.1% received ≥ 1 prescribed anti-HBV drug including interferon or nucleos(t)ide analogues and 64.4% had ≥ 1 hospitalization compared to 80.4% and 79.4% HBV/HDV patients. Estimated total healthcare costs for CHB and HBV/HDV were US$786 million and $62 million, respectively. CONCLUSIONS These findings provide insights to the epidemiology, clinical burden, treatment patterns, and healthcare costs of CHB and HBV/HDV co-infection in South Korea.
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Affiliation(s)
- Yuri Cho
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10408, Republic of Korea.
| | | | | | - WonJung Choi
- Janssen Pharmaceuticals, Seoul, Republic of Korea
| | - Book Kim
- Cerner Enviza, Seoul, Republic of Korea
| | - Helin Han
- Cerner Enviza, Seoul, Republic of Korea
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16
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Astrologo NCN, Gaudillo JD, Albia JR, Roxas-Villanueva RML. Genetic risk assessment based on association and prediction studies. Sci Rep 2023; 13:15230. [PMID: 37709797 PMCID: PMC10502006 DOI: 10.1038/s41598-023-41862-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 09/01/2023] [Indexed: 09/16/2023] Open
Abstract
The genetic basis of phenotypic emergence provides valuable information for assessing individual risk. While association studies have been pivotal in identifying genetic risk factors within a population, complementing it with insights derived from predictions studies that assess individual-level risk offers a more comprehensive approach to understanding phenotypic expression. In this study, we established personalized risk assessment models using single-nucleotide polymorphism (SNP) data from 200 Korean patients, of which 100 experienced hepatitis B surface antigen (HBsAg) seroclearance and 100 patients demonstrated high levels of HBsAg. The risk assessment models determined the predictive power of the following: (1) genome-wide association study (GWAS)-identified candidate biomarkers considered significant in a reference study and (2) machine learning (ML)-identified candidate biomarkers with the highest feature importance scores obtained by using random forest (RF). While utilizing all features yielded 64% model accuracy, using relevant biomarkers achieved higher model accuracies: 82% for 52 GWAS-identified candidate biomarkers, 71% for three GWAS-identified biomarkers, and 80% for 150 ML-identified candidate biomarkers. Findings highlight that the joint contributions of relevant biomarkers significantly influence phenotypic emergence. On the other hand, combining ML-identified candidate biomarkers into the pool of GWAS-identified candidate biomarkers resulted in the improved predictive accuracy of 90%, demonstrating the capability of ML as an auxiliary analysis to GWAS. Furthermore, some of the ML-identified candidate biomarkers were found to be linked with hepatocellular carcinoma (HCC), reinforcing previous claims that HCC can still occur despite the absence of HBsAg.
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Affiliation(s)
- Nicole Cathlene N Astrologo
- Data Analytics Research Laboratory (DARELab), Institute of Mathematical Sciences and Physics, University of the Philippines Los Baños, 4031, Los Baños, Laguna, Philippines
- Computational Interdisciplinary Research Laboratory (CINTERLabs), University of the Philippines Los Baños, 4031, Los Baños, Laguna, Philippines
| | - Joverlyn D Gaudillo
- Data Analytics Research Laboratory (DARELab), Institute of Mathematical Sciences and Physics, University of the Philippines Los Baños, 4031, Los Baños, Laguna, Philippines.
- Computational Interdisciplinary Research Laboratory (CINTERLabs), University of the Philippines Los Baños, 4031, Los Baños, Laguna, Philippines.
- Domingo AI Research Center (DARC Labs), 1606, Pasig, Philippines.
| | - Jason R Albia
- Domingo AI Research Center (DARC Labs), 1606, Pasig, Philippines
- Venn Biosciences Corporation Dba InterVenn Biosciences, Metro Manila, Pasig, Philippines
- Graduate School, University of the Philippines Los Baños, 4031, Los Baños, Laguna, Philippines
| | - Ranzivelle Marianne L Roxas-Villanueva
- Data Analytics Research Laboratory (DARELab), Institute of Mathematical Sciences and Physics, University of the Philippines Los Baños, 4031, Los Baños, Laguna, Philippines
- Computational Interdisciplinary Research Laboratory (CINTERLabs), University of the Philippines Los Baños, 4031, Los Baños, Laguna, Philippines
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17
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Howell J, Seaman C, Wallace J, Xiao Y, Scott N, Davies J, de Santis T, Adda D, El-Sayed M, Feld JJ, Gane E, Lacombe K, Lesi O, Mohamed R, Silva M, Tu T, Revill P, Hellard ME. Pathway to global elimination of hepatitis B: HBV cure is just the first step. Hepatology 2023; 78:976-990. [PMID: 37125643 PMCID: PMC10442143 DOI: 10.1097/hep.0000000000000430] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 02/04/2023] [Accepted: 02/10/2023] [Indexed: 05/02/2023]
Abstract
Hepatitis B (HBV) is a major cause of global morbidity and mortality, and the leading cause of liver cancer worldwide. Significant advances have recently been made toward the development of a finite HBV treatment that achieves permanent loss of HBsAg and HBV DNA (so-called "HBV cure"), which could provide the means to eliminate HBV as a public health threat. However, the HBV cure is just one step toward achieving WHO HBV elimination targets by 2030, and much work must be done now to prepare for the successful implementation of the HBV cure. In this review, we describe the required steps to rapidly scale-up future HBV cure equitably. We present key actions required for successful HBV cure implementation, integrated within the World Health Organization (WHO) Global Health Sector Strategy (GHSS) 2022-2030 framework. Finally, we highlight what can be done now to progress toward the 2030 HBV elimination targets using available tools to ensure that we are preparing, but not waiting, for the cure.
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Affiliation(s)
- Jessica Howell
- Disease Elimination, Burnet Institute, Melbourne, Victoria, Australia
- Department Gastroenterology, St Vincent’s Hospital, Melbourne, Victoria, Australia
- Department Medicine, University of Melbourne, Melbourne, Victoria, Australia
- Department Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Chris Seaman
- Disease Elimination, Burnet Institute, Melbourne, Victoria, Australia
- Department Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Jack Wallace
- Disease Elimination, Burnet Institute, Melbourne, Victoria, Australia
| | - Yinzong Xiao
- Disease Elimination, Burnet Institute, Melbourne, Victoria, Australia
| | - Nick Scott
- Disease Elimination, Burnet Institute, Melbourne, Victoria, Australia
| | - Jane Davies
- Department Global Health and Infectious diseases, Menzies School of Public Health, Darwin, Northern Territory, Australia
| | - Teresa de Santis
- Department Global Health and Infectious diseases, Menzies School of Public Health, Darwin, Northern Territory, Australia
| | | | - Manal El-Sayed
- Department Paediatrics, Ain Shams University, Cairo, Egypt
| | - Jordan J. Feld
- Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Edward Gane
- Department Medicine, University of Auckland, Auckland, New Zealand
| | - Karine Lacombe
- Sorbonne Université, IPLESP, Saint-Antoine Hospital, AP-HP, Paris, France
| | - Olufunmilayo Lesi
- Global HIV, Hepatitis, and STI Programme, World Health Organisation, Geneva, Switzerland
| | - Rosmawati Mohamed
- Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Marcelo Silva
- Department Hepatology and Liver Transplantation, Austral University Hospital, Buenos Aires, Argentina
| | - Thomas Tu
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, New South Wales, Australia
- University of Sydney Institute for Infectious Diseases, University of Sydney, Sydney, New South Wales, Australia
| | - Peter Revill
- Victorian Infectious Diseases Reference Laboratory (VIDRL), Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Margaret E. Hellard
- Disease Elimination, Burnet Institute, Melbourne, Victoria, Australia
- Department Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
- Department Infectious Diseases, Alfred Hospital, Melbourne, Victoria, Australia
- Department Infectious Diseases, School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia
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18
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Patwa AK, Amardeep, Atam V, Mishra P, Rungta S, Gangwar A, Yadav A, Gupta KK, Agrawal B, Verma SK, Goel A. KGHeBTA (King George's Medical University Hepatitis B Therapeutic Algorithm): A New Diagnostic and Therapeutic Algorithm and Clinico-epidemiological Spectrum of Hepatitis B. J Clin Exp Hepatol 2023; 13:629-637. [PMID: 37440941 PMCID: PMC10333945 DOI: 10.1016/j.jceh.2023.02.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 02/28/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND Diagnostic and therapeutic algorithms given by various societies for hepatitis B are fragmented and complex. The clinico-epidemiologic spectrum of hepatitis B is not studied with large-scale data from our region. We aimed to develop a comprehensive algorithm for the treatment of hepatitis B and study its clinico-epidemiological spectrum. METHODS From 2014-2019, the clinico-laboratory data of hepatitis B surface antigen (HbsAg)-positive patients were prospectively recorded. King George's Medical University hepatitis B therapeutic algorithm (KGHeBTA) was developed on the basis of the standard existing guidelines. The prevalence of different clinical stages of HBsAg-positive patients was calculated and their treatment records reviewed. Testing circumstances and risk factors were noted. RESULTS Among 1,508 data record sheets, 421 were complete. According to the KGHeBTA algorithm, 221 had detectable hepatitis B virus DNA. 21% were cirrhotic and 79% non-cirrhotic. 72% were incidentally detected asymptomatic hepatitis B, 7% were hepatitis B with acute symptoms, 0.7% were acute hepatitis B, and 22% were chronic hepatitis B. 20% patients were eligible for antivirals and 80% patients were not eligible. 32% patients were actually treated with antivirals due to the inclusion of some special indications as pregnancy and family history. Screening during various medical illnesses (40%) was the most common and during health camps (0.2%), the least common testing approach. Road-side shaving (52%) was the most common and intravenous drug abuse (0.2%) and the least common risk factor for the detection of hepatitis B in our data pool. CONCLUSIONS HBsAg-positive patients can be easily worked up and treated based on the proposed algorithm (KGHeBTA). About one fourth to one fifth of all HBsAg-positive patients were eligible and treated with oral antivirals. Most of the patients were incidentally detected asymptomatic hepatitis B screened during medical illnesses. Roadside shaving and intravenous drug abuse were the most and the least common risk factors.
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Affiliation(s)
- Ajay K. Patwa
- Department of Medicine, King George's Medical University, Lucknow, India
| | - Amardeep
- Department of Medical Gastroenterology, King George's Medical University, Lucknow, India
| | - Virendra Atam
- Department of Medicine, King George's Medical University, Lucknow, India
| | - Pratishtha Mishra
- Department of Medicine, King George's Medical University, Lucknow, India
| | - Sumit Rungta
- Department of Medical Gastroenterology, King George's Medical University, Lucknow, India
| | - Anil Gangwar
- Department of Medical Gastroenterology, King George's Medical University, Lucknow, India
| | - Ankur Yadav
- Department of Medical Gastroenterology, King George's Medical University, Lucknow, India
| | - Kamlesh K. Gupta
- Department of Medicine, King George's Medical University, Lucknow, India
| | - Bhaskar Agrawal
- Department of Prosthodontics, King George's Medical University, Lucknow, India
| | - Sanjeev K. Verma
- Department of Pediatrics, King George's Medical University, Lucknow, India
| | - Amit Goel
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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19
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Morais E, Mason L, Dever J, Martin P, Chen JV, Felton L, Kendrick S, Theodore D, Gillespie IA. Clinical Consequences of Hepatitis B Surface Antigen Loss in Chronic Hepatitis B Infection: A Systematic Literature Review and Meta-Analysis. GASTRO HEP ADVANCES 2023; 2:992-1004. [PMID: 39130769 PMCID: PMC11307919 DOI: 10.1016/j.gastha.2023.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 06/12/2023] [Indexed: 08/13/2024]
Abstract
Background and Aims Functional cure, which requires sustained hepatitis B surface antigen (HBsAg) loss after treatment cessation, is currently the optimal treatment endpoint for chronic hepatitis B virus infection. We performed a systematic literature review (SLR) and meta-analyses to assess the association between HBsAg loss and long-term clinical outcomes. Methods We performed a SLR of scientific literature published in Medline and Embase reporting the incidence of cirrhosis, hepatic decompensation (HD), hepatocellular carcinoma (HCC), liver-related mortality (LRM), and all-cause mortality (ACM) in relation to HBsAg status. Bayesian hierarchical commensurate prior meta-analyses synthesized evidence on the association between HBsAg loss and each outcome. Results Thirty-eight studies, comprising 50,354 patients with 350,734 patient-years of follow-up, were included in the meta-analyses, reporting on cirrhosis (n = 12), HD (n = 12), HCC (n = 36), LRM (n = 12), and ACM (n = 16). Pooled incidence rate ratios (IRRs; vs HBsAg persistence) and respective credible intervals (Crls) were 0.28 (0.060-1.070) for cirrhosis, 0.13 (0.013-0.38) for HD, 0.27 (0.11-0.53) for HCC, 0.17 (0.028-0.61) for LRM, and 0.64 (0.24-1.17) for ACM. Single-predictor-adjusted IRRs remained consistent with those from the primary analyses for all outcomes except cirrhosis and LRM. Outcome incidence rates were modified by selected study, patient and infection characteristics, but trended in the same direction of reduced risk after loss. Conclusion Overall, HBsAg loss was associated with a reduced risk of most clinically relevant outcomes. While the magnitude of the effect differed across subgroups, the direction of the association remained similar. Our results validate the need to develop new strategies to achieve HBsAg loss.
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Affiliation(s)
| | - Lauren Mason
- Pallas Health Research and Consultancy, Rotterdam, The Netherlands
| | - John Dever
- Business Intelligence, Three Rivers Federal Credit Union, Fort Wayne, Indiana
| | - Pam Martin
- Modeling & Analytics, Medical Decision Modeling Inc., Indianapolis, Indiana
| | - Jing Voon Chen
- Evidence Strategy, Genesis Research, Hoboken, New Jersey
| | - Leigh Felton
- Development Clinical Sciences, Hepatology and GI, GSK, London, UK
| | | | - Dickens Theodore
- Development Clinical Sciences, Hepatology and GI, GSK, London, UK
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Choi J. Quantitative Hepatitis B Surface Antigen, the Trustworthy Biomarker for Functional Cure of Chronic Hepatitis B. Gut Liver 2023; 17:179-180. [PMID: 36918269 PMCID: PMC10018298 DOI: 10.5009/gnl230070] [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: 03/16/2023] Open
Affiliation(s)
- Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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21
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Yip TCF, Wong VWS, Lai MSM, Lai JCT, Hui VWK, Liang LY, Tse YK, Chan HLY, Wong GLH. Risk of hepatic decompensation but not hepatocellular carcinoma decreases over time in patients with hepatitis B surface antigen loss. J Hepatol 2023; 78:524-533. [PMID: 36463985 DOI: 10.1016/j.jhep.2022.11.020] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 10/23/2022] [Accepted: 11/16/2022] [Indexed: 12/03/2022]
Abstract
BACKGROUND & AIMS We examined the long-term incidence of hepatocellular carcinoma (HCC) and hepatic decompensation among chronic hepatitis B (CHB) patients who have achieved hepatitis B surface antigen (HBsAg) seroclearance. METHODS All adult CHB-monoinfected patients who cleared HBsAg between January 2000 and December 2020 were identified using a territory-wide database in Hong Kong. Patients who underwent liver transplantation and/or developed HCC before HBsAg seroclearance or less than 6 months follow-up were excluded. The primary and secondary endpoints were HCC and hepatic decompensation respectively. RESULTS We identified 9,769 patients with CHB who achieved HBsAg seroclearance (mean age 57 years, 60.0% male, 13.2% cirrhosis); most had compensated liver function at HBsAg loss. At a median (25th-75th percentile) follow-up of 4.6 (2.2-8.4) years, 106 (1.1%) patients developed HCC. Patients who developed HCC were older, more likely to be male and have cirrhosis, and had higher alanine aminotransferase and lower platelets at the time of HBsAg loss than patients without HCC. The cumulative incidence of HCC remained steady 0-7 and 8-12 years after HBsAg loss (p = 0.898) (crude annual incidence drop: -0.04%, 95% CI -0.13% to 0.04%, p = 0.265). Moreover, 124/9,640 (1.3%) patients developed hepatic decompensation. The growth in cumulative incidence of hepatic decompensation decelerated 8-12 years after HBsAg loss (p = 0.009) (crude annual incidence drop: -0.23%, 95% CI -0.40% to -0.06%, p = 0.012). In multivariable analysis, HBsAg loss for over 7 years was associated with a reduced risk of hepatic decompensation (adjusted subdistribution hazard ratio [aSHR] 0.55, 95% CI 0.31-0.97, p = 0.039) but not HCC (aSHR 1.35, 95% CI 0.83-2.19, p = 0.230). CONCLUSION HCC risk persists in patients after HBsAg loss, whereas the risk of hepatic decompensation decreases over time. IMPACT AND IMPLICATIONS Patients with chronic hepatitis B (CHB) still have a non-negligible risk of hepatocellular carcinoma (HCC) after 12 years of HBsAg seroclearance, especially among those with cirrhosis. The risk of developing hepatic decompensation decreases over time after HBsAg seroclearance. In clinical practice, although patients with CHB who cleared HBsAg have a more favourable clinical outcome than those who remain chronically infected, long-term HCC surveillance would still be necessary for patients with cirrhosis and other high-risk subgroups after HBsAg seroclearance.
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Affiliation(s)
- Terry Cheuk-Fung Yip
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong; Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong; Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Mandy Sze-Man Lai
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong
| | - Jimmy Che-To Lai
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong; Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Vicki Wing-Ki Hui
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong
| | - Lilian Yan Liang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong
| | - Yee-Kit Tse
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong; Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Henry Lik-Yuen Chan
- Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong; Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong; Department of Internal Medicine, Union Hospital, Hong Kong
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong; Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.
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22
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Isolated Hepatitis B Core Antibody Positivity and Long-Term Liver-Related Mortality in Korea: A Cohort Study. Am J Gastroenterol 2023; 118:95-104. [PMID: 36087102 DOI: 10.14309/ajg.0000000000001994] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/23/2022] [Indexed: 01/28/2023]
Abstract
INTRODUCTION Whether isolated hepatitis B core antibody (anti-HBc) positivity is a risk factor for long-term liver-related outcomes in hepatitis B virus (HBV)-endemic areas remains unclear. We aimed to investigate liver-related and liver cancer mortality of isolated anti-HBc positivity in Korean adults. METHODS A cohort study comprised 609,299 Korean adults who underwent hepatitis B serologic markers, as a part of health examination. Liver-related and liver cancer mortality were determined using the National Death Records. RESULTS During a median follow-up of 9.0 years (interquartile range, 5.5-13.7 years), 554 liver-related deaths were identified (liver-related mortality, 9.6 cases per 10 5 person-years). The prevalence of isolated anti-HBc positivity was 3.8% (n = 23,399) and was age-dependent. After adjustment for age, sex, and other confounders, hazard ratios (95% confidence interval) for liver-related mortality in isolated anti-HBc-positive and hepatitis B surface antigen-positive subjects compared with HBV-unexposed subjects were 1.69 (1.22-2.33) and 27.02 (21.45-34.04), respectively. These associations were pronounced in the analyses using liver cancer mortality as an outcome. Among isolated anti-HBc-positive patients, the risks of liver-related and liver cancer mortality were significantly higher in those with high fibrosis-4 scores compared with patients unexposed to HBV with the multivariable-adjusted hazard ratios (95% confidence interval) of 15.59 (9.21-26.37) and 72.66 (36.96-142.86), respectively. DISCUSSION In this cohort of Korean adults, isolated anti-HBc positivity was associated with an increased risk of liver-related and liver cancer mortality, especially when accompanied by a high fibrosis score. Isolated anti-HBc positivity may be an independent risk factor for liver-related outcomes, especially in high-endemic areas.
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23
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Choi WM, Choi J, Lim YS. Hepatitis B: epidemiology, natural history, and diagnosis. COMPREHENSIVE GUIDE TO HEPATITIS ADVANCES 2023:183-203. [DOI: 10.1016/b978-0-323-98368-6.00007-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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24
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Mak LY, Cheung KS, Hui RWH, Wong DKH, Fung J, Yuen MF, Seto WK. Enhanced Liver Fibrosis Score Stratifies Hepatocellular Carcinoma Risk in Patients With Hepatitis B Surface Antigen Seroclearance. Clin Infect Dis 2022; 75:2257-2259. [PMID: 35594565 DOI: 10.1093/cid/ciac387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 04/27/2022] [Accepted: 05/13/2022] [Indexed: 01/19/2023] Open
Abstract
In this prospective study involving 337 chronic hepatitis B patients who achieved spontaneous hepatitis B surface antigen (HBsAg) seroclearance (SC), serum enhanced liver fibrosis (ELF) before SC was associated with hepatocellular carcinoma (HCC) (hazard ratio 2.588), and ELF <10.8 was associated with >97% reduction in risk of HCC development in patients with age SC ≥ 50 (n = 190).
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Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - Ka-Shing Cheung
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.,Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Rex Wan-Hin Hui
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong
| | - Danny Ka-Ho Wong
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - James Fung
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong.,Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
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25
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Xu B, Liu A, Liu Y, Han T, Guo H, Ding X, Xiang H. Correlations between serum hepatitis B core-related antigen and hepatitis B surface antigen in patients with hepatitis B cirrhosis and a hepatitis B virus-DNA-negative status: a retrospective study. J Int Med Res 2022; 50:3000605221130714. [PMID: 36224762 PMCID: PMC9561681 DOI: 10.1177/03000605221130714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE This study aimed to examine the correlations between serum hepatitis B core-related antigen (HBcrAg) and hepatitis B surface antigen (HBsAg) titers in patients with hepatitis B cirrhosis and a hepatitis B virus (HBV)-DNA-negative status. METHODS We retrospectively analyzed the data and blood samples of patients who were diagnosed with HBV liver cirrhosis and an HBV-DNA negative status. These patients were hospitalized between October 2018 and October 2019 at one hospital. RESULTS A total of 180 patients were included. The median (interquartile range) HBsAg and HBcrAg concentrations were 2.77 log10 IU/mL (1.60-3.15) and 3.96 log10 U/mL (2.70-4.97), respectively. A non-linear significant relationship was found between HBsAg and HBcrAg concentrations. The inflection point was 0.58. The effect size and confidence interval on the left and right sides of the inflection point were 0.10 (-0.23-0.42) and 0.62 (0.46-0.78), respectively. When HBsAg concentrations were ≥0.58 log10 IU/mL, HBsAg concentrations were positively correlated with HBcrAg concentrations. When HBsAg concentrations increased by 1 log10 IU/mL, HBcrAg concentrations increased by 0.62 log10 U/mL (95% confidence interval: 0.46, 0.78). CONCLUSIONS There might be a non-linear relationship between HBcrAg and HBsAg concentrations in patients with hepatitis B cirrhosis and an HBV-DNA-negative status.
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Affiliation(s)
- Baiguo Xu
- Department of Hepatology and Gastroenterology, The Third Central
Clinical College of Tianjin Medical University, Tianjin, China; Tianjin
Institute of Hepatobiliary Disease, Tianjin, China
| | - Anjing Liu
- Center of Infectious Diseases, Tanggu Infectious Disease
Hospital of Tianjin, Tianjin, China
| | - Ying Liu
- Department of Hepatology and Gastroenterology, The Third Central
Clinical College of Tianjin Medical University, Tianjin, China; Tianjin
Institute of Hepatobiliary Disease, Tianjin, China
| | - Tao Han
- Department of Hepatology and Gastroenterology, The Third Central
Clinical College of Tianjin Medical University, Tianjin, China; Tianjin
Institute of Hepatobiliary Disease, Tianjin, China
| | - Hua Guo
- Institute of Hepatobiliary Disease of Tianjin, Tianjin, China;
The Third Central Hospital of Tianjin, Tianjin, China
| | - Xian Ding
- Department of Clinical Laboratory, The Third Central Hospital of
Tianjin, Tianjin, China; Institute of Hepatobiliary Disease of Tianjin, Tianjin,
China
| | - Huiling Xiang
- Department of Hepatology and Gastroenterology, The Third Central
Clinical College of Tianjin Medical University, Tianjin, China; Tianjin
Institute of Hepatobiliary Disease, Tianjin, China,Huiling Xiang, Department of Hepatology and
Gastroenterology, The Third Central Clinical College of Tianjin Medical
University, #83 Jintang Road, Hedong District, Tianjin 300170, China.
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Yoo S, Kim JY, Lim YS, Han S, Choi J. Impact of HBsAg seroclearance on late recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection. J Hepatol 2022; 77:939-946. [PMID: 35643206 DOI: 10.1016/j.jhep.2022.05.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 05/04/2022] [Accepted: 05/13/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS It is unknown whether HBsAg seroclearance affects the risk of hepatocellular carcinoma (HCC) recurrence after liver resection. We aimed to investigate the impact of HBsAg seroclearance on the recurrence of HCC after curative liver resection, with a focus on late recurrence. METHODS This study comprised 2,520 consecutive patients who received curative liver resection for HBV-related HCC of Barcelona Clinic Liver Cancer stage 0 or A in Korea between 2000 and 2017. To focus on late recurrence, patients with recurrence or a follow-up duration less than 2 years were excluded. The impact of HBsAg seroclearance on HCC recurrence was assessed by landmark analysis (2-, 5-and 8-year after liver resection), time-dependent Cox and multistate modeling. RESULTS The mean patient age was 54.4 years and 75.7% were men. A total of 891 (35.4%) patients developed HCC recurrence at rates of 11.2%, 25.5%, and 46.8% at 3, 5, and 10 years after resection. HBsAg seroclearance was achieved in 172 (6.8%) patients during a median follow-up duration of 6.9 years after resection. HBsAg seroclearance, compared with persistent HBsAg positivity, was associated with a lower risk of late HCC recurrence in the 2-, 5-, and 8-year landmark analysis (p = 0.04, p = 0.02 and p = 0.03, respectively) and on time-dependent multivariable Cox modeling (adjusted hazard ratio 0.62; p = 0.005). Based on a 3-state unidirectional illness-death model, patients without HBsAg seroclearance transitioned to HCC recurrence more rapidly than patients who experienced HBsAg seroclearance. CONCLUSIONS HBsAg seroclearance is associated with a lower risk of late recurrence of HBV-related HCC among Korean patients who undergo curative liver resection. LAY SUMMARY Hepatitis B virus (HBV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma (HCC). Suppression of HBV replication is known to lower the risk of HCC recurrence after liver resection (a procedure used to treat and in some cases cure HCC). However, whether the loss of a specific HBV protein (hepatitis B surface antigen or HBsAg) has an impact on recurrence after liver resection remains unknown. Herein, we show that loss of HBsAg is associated with a reduce risk of late recurrence of HCC after liver resection in patients with HBV-related HCC.
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Affiliation(s)
- Sun Yoo
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ji Yoon Kim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seungbong Han
- Department of Biostatistics, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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Yuen MF, Heo J, Kumada H, Suzuki F, Suzuki Y, Xie Q, Jia J, Karino Y, Hou J, Chayama K, Imamura M, Lao-Tan JY, Lim SG, Tanaka Y, Xie W, Yoon JH, Duan Z, Kurosaki M, Park SJ, Labio ME, Kumar R, Kweon YO, Yim HJ, Tao Y, Cremer J, Elston R, Davies M, Baptiste-Brown S, Han K, Campbell FM, Paff M, Theodore D. Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy. J Hepatol 2022; 77:967-977. [PMID: 35714812 DOI: 10.1016/j.jhep.2022.05.031] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 04/26/2022] [Accepted: 05/16/2022] [Indexed: 01/09/2023]
Abstract
BACKGROUND & AIMS Bepirovirsen, an antisense oligonucleotide targeting pregenomic and mRNA transcripts of HBV, has been conjugated to N-acetyl galactosamine (GSK3389404) to enhance hepatocyte delivery. This dose-finding study was the first to assess GSK3389404 for chronic HBV infection. METHODS This phase IIa, randomised, double-blind, placebo-controlled, 2-part study was conducted in 22 centres in Asia (NCT03020745). Pharmacokinetic findings from Part 1 informed Part 2 dosing. In Part 2, patients with chronic hepatitis B on nucleos(t)ide analogue therapy were randomised 11:2 to GSK3389404 (30, 60, 120 mg weekly or 120 mg bi-weekly) or placebo until Day 85. Coprimary endpoints included HBsAg response (≥1.5 log10 IU/ml reduction from baseline) rate, safety and pharmacokinetics. RESULTS Parts 1 and 2 included 12 (9 GSK3389404, 3 placebo) and 66 patients (56 GSK3389404, 10 placebo), respectively. In Part 2, one patient each in the 60 mg weekly, 120 mg weekly and 120 mg bi-weekly arms achieved a HBsAg response. HBsAg reductions were dose-dependent (Day 85: mean 0.34 [60 mg weekly] to 0.75 log10 IU/ml [120 mg weekly]) and occurred in hepatitis B e antigen-positive and -negative patients. No patient achieved HBsAg seroclearance. 43/56 (77%) GSK3389404- and 9/10 (90%) placebo-treated patients reported adverse events. No deaths were reported. Alanine aminotransferase flares (>2x upper limit of normal) occurred in 2 GSK3389404-treated patients (120 mg weekly, 120 mg bi-weekly); both were associated with decreased HBsAg, but neither was considered a responder. GSK3389404 plasma concentrations peaked 2-4 hours post dose; mean plasma half-life was 3-5 hours. CONCLUSIONS GSK3389404 showed an acceptable safety profile and target engagement, with dose-dependent reductions in HBsAg. However, no efficacious dosing regimen was identified. CLINICAL TRIAL NUMBER NCT03020745. LAY SUMMARY Hepatitis B virus (HBV) can result in chronic HBV infection, which may ultimately lead to chronic liver disease, primary liver cancer and death; HBV proteins may prevent the immune system from successfully controlling the virus. GSK3389404 is an investigational agent that targets HBV RNA, resulting in reduced viral protein production. This study assessed the safety of GSK3389404 and its ability to reduce the viral proteins in patients with chronic HBV infection. GSK3389404 showed dose-dependent reduction in hepatitis B surface antigen, with an acceptable safety profile. While no clear optimal dose was identified, the findings from this study may help in the development of improved treatment options for patients with chronic HBV infections.
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Affiliation(s)
- Man-Fung Yuen
- Department of Medicine and State Key Laboratory of Liver Research, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
| | - Jeong Heo
- Department of Internal Medicine, College of Medicine, Pusan National University, and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Hiromitsu Kumada
- Department of Hepatology, Toranomon Hospital Kajigaya, Kanagawa, Japan
| | - Fumitaka Suzuki
- Department of Hepatology, Toranomon Hospital Kajigaya, Kanagawa, Japan
| | | | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yoshiyasu Karino
- Department of Hepatology, Hokkaido P.W.F.a.C. Sapporo-Kosei General Hospital, Hokkaido, Japan
| | - Jinlin Hou
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Kazuaki Chayama
- Collaborative Research Laboratory of Medical Innovation, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Judy Y Lao-Tan
- Gastroenterology, Cebu Doctors University Hospital, Cebu, Philippines
| | - Seng Gee Lim
- Division of Gastroenterology & Hepatology, Department of Medicine, National University Health System, Singapore
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Wen Xie
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Zhongping Duan
- Artifical Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Sung-Jae Park
- Department of Gastroenterology and Hepatology, Inje University Busan Paik Hospital, Busan, Republic of Korea
| | - Madalinee Eternity Labio
- Section of Gastroenterology and Hepatology, Department of Medicine, Makati Medical Center, Makati, Philippines
| | - Rajneesh Kumar
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
| | - Young-Oh Kweon
- Division of Gastroenterology and Hepatology, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Hyung Joon Yim
- Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea
| | - Yu Tao
- R&D Projects Clinical Platforms and Sciences, GSK, Collegeville, PA, USA
| | | | - Robert Elston
- Hepatology GI Clinical Sciences, GSK, Hertfordshire, UK
| | | | | | - Kelong Han
- Clinical Pharmacology Modeling & Simulation, GSK, PA, USA
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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.
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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.
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Masaki Y, Akutsu N, Adachi Y, Ishigami K, Iwata N, Endo T, Ishii Y, Sasaki Y, Nagayama M, Kimura Y, Nakase H. Genomic analysis of an aggressive case with metastatic intrahepatic mucinous cholangiocarcinoma. Clin J Gastroenterol 2022; 15:809-817. [PMID: 35699889 DOI: 10.1007/s12328-022-01649-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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 05/22/2022] [Indexed: 12/09/2022]
Abstract
Intrahepatic mucinous cholangiocarcinoma (IHMC) is rare and behaves notoriously; however, the details of the clinicopathological characteristics of IHMC remain unknown. A 70-year-old man was admitted for examination of the hepatic mass in the S1 segment. He underwent extended left hepatic lobectomy. Histopathological evaluation demonstrated mixed papillary carcinoma that comprised well to moderately differentiated tubular adenocarcinoma and signet-ring cell carcinoma with large amounts of mucus lakes. Tumor was relapsed 9 months after surgery. Although he received chemotherapy with the combination of gemcitabine and cisplatin, he had renal failure and discontinued the chemotherapy. He received palliative radiotherapy for metastasis in the cervical spine. Then, the patient treated with S-1, however, he died 16 months after the initial diagnosis. The autopsy findings showed multiple nodules in the lungs, pleura, kidneys, adrenal glands, stomach, pancreas, and lymph nodes. Histological examination revealed that all nodules were IHMC. Next-generation sequencing revealed that somatic mutations in ADGRB3, TAF1L and EPHA3 may affect carcinogenesis, and those in TAF1, EPHA3, PIK3C2B, FN1, ERBB3, BRIP1, SYNE1 and TGFBR2 may affect metastasis. Molecular carcinogenesis of IHMC may be distinct from that of ordinary cholangiocarcinoma. Further studies are needed to elucidate the genetic mutations and their functions in IHMC.
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Affiliation(s)
- Yoshiharu Masaki
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuoku, Sapporo, Hokkaido, 060-8543, Japan.
| | - Noriyuki Akutsu
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuoku, Sapporo, Hokkaido, 060-8543, Japan
| | - Yasushi Adachi
- Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba-Dai Hospital, Sapporo, Japan
| | - Keisuike Ishigami
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuoku, Sapporo, Hokkaido, 060-8543, Japan
| | - Norikazu Iwata
- Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba-Dai Hospital, Sapporo, Japan
| | - Takao Endo
- Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba-Dai Hospital, Sapporo, Japan
| | - Yoshifumi Ishii
- Department of Pathology, Sapporo Shirakaba-Dai Hospital, Sapporo, Japan
| | - Yasushi Sasaki
- Department of Biology, Sapporo Medical University, Sapporo, Japan
| | - Minoru Nagayama
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Japan
| | - Yasutoshi Kimura
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuoku, Sapporo, Hokkaido, 060-8543, Japan
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2022; 28:276-331. [PMID: 35430783 PMCID: PMC9013624 DOI: 10.3350/cmh.2022.0084] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 01/10/2023] Open
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31
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Yuen MF, Wong DKH, Schluep T, Lai CL, Ferrari C, Locarnini S, Lo RCL, Gish RG, Hamilton J, Wooddell CI, Mak LY, Given BD. Long-term serological, virological and histological responses to RNA inhibition by ARC-520 in Chinese chronic hepatitis B patients on entecavir treatment. Gut 2022; 71:789-797. [PMID: 33712437 DOI: 10.1136/gutjnl-2020-323445] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 02/27/2021] [Accepted: 03/01/2021] [Indexed: 12/20/2022]
Abstract
OBJECTIVE We examined the serological, virological (in serum and liver) and histological profiles in chronic hepatitis B virus (HBV) patients during and after completion of multiple dose (MD) ARC-520. DESIGN The present phase 1b study was a multidose, open-label extension cohort of patients that had received single dose ARC-520 in our previous study. Eight patients received 4-9 4 weekly doses of MD ARC-520 and entecavir. Liver biopsies were performed in six patients. Intrahepatic and serum HBV DNA, HBV RNA and viral antigens were measured. RESULTS All patients had 28.9-30.4 months of follow-up after the last MD. All three hepatitis B e antigen (HBeAg)-positive patients had profound reductions in hepatitis B surface antigen (HBsAg), HBeAg, hepatitis B core-related antigen and HBV RNA with two undergoing HBeAg seroconversion. One further achieved HBsAg seroconversion (anti-HBs level of 25.1 IU/L) and the remaining two had HBsAg reductions of -1.7 and -3.5 log IU/mL >30 months after MD. Among the five HBeAg-negative patients, four had modest HBsAg reduction >29 months after completion of MD and one achieved HBsAg seroconversion (anti-HBs level of 152.5 IU/L) and was negative for liver HBsAg staining. Entecavir was successfully stopped in this patient 12 months after HBsAg seroconversion. Temporally related alanine aminotransferase elevations preceded by HBsAg reductions were observed in three patients suggesting immune activation. HBcAg staining was negative in all six biopsied patients. Two patients with <10% HBsAg positive staining of hepatocytes had correspondingly low serum HBsAg levels of 1.5 and 11.5 IU/mL. CONCLUSIONS MD ARC-520 therapy achieved sustained and profound reductions of viral antigens and HBV RNA. HBsAg seroclearance was achievable. TRIAL REGISTRATION NUMBER NCT02065336.
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Affiliation(s)
- Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Danny Ka-Ho Wong
- Department of Medicine, The University of Hong Kong, Hong Kong, China
| | | | - Ching-Lung Lai
- Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Carlo Ferrari
- Unit of Infectious Diseases and Hepatology, University of Parma, Parma, Italy
| | - Stephen Locarnini
- Victorian Infectious Diseases Reference Laboratory, Melbourne, Victoria, Australia
| | - Regina Cheuk-Lam Lo
- The University of Hong Kong, Hong Kong, Hong Kong.,Department of Pathology, The University of Hong Kong, Hong Kong, China
| | | | | | | | - Lung Yi Mak
- Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Bruce D Given
- Arrowhead Pharmaceuticals, Pasadena, California, USA
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32
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Costa APDM, da Silva MACN, Castro RS, Sampaio ALDO, Alencar Júnior AM, da Silva MC, Ferreira ADSP. PAGE-B and REACH-B Predicts the Risk of Developing Hepatocellular Carcinoma in Chronic Hepatitis B Patients from Northeast, Brazil. Viruses 2022; 14:v14040732. [PMID: 35458462 PMCID: PMC9033073 DOI: 10.3390/v14040732] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/25/2022] [Accepted: 03/29/2022] [Indexed: 12/14/2022] Open
Abstract
This study aims to evaluate the accuracy of the PAGE-B and REACH-B scores in predicting the risk of developing HCC in patients with chronic hepatitis B regularly followed up at a reference service in the State of Maranhão. A historical, longitudinal, retrospective cohort study, carried out from the review of medical records of patients with chronic Hepatitis B. PAGE-B and REACH-B scores were calculated and the accuracy of the scores in predicting the risk of HCC in the studied population was evaluated. A total of 978 patients were included, with a median age of around 47 years, most of them female and not cirrhotic. HCC was identified in 34 patients. Thrombocytopenia, high viral load, male gender and age were associated with the occurrence of HCC. The ROC curve for the PAGE-B score showed a value of 0.78 and for the REACH-B score of 0.79. The cutoff point for PAGE-B was 11 points for greater sensitivity and for REACH-B 7.5 points considering greater sensitivity and 9.5 points considering greater specificity. PAGE-B and REACH-B scores were able to predict the risk of developing HCC in the studied population. The use of risk stratification scores is useful to reduce costs associated with HCC screening.
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Affiliation(s)
- Alessandra Porto de Macedo Costa
- Center for Liver Studies, University Hospital of the Federal University of Maranhão, Saint Louis CEP 65020-070, MA, Brazil; (A.P.d.M.C.); (R.S.C.); (A.L.d.O.S.); (A.M.A.J.)
| | | | - Rogério Soares Castro
- Center for Liver Studies, University Hospital of the Federal University of Maranhão, Saint Louis CEP 65020-070, MA, Brazil; (A.P.d.M.C.); (R.S.C.); (A.L.d.O.S.); (A.M.A.J.)
| | - Ana Leatrice de Oliveira Sampaio
- Center for Liver Studies, University Hospital of the Federal University of Maranhão, Saint Louis CEP 65020-070, MA, Brazil; (A.P.d.M.C.); (R.S.C.); (A.L.d.O.S.); (A.M.A.J.)
| | - Antônio Machado Alencar Júnior
- Center for Liver Studies, University Hospital of the Federal University of Maranhão, Saint Louis CEP 65020-070, MA, Brazil; (A.P.d.M.C.); (R.S.C.); (A.L.d.O.S.); (A.M.A.J.)
| | - Márcia Costa da Silva
- Epidemiological Surveillance Service, State Health Department, Saint Louis CEP 65076-820, MA, Brazil;
| | - Adalgisa de Souza Paiva Ferreira
- Center for Liver Studies, University Hospital of the Federal University of Maranhão, Saint Louis CEP 65020-070, MA, Brazil; (A.P.d.M.C.); (R.S.C.); (A.L.d.O.S.); (A.M.A.J.)
- Correspondence: (M.A.C.N.d.S.); (A.d.S.P.F.)
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HBsAg Loss as a Treatment Endpoint for Chronic HBV Infection: HBV Cure. Viruses 2022; 14:v14040657. [PMID: 35458387 PMCID: PMC9029793 DOI: 10.3390/v14040657] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/01/2022] [Accepted: 03/10/2022] [Indexed: 02/07/2023] Open
Abstract
Despite the availability of effective vaccines and antiviral therapy over the past two to three decades, chronic hepatitis B virus (HBV) infection remains a major global health threat as a leading cause of cirrhosis and liver cancer. Functional HBV cure defined as hepatitis B surface antigen (HBsAg) loss and undetectable serum HBV DNA is associated with improved clinical outcomes in patients with chronic HBV infection. However, spontaneous loss of HBsAg is rare and occurs in only 1% of all HBsAg-positive individuals annually. Furthermore, the rate of functional cure with currently available antiviral therapy is even lower, <1% patients on treatment per year. Nonetheless, HBsAg loss has become the new target or therapeutic endpoint for antiviral treatment. Recently, there has been much excitement surrounding the development of novel antiviral agents such as small interfering RNA (siRNA), core assembly modulators (CAMs), nucleic acid polymers (NAPs) among others, which may be used in combination with nucleos(t)ide analogs and possibly immunomodulatory therapies to achieve functional cure in a significant proportion of patients with chronic hepatitis B. Novel assays with improved sensitivity for detection of very low levels of HBsAg and to determine the source of HBsAg production will also be required to measure efficacy of newer antiviral treatments for HBV cure. In this narrative review, we will define HBV cure, discuss various sources of HBsAg production, evaluate rates of HBsAg loss with current and future antiviral agents, review clinical factors associated with spontaneous HBsAg loss, and explore clinical implications of functional cure.
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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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35
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Cheng HY, Lin HC, Lin HL, Uang YS, Keller JJ, Wang LH. Association Between Nonselective Beta-Blocker Use and Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Without Cirrhosis and Decompensation. Front Pharmacol 2022; 12:805318. [PMID: 35069216 PMCID: PMC8777254 DOI: 10.3389/fphar.2021.805318] [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] [Received: 10/30/2021] [Accepted: 11/29/2021] [Indexed: 12/11/2022] Open
Abstract
Background: Nonselective beta-blockers (NSBBs) can reduce the incidence or mortality of certain types of cancers, and NSBBs exert a protective effect on hepatocellular carcinoma (HCC) in patients with cirrhosis. However, the potential preventive effect of NSBBs has not yet been investigated in patients with chronic hepatitis B (CHB) who have a high HCC risk regardless of the presence of underlying cirrhosis. Aim: This study evaluated the association between NSBB use and HCC incidence in patients with CHB without cirrhosis and decompensation. Methods: From the 2000 Longitudinal Generation Tracking Database, we enrolled patients who were newly diagnosed as having CHB from January 2001 to December 2011 and then followed them up for at least 5 years. To estimate the causal effect of NSBBs on the time-to-event outcomes of HCC, a marginal Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: After adjustment, no significant benefit of HCC risk reduction was observed between the NSBB users and nonusers (adjusted HR, 0.82; 95% CI, 0.52–1.31). The cumulative defined daily dose (cDDD) analysis revealed no significant dose correlation among the three groups [adjusted HR (95% CI): 1.08, (0.56–2.05), 0.54 (0.17–1.77), and 0.76 (0.40–1.42) in the <90 cDDD, 90 to <180 cDDD, and ≥180 cDDD groups, respectively]. Duration-dependent associations were not observed. Multivariable stratified analysis results demonstrated that HCC risk markedly decreased in the patients aged >55 years (adjusted HR, 0.49; 95% CI, 0.25–0.96; p = 0.04). Conclusion: NSBB did not significantly prevent HCC in the patients with CHB infection without cirrhosis and decompensation. This study provided one of valuable results that it is not clinically required to use NSBBs as recommended chemoprevention for HCC in high-risk patients who have CHB.
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Affiliation(s)
- He-Yun Cheng
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Hsiu C Lin
- Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Clinical Pathology, Taipei Medical University Hospital, Taipei, Taiwan
| | - Hsiu L Lin
- Department of Neurology, General Cathay Hospital, New Taipei City, Taiwan
| | - Yow S Uang
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Joseph J Keller
- College of Medicine, Ohio State University, Columbus, OH, United States
| | - Li H Wang
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.,Department of Pharmacy, Taipei Medical University Hospital, Taipei, Taiwan
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36
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Vittal A, Sharma D, Hu A, Majeed NA, Terry N, Auh S, Ghany MG. Systematic review with meta-analysis: the impact of functional cure on clinical outcomes in patients with chronic hepatitis B. Aliment Pharmacol Ther 2022; 55:8-25. [PMID: 34850415 DOI: 10.1111/apt.16659] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/17/2021] [Accepted: 10/06/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Although hepatitis B surface antigen (HBsAg) loss is considered the ideal therapeutic endpoint for the treatment of chronic hepatitis B virus (HBV) infection, its impact on clinical outcomes remains uncertain. AIM To assess the impact of HBsAg loss on clinical outcomes following spontaneous and treatment-related HBsAg loss. METHODS We searched PUBMED, Embase, the Cochrane library, and published abstracts through to May 2021 for studies that reported HBsAg loss, had >1 year of follow-up and reported at least one clinical outcome in adults with chronic HBV infection. RESULTS We identified 57 studies (258 744 HBsAg-positive patients, 63 270 with HBsAg loss). Based on 24 studies including 160 598 patients with and without HBsAg loss, HBsAg loss was associated with a non-significant 23% relative risk reduction of developing hepatocellular carcinoma (HCC) compared to those who remained HBsAg-positive (RR = 0.77; 95% CI: 0.38-1.57). In subgroup meta-analysis of 10 studies, treatment-related HBsAg loss was associated with a non-significant higher pooled proportion of HCC (0.94%) compared to spontaneous HBsAg loss (0.45%). HCC development after HBsAg loss was significantly higher in males, those with underlying cirrhosis, and those with a family history of HCC. HBsAg loss was associated with lower pooled proportions of incident cirrhosis, hepatic decompensation, overall and liver-related mortality compared to no HBsAg loss. Substantial heterogeneity was noted across studies for all outcomes. CONCLUSION HBsAg loss is associated with a reduced risk of clinical outcomes. However, several shortcomings in the published studies prevent a more definitive conclusion on the potential benefits of HBsAg loss.
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Affiliation(s)
- Anusha Vittal
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Disha Sharma
- Department of Internal Medicine, Medstar Washington Hospital Center, Washington DC, USA
| | - Alvin Hu
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Nehna A Majeed
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Nancy Terry
- Division of Library Services, National Institutes of Health Library, National Institutes of Health, Bethesda, Maryland, USA
| | - Sungyoung Auh
- Biostatistics Program, Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Marc G Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
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37
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Wu S, Zeng N, Sun F, Zhou J, Wu X, Sun Y, Wang B, Zhan S, Kong Y, Jia J, You H, Yang HI. Hepatocellular Carcinoma Prediction Models in Chronic Hepatitis B: A Systematic Review of 14 Models and External Validation. Clin Gastroenterol Hepatol 2021; 19:2499-2513. [PMID: 33667678 DOI: 10.1016/j.cgh.2021.02.040] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 02/25/2021] [Accepted: 02/26/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The aim of our study was to characterize the performance of hepatocellular carcinoma (HCC) prediction models in chronic hepatitis B (CHB) patients through meta-analysis followed by external validation. METHODS We performed a systematic review and meta-analysis of current literature, followed by external validation in independent multi-center cohort with 986 patients with CHB undergoing entecavir treatment (median follow-up: 4.7 years). Model performance to predict HCC within 3, 5, 7, and 10 years was assessed using area under receiver operating characteristic curve (AUROC) and calibration index. Subgroup analysis were conducted by treatment status, cirrhotic, race and baseline alanine aminotransferase. RESULTS We identified 14 models with 123,885 patients (5,452 HCC cases), with REACH-B, CU-HCC, GAG-HCC, PAGE-B and mPAGE-B models being broadly externally validated. Discrimination was generally acceptable for all models, with pooled AUC ranging from 0.70 (95% CI, 0.63-0.76 for REACH-B) to 0.83 (95% CI, 0.78-0.87 for REAL-B) for 3-year, 0.68 (95% CI, 0.64-0.73 for REACH-B) to 0.81 (95% CI, 0.77-0.85 for REAL-B) for 5-year and 0.70 (95% CI, 0.58-0.80 for PAGE-B) to 0.81 (95% CI, 0.78-0.84 for REAL-B and 0.77-0.86 for AASL-HCC) for 10-year prediction. However, calibration performance was poorly reported in most studies. In external validation cohort, REAL-B showed highest discrimination with 0.76 (95% CI, 0.69-0.83) and 0.75 (95% CI, 0.70-0.81) for 3 and 5-year prediction. The REAL-B model was also well calibrated in the external validation cohort (3-year Brier score 0.066). Results were consistent in subgroup analyses. CONCLUSIONS In a systematic review of available HCC models, the REAL-B model exhibited best discrimination and calibration.
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Affiliation(s)
- Shanshan Wu
- National Clinical Research Center of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland China
| | - Na Zeng
- National Clinical Research Center of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland China
| | - Feng Sun
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, Mainland China
| | - Jialing Zhou
- Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland China
| | - Xiaoning Wu
- Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland China
| | - Yameng Sun
- Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland China
| | - Bingqiong Wang
- Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland China
| | - Siyan Zhan
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, Mainland China
| | - Yuanyuan Kong
- National Clinical Research Center of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland China
| | - Jidong Jia
- National Clinical Research Center of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland China; Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland China
| | - Hong You
- National Clinical Research Center of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland China; Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland China.
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Ferrando-Martinez S, Snell Bennett A, Lino E, Gehring AJ, Feld J, Janssen HLA, Robbins SH. Functional Exhaustion of HBV-Specific CD8 T Cells Impedes PD-L1 Blockade Efficacy in Chronic HBV Infection. Front Immunol 2021; 12:648420. [PMID: 34589081 PMCID: PMC8473828 DOI: 10.3389/fimmu.2021.648420] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 08/24/2021] [Indexed: 01/12/2023] Open
Abstract
Background A functional cure for chronic HBV could be achieved by boosting HBV-specific immunity. In vitro studies show that immunotherapy could be an effective strategy. However, these studies include strategies to enrich HBV-specific CD8 T cells, which could alter the expression of the anti-PD-1/anti-PD-L1 antibody targets. Our aim was to determine the efficacy of PD-L1 blockade ex vivo. Methods HBV-specific CD8 T cells were characterized ex vivo by flow cytometry for the simultaneous analysis of six immune populations and 14 activating and inhibitory receptors. Ex vivo functionality was quantified by ELISpot and by combining peptide pool stimulation, dextramers and intracellular flow cytometry staining. Results The functionality of HBV-specific CD8 T cells is associated with a higher frequency of cells with low exhaustion phenotype (LAG3-TIM3-PD-1+), independently of the clinical parameters. The accumulation of HBV-specific CD8 T cells with a functionally exhausted phenotype (LAG3+TIM3+PD-1+) is associated with lack of ex vivo functionality. PD-L1 blockade enhanced the HBV-specific CD8 T cell response only in patients with lower exhaustion levels, while response to PD-L1 blockade was abrogated in patients with higher frequencies of exhausted HBV-specific CD8 T cells. Conclusion Higher levels of functionally exhausted HBV-specific CD8 T cells are associated with a lack of response that cannot be restored by blocking the PD-1:PD-L1 axis. This suggests that the clinical effectiveness of blocking the PD-1:PD-L1 axis as a monotherapy may be restricted. Combination strategies, potentially including the combination of anti-LAG-3 with other anti-iR antibodies, will likely be required to elicit a functional cure for patients with high levels of functionally exhausted HBV-specific CD8 T cells.
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Affiliation(s)
- Sara Ferrando-Martinez
- Microbial Sciences, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
| | - Angie Snell Bennett
- Microbial Sciences, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
| | - Elisabete Lino
- Microbial Sciences, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
| | - Adam J Gehring
- Toronto Center for Liver Disease, Toronto General Hospital, University Health Network, Toronto, ON, Canada.,Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Jordan Feld
- Toronto Center for Liver Disease, Toronto General Hospital, University Health Network, Toronto, ON, Canada
| | - Harry L A Janssen
- Toronto Center for Liver Disease, Toronto General Hospital, University Health Network, Toronto, ON, Canada
| | - Scott H Robbins
- Late Stage Oncology Development, Oncology R&D, AstraZeneca, Gaithersburg, MD, United States
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Lou T, Li B, Xiong P, Jin C, Chen Y. External validation of hepatocellular carcinoma risk scores in patients with chronic hepatitis B virus infection in China. J Viral Hepat 2021; 28:1373-1380. [PMID: 34218498 DOI: 10.1111/jvh.13569] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/18/2021] [Accepted: 06/19/2021] [Indexed: 02/06/2023]
Abstract
Several scores have been proposed in untreated or treated patients with chronic hepatitis B (CHB) to predict risks of hepatocellular carcinoma (HCC) occurrence. However, it is still unclear which score suits all chronic hepatitis B virus (HBV)-infected patients well, regardless of whether they are chronic carriers or CHB patients. In this study, we validated and compared the predictability of CU-HCC, REACH-B, PAGE-B and mPAGE-B in patients with chronic HBV infection in China. 1,786 patients with no history of HCC were recruited, with 978 carriers and 808 CHB patients on antiviral therapy. Patients were classified into low- and high-risk groups according to the predefined cut-off values of 5, 8, 10 and 9 for CU-HCC, REACH-B, PAGE-B and mPAGE-B. The median follow-up period was 43.7months, during which 18 (1.0%) patients developed HCC. The areas under the receiver operating characteristic curves (AUROCs) of CU-HCC, REACH-B, PAGE-B and mPAGE-B scores to predict HCC risk at 36 months were 0.815, 0.703, 0.794 and 0.825, respectively (all p < 0.05). No significant difference among AUROCs of these scores was observed except those of mPAGE-B and REACH-B at 36 months. The cumulative incidence of HCC in low- and high- risk groups based on CU-HCC, REACH-B, PAGE-B and mPAGE-B were 0.4% vs. 3.2%, 0.7% vs. 1.5%, 0.2% vs. 1.3%, and 0.2% vs. 1.7% at 36 months, respectively (all p < 0.05, except PAGE-B, log-rant test). Both CU-HCC and mPAGE-B scores accurately predict HCC risk in Chinese chronic HBV-infected patients. Patients with CU-HCC <5 or mPAGE-B <9 could be exempt from HCC surveillance within 36 months.
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Affiliation(s)
- Tao Lou
- Department of Infectious Diseases, The Fourth Affiliated Hospital Zhejiang University School of Medicine, Yiwu, Zhejiang Province, China
| | - Bin Li
- Department of Infectious Diseases, The Fourth Affiliated Hospital Zhejiang University School of Medicine, Yiwu, Zhejiang Province, China
| | - Pian Xiong
- Department of Infectious Diseases, The Fourth Affiliated Hospital Zhejiang University School of Medicine, Yiwu, Zhejiang Province, China
| | - Caiting Jin
- Department of Infectious Diseases, The Fourth Affiliated Hospital Zhejiang University School of Medicine, Yiwu, Zhejiang Province, China
| | - Yagang Chen
- Department of Infectious Diseases, The Fourth Affiliated Hospital Zhejiang University School of Medicine, Yiwu, Zhejiang Province, China
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40
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Khoo T, Lam D, Olynyk JK. Impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes of liver disease. World J Gastroenterol 2021; 27:4831-4845. [PMID: 34447229 PMCID: PMC8371504 DOI: 10.3748/wjg.v27.i29.4831] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/14/2021] [Accepted: 07/21/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic infections with the hepatitis B and C viruses have significant worldwide health and economic impacts. Previous treatments for hepatitis C such as interferon and ribavirin therapy were ineffective and poorly tolerated by patients. The introduction of directly acting curative antiviral therapy for hepatitis C and the wider use of nucleos(t)ide analogues for suppression of chronic Hepatitis B infection have resulted in many positive developments. Decreasing the prevalence of hepatitis B and C have concurrently reduced transmission rates and hence, the number of new infections. Antiviral treatments have decreased the rates of liver decompensation and as a result, lowered hospitalisation and mortality rates for both chronic hepatitis B and C infection. The quality of life of chronically infected patients has also been improved significantly by modern treatment. Antiviral therapy has stopped the progression of liver disease to cirrhosis in certain patient cohorts and prevented ongoing hepatocellular damage in patients with existing cirrhosis. Longer term benefits of antiviral therapy include a reduced risk of developing hepatocellular carcinoma and decreased number of patients requiring liver transplantation. This review article assesses the literature and summarises the impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes from liver disease.
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Affiliation(s)
- Tiffany Khoo
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch 6150, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
| | - Danielle Lam
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch 6150, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
| | - John K Olynyk
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch 6150, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
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41
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Cost-effectiveness analysis of first-line treatment for chronic hepatitis B in China. Clin Microbiol Infect 2021; 28:300.e1-300.e8. [PMID: 34197929 DOI: 10.1016/j.cmi.2021.06.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 06/07/2021] [Accepted: 06/12/2021] [Indexed: 11/21/2022]
Abstract
OBJECTIVES Hepatitis B virus infection is an important public health problem. We analysed the cost-effectiveness of the first-line therapies, including nucleotide analogues (namely tenofovir alafenamide fumarate (TAF), tenofovir disoproxil fumarate (TDF) and entecavir) and pegylated interferon (Peg-IFN) for patients with chronic hepatitis B (CHB) in China. METHODS A Markov model describing CHB disease progression was constructed to compare the cost-effectiveness of the first-line therapies, considering both satisfactory (HBeAg seroconversion) and optimal (HBsAg seroclearance) treatment goals. We examined the main outcomes, including cumulative lifetime cost per patient, incremental quality-adjusted life years (QALYs), incremental cost-effectiveness ratio and net monetary benefit. Uncertainty analysis was conducted to identify key influential parameters. RESULTS Compared with the baseline strategy, Peg-IFN had the highest QALY gain for HBeAg-positive (HBeAg+) CHB patients achieving a satisfactory goal and an optimal goal (3.19 and 6.32 respectively), and TDF was the most cost-effective therapy for HBeAg-negative CHB patients ($1418/QALY) achieving a satisfactory goal. Among nucleotide analogues, TAF was the most-effective strategy and had higher acceptability to achieve an optimal goal in the Eastern region of China (under 1 x GDP per capita threshold). CONCLUSIONS Among nucleotide analogues, TDF was the most cost-effective treatment in China for CHB patients to achieve satisfactory and optimal treatment goals, whereas TAF was cost-effective and more effective in the wealthier region. Peg-IFN was most cost-effective among HBeAg+ CHB patients to achieve both goals, with better clinical outcomes. Our findings also indicate the importance of regular monitoring during and after CHB treatment, and could inform treatment strategies in China and other countries.
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Mak LY, Seto WK, Yuen MF. Novel Antivirals in Clinical Development for Chronic Hepatitis B Infection. Viruses 2021; 13:1169. [PMID: 34207458 PMCID: PMC8235765 DOI: 10.3390/v13061169] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/06/2021] [Accepted: 06/15/2021] [Indexed: 02/07/2023] Open
Abstract
Globally, chronic hepatitis B (CHB) infection is one of the leading causes of liver failure, decompensated cirrhosis, and hepatocellular carcinoma. Existing antiviral therapy can suppress viral replication but not fully eradicate the virus nor the risk of liver-related complications. Novel treatments targeting alternative steps of the viral cycle or to intensify/restore the host's immunity are being developed. We discuss novel drugs that have already entered clinical phases of development. Agents that interfere with specific steps of HBV replication include RNA interference, core protein allosteric modulation, and inhibition of viral entry or viral protein excretion (NAPs and STOPS). Agents that target the host's immunity include toll-like receptor agonists, therapeutic vaccines, immune checkpoint modulators, soluble T-cell receptors, and monoclonal antibodies. Most have demonstrated favorable results in suppression of viral proteins and genomic materials (i.e., HBV DNA and/or pre-genomic RNA), and/or evidence on host-immunity restoration including cytokine responses and T-cell activation. Given the abundant clinical experience and real-world safety data with the currently existing therapy, any novel agent for CHB should be accompanied by convincing safety data. Combination therapy of nucleos(t)ide analogue, a novel virus-directing agent, and/or an immunomodulatory agent will be the likely approach to optimize the chance of a functional cure in CHB.
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Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam Road 102, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Wai-Kay Seto
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam Road 102, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam Road 102, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
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Liu Y, Veeraraghavan V, Pinkerton M, Fu J, Douglas MW, George J, Tu T. Viral Biomarkers for Hepatitis B Virus-Related Hepatocellular Carcinoma Occurrence and Recurrence. Front Microbiol 2021; 12:665201. [PMID: 34194408 PMCID: PMC8236856 DOI: 10.3389/fmicb.2021.665201] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 05/06/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the fourth leading cause of cancer-related death. The most common risk factor for developing HCC is chronic infection with hepatitis B virus (HBV). Early stages of HBV-related HCC (HBV-HCC) are generally asymptomatic. Moreover, while serum alpha-fetoprotein (AFP) and abdominal ultrasound are widely used to screen for HCC, they have poor sensitivity. Thus, HBV-HCC is frequently diagnosed at an advanced stage, in which there are limited treatment options and high mortality rates. Serum biomarkers with high sensitivity and specificity are crucial for earlier diagnosis of HCC and improving survival rates. As viral-host interactions are key determinants of pathogenesis, viral biomarkers may add greater diagnostic power for HCC than host biomarkers alone. In this review, we summarize recent research on using virus-derived biomarkers for predicting HCC occurrence and recurrence; including circulating viral DNA, RNA transcripts, and viral proteins. Combining these viral biomarkers with AFP and abdominal ultrasound could improve sensitivity and specificity of early diagnosis, increasing the survival of patients with HBV-HCC. In the future, as the mechanisms that drive HBV-HCC to become clearer, new biomarkers may be identified which can further improve early diagnosis of HBV-HCC.
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Affiliation(s)
- Yuanyuan Liu
- Department of Infectious Diseases, The Affiliated Xi'an Central Hospital of Xi'an Jiaotong University, Xi'an, China.,Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia
| | - Vaishnavi Veeraraghavan
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia.,School of Medical Science, The University of Sydney, Camperdown, NSW, Australia
| | - Monica Pinkerton
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia.,School of Medical Science, The University of Sydney, Camperdown, NSW, Australia
| | - Jianjun Fu
- Department of Infectious Diseases, The Affiliated Xi'an Central Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Mark W Douglas
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia.,Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, NSW, Australia.,Centre for Infectious Diseases and Microbiology, Westmead Hospital, Sydney, NSW, Australia
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia
| | - Thomas Tu
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia.,Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, NSW, Australia
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44
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Choi J, Yoo S, Lim YS. Comparison of Long-Term Clinical Outcomes Between Spontaneous and Therapy-Induced HBsAg Seroclearance. Hepatology 2021; 73:2155-2166. [PMID: 33131063 DOI: 10.1002/hep.31610] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/19/2020] [Accepted: 10/04/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS HBsAg seroclearance is considered a realistic goal in patients with chronic hepatitis B (CHB), known as "functional cure." However, it remains elusive whether nucleos(t)ide analogue (NUC)-induced HBsAg seroclearance, compared with spontaneous HBsAg seroclearance, differs in its association with favorable long-term clinical outcomes. APPROACH AND RESULTS A total of 1,972 CHB patients with confirmed HBsAg seroclearance at least two consecutive times, 6 months apart, were retrospectively analyzed. Risks of HCC development and composite clinical events, including HCC, liver-related death, and liver transplantation, were compared between spontaneous and NUC-induced HBsAg seroclearance. Of 1,972 patients, mean patient age was 53.7 years, and 64.4% were men. Cirrhosis was present in 297 (15.1%) patients. HBsAg seroclearance was achieved spontaneously in 1,624 (82.4%) patients and by NUC treatment in 348 (17.6%). HCC developed in 49 patients, with an annual incidence of 0.38 of 100 person-years (PY) during a median follow-up of 5.6 years. With 336 propensity-score-matched pairs, risks of HCC (P = 0.52) and clinical events (P = 0.14) were not significantly different between NUC-induced and spontaneous HBsAg seroclearance. By multivariable analysis, NUC-induced HBsAg seroclearance, compared with spontaneous HBsAg seroclearance, was not associated with the significantly higher risk of HCC (adjusted HR [AHR], 1.49; P = 0.26) and clinical events (AHR, 1.78; P = 0.06). CONCLUSIONS Risks of HCC and clinical events were not significantly different between spontaneous and NUC-induced HBsAg seroclearance. Nonetheless, annual risk of HCC exceeds the recommended cutoff for HCC surveillance even after HBsAg seroclearance, suggesting that continued HCC surveillance is required.
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Affiliation(s)
- Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sun Yoo
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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45
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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.
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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
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Wooddell CI, Gehring AJ, Yuen MF, Given BD. RNA Interference Therapy for Chronic Hepatitis B Predicts the Importance of Addressing Viral Integration When Developing Novel Cure Strategies. Viruses 2021; 13:v13040581. [PMID: 33808298 PMCID: PMC8065501 DOI: 10.3390/v13040581] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 03/26/2021] [Accepted: 03/29/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B infection remains a globally important cause of morbidity and mortality and has recently undergone a renaissance in therapeutic interest with increased pre-clinical and clinical testing of new drug classes. One of the first new classes in the clinic was RNA interference agents, which have the potential to impact the entire viral life cycle by reducing all virus-produced mRNA. Early clinical testing with the first of these agents in the clinic, ARC-520, demonstrated that rapid and deep reductions in viral proteins, RNA and DNA could be produced with this approach, but also the surprising insight that HBsAg production from incomplete HBV DNA integrated into the host genome appears to play a heretofore unappreciated and important role in maintaining circulating HBsAg, thought to play a fundamental role in preventing host clearance of the virus. Thus, accounting for viral DNA integration in novel HBV treatment approaches may prove to be essential to achieving successful finite therapies of this difficult to treat chronic infection.
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Affiliation(s)
- Christine I. Wooddell
- Arrowhead Pharmaceuticals, 502 South Rosa Road, Madison, WI 53719, USA;
- Correspondence: ; Tel.: +1-608-316-3930
| | - Adam J. Gehring
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada;
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China;
| | - Bruce D. Given
- Arrowhead Pharmaceuticals, 502 South Rosa Road, Madison, WI 53719, USA;
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Association Between Seroclearance of Hepatitis B Surface Antigen and Long-term Clinical Outcomes of Patients With Chronic Hepatitis B Virus Infection: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2021; 19:463-472. [PMID: 32473348 DOI: 10.1016/j.cgh.2020.05.041] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 05/11/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Seroclearance of hepatitis B surface antigen (HBsAg) is the desired end point of treatment for chronic hepatitis B virus (HBV) infection, according to guidelines. We performed a systematic review and meta-analysis to evaluate the strength of the association between HBsAg seroclearance and long-term clinical outcomes. METHODS We performed a systematic review of the PubMed, EMBASE, and Cochrane Library databases for articles that assessed HBsAg status and reported the incidence of hepatocellular carcinoma (HCC), liver decompensation, liver transplantation, and/or all-cause mortality during follow-up evaluation. We performed a meta-analysis of rate ratios (RR) using a random-effects model independently for each end point and for a composite end point. RESULTS We analyzed data from 28 studies, comprising a total of 188,316 patients with chronic HBV infection (treated and untreated), and 1,486,081 person-years (PY) of follow-up evaluation; 26 reported data on HCC, 7 on liver decompensation, and 13 on liver transplantation and/or death. The composite event rates were 0.19/1000 PY for the HBsAg seroclearance group and 2.45/1000 PY for the HBsAg-persistent group. Pooled RRs for the HBsAg seroclearance group were 0.28 for liver decompensation (95% CI, 0.13-0.59; P = .001), 0.30 for HCC (95% CI, 0.20-0.44; P < .001), 0.22 for liver transplantation and/or death (95% CI, 0.13-0.39; P < .001), and 0.31 for the composite end point (95% CI, 0.23-0.43; P < .001). No differences in RR estimates were observed among subgroups of different study or patient characteristics. CONCLUSIONS In a systematic review and meta-analysis, we found seroclearance of HBsAg to be associated significantly with improved patient outcomes. The results are consistent among different types of studies, in all patient subpopulations examined, and support the use of HBsAg seroclearance as a primary end point of trials of patients with chronic HBV infection.
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48
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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.
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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
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Mak LY, Yuen MF. Novel Therapy for Functional Cure of Chronic Hepatitis B Virus Infection. HEPATITIS B VIRUS AND LIVER DISEASE 2021:455-473. [DOI: 10.1007/978-981-16-3615-8_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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50
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Yip TCF, Wong VWS, Tse YK, Liang LY, Hui VWK, Zhang X, Li GL, Lui GCY, Chan HLY, Wong GLH. Similarly low risk of hepatocellular carcinoma after either spontaneous or nucleos(t)ide analogue-induced hepatitis B surface antigen loss. Aliment Pharmacol Ther 2021; 53:321-331. [PMID: 33222272 DOI: 10.1111/apt.16174] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 10/28/2020] [Accepted: 11/04/2020] [Indexed: 12/09/2022]
Abstract
BACKGROUND It is unknown whether patients with chronic hepatitis B (CHB) who achieved hepatitis B surface antigen (HBsAg) seroclearance spontaneously or following anti-viral therapy have similar clinical outcomes. AIM To compare the risk of hepatocellular carcinoma (HCC) in patients with CHB who either cleared HBsAg spontaneously or following anti-viral therapy METHODS: Adult CHB-monoinfected patients who cleared HBsAg between January 2000 and March 2019 were identified from a territory-wide database in Hong Kong. Patients with liver transplantation and/or HCC before HBsAg loss were excluded. Patients' demographics, comorbidities, anti-viral treatment, laboratory parameters and HCC development were analysed. RESULTS Of 7,124 identified patients with CHB who cleared HBsAg, mean age was 58.1 ± 13.8 years; 4,340 (60.9%) were male; 451 (6.3%) had cirrhosis; 5,917 (83.1%) and 1,207 (16.9%) had spontaneous and nucleos(t)ide analogue (NA)-induced HBsAg seroclearance, respectively. Most patients had normal liver function at HBsAg loss. Patients with NA-induced HBsAg seroclearance were younger, and more likely to be male and cirrhotic than patients with spontaneous HBsAg loss. At a median (interquartile range) follow-up of 4.3 (2.2-7.6) years, 97 (1.6%) and 16 (1.3%) patients with spontaneous and NA-induced HBsAg loss developed HCC, respectively. Patients who achieved NA-induced HBsAg loss had comparable HCC risk as those with spontaneous HBsAg loss (adjusted subdistribution hazard ratio 0.75, 95% CI 0.43-1.32, P = 0.323). The results remained robust in propensity score weighting and matching analyses. CONCLUSION The HCC risk was similarly low after either spontaneous or NA-induced HBsAg seroclearance in a territory-wide cohort of patients with CHB who had cleared HBsAg.
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Affiliation(s)
- Terry Cheuk-Fung Yip
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
- Medical Data Analytic Centre (MDAC), The Chinese University of Hong Kong, Hong Kong SAR, China
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
- Medical Data Analytic Centre (MDAC), The Chinese University of Hong Kong, Hong Kong SAR, China
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yee-Kit Tse
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
- Medical Data Analytic Centre (MDAC), The Chinese University of Hong Kong, Hong Kong SAR, China
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Lilian Yan Liang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Vicki Wing-Ki Hui
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Xinrong Zhang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Guan-Lin Li
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Grace Chung-Yan Lui
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
- Medical Data Analytic Centre (MDAC), The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Henry Lik-Yuen Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
- Medical Data Analytic Centre (MDAC), The Chinese University of Hong Kong, Hong Kong SAR, China
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
- Medical Data Analytic Centre (MDAC), The Chinese University of Hong Kong, Hong Kong SAR, China
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
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