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1
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Tonon M, Gagliardi R, Zeni N, Piano S. Recompensation of cirrhosis in candidates of transplant: Tips and tricks for delisting. Liver Transpl 2024; 30:1181-1187. [PMID: 38926937 DOI: 10.1097/lvt.0000000000000409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 05/16/2024] [Indexed: 06/28/2024]
Abstract
Liver transplantation (LT) is the most successful treatment for patients with decompensated cirrhosis. The availability of effective and safe etiological treatments has altered the natural history of decompensated cirrhosis. Recently, the concept of recompensation has been defined. Patients who achieve recompensation may be removed from the waiting list for LT. Therefore, achieving an etiological cure is the cornerstone in the treatment of patients with decompensated cirrhosis. However, most patients improve their liver function after an etiologic cure, and only a proportion of patients achieve true recompensation after an etiological cure. Some patients maintain a condition of "MELD purgatory," that is, an improvement in the Model for End-Stage Liver Disease score without relevant clinical improvement that prevents delisting and may be even detrimental because lower Model for End-Stage Liver Disease score delays LT. Herein, we review the available evidence regarding recompensation and the management of recompensated patients on the waiting list for LT.
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Affiliation(s)
- Marta Tonon
- Unit of Internal Medicine and Hepatology, Department of Medicine-DIMED, University and Hospital of Padova, Padova, Italy
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2
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Sometani E, Hikita H, Murai K, Toyoda H, Tanaka S, Oze T, Sung J, Shimoda A, Fukuoka M, Shigeno S, Fukutomi K, Shirai K, Tahata Y, Saito Y, Nishio A, Furuta K, Kodama T, Sakamori R, Tatsumi T, Mita E, Umezawa A, Tanaka Y, Takehara T. High serum growth differentiation factor 15 is a risk factor for the occurrence of hepatocellular carcinoma in chronic hepatitis B patients treated with nucleos(t)ide analogs. Hepatol Res 2024. [PMID: 39291388 DOI: 10.1111/hepr.14111] [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: 02/20/2024] [Revised: 08/06/2024] [Accepted: 08/26/2024] [Indexed: 09/19/2024]
Abstract
AIM Patients with chronic hepatitis B (CHB) remain at risk for hepatocellular carcinoma (HCC) even with nucleos(t)ide analog therapy. We evaluated risk factors for HCC development, including serum hepatitis B virus (HBV) RNA, hepatitis B core-related antigen level, and growth differentiation factor 15 (GDF15) level, a predictor of HCC development in patients with chronic hepatitis C. METHODS We collected clinical data and stored serum from CHB patients without a history of HCC who were receiving nucleos(t)ide analog treatment for more than 1 year and whose HBV DNA level was less than 3.0 log IU/mL. We measured the serum levels of HBV RNA and GDF15. RESULTS Among 242 CHB patients, 57 had detectable HBV RNA, and GDF15 was quantified in all patients. The median GDF15 level was 0.86 ng/mL. Cox proportional hazards analysis revealed that male sex and higher GDF15, FIB-4 index, alpha-fetoprotein and gamma-glutamyl transpeptidase were independent risk factors for HCC. The presence of HBV RNA above the lower limit of quantification was not a risk factor. When we set cutoff values based on the Youden index, the cumulative incidence of HCC was significantly higher in the male, AFP ≥3.0 ng/mL, gamma-glutamyl transpeptidase ≥22 U/L, FIB-4 index ≥1.93, and GDF-15 ≥1.17 ng/mL groups. In patients with no or more than three of these five risk factors, the 10-year HCC cumulative incidence rates were 0% and 41.0%, respectively. CONCLUSIONS High serum GDF15 is an independent risk factor for the occurrence of HCC in CHB patients treated with nucleos(t)ide analogs.
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Affiliation(s)
- Emi Sometani
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kazuhiro Murai
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Satoshi Tanaka
- Department of Gastroenterology and Hepatology, NHO Osaka National Hospital, Osaka, Japan
| | - Tsugiko Oze
- Department of Gastroenterology and Hepatology, Koga Community Hospital, Yaizu, Japan
| | - Jihyun Sung
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Akiyoshi Shimoda
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Makoto Fukuoka
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Satoshi Shigeno
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Keisuke Fukutomi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kumiko Shirai
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yuki Tahata
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yoshinobu Saito
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Akira Nishio
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kunimaro Furuta
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, NHO Osaka National Hospital, Osaka, Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Eiji Mita
- Department of Gastroenterology and Hepatology, NHO Osaka National Hospital, Osaka, Japan
| | - Akihiro Umezawa
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Tokyo, Japan
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Kumamoto University, Graduate School of Medical Sciences, Kumamoto, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
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3
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Chinese consensus on the management of liver cirrhosis. J Dig Dis 2024; 25:332-352. [PMID: 39044465 DOI: 10.1111/1751-2980.13294] [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: 04/19/2024] [Revised: 05/19/2024] [Accepted: 06/11/2024] [Indexed: 07/25/2024]
Abstract
Liver cirrhosis, characterized by diffuse necrosis, insufficient regeneration of hepatocytes, angiogenesis, severe fibrosis, and the formation of pseudolobules, is a progressive, chronic liver disease induced by a variety of causes. It is clinically characterized by liver function damage and portal hypertension, and many complications may occur in its late stage. Based on the updated practice guidelines, expert consensuses, and research advances on the diagnosis and treatment of cirrhosis, the Chinese Society of Gastroenterology of Chinese Medical Association established the current consensus to standardize the clinical diagnosis and management of liver cirrhosis and guide clinical practice. This consensus contains 43 statements on the etiology, pathology and pathogenesis, clinical manifestations, major complications, diagnosis, treatment, prognosis, and chronic disease control of liver cirrhosis. Since several practice guidelines and expert consensuses on the complications of liver cirrhosis have been published, this consensus emphasizes the research progress of liver cirrhosis itself.
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Seong MS, Jang JA, Jeong YR, Kim YB, Kyaw YY, Kong HJ, Lee JH, Cheong J. Fibroblast Growth Factor 11 Inhibits Hepatitis B Virus Gene Expression Through FXRα Suppression. J Microbiol 2023; 61:693-702. [PMID: 37646922 PMCID: PMC10477102 DOI: 10.1007/s12275-023-00065-1] [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: 01/26/2023] [Revised: 06/29/2023] [Accepted: 07/06/2023] [Indexed: 09/01/2023]
Abstract
Fibroblast growth factor 11 (FGF11) is a member of the intracellular FGF family, which shows different signal transmission compared with other FGF superfamily members. The molecular function of FGF11 is not clearly understood. In this study, we identified the inhibitory effect of FGF11 on hepatitis B virus (HBV) gene expression through transcriptional suppression. FGF11 decreased the mRNA and protein expression of HBV genes in liver cells. While the nuclear receptor FXRα1 increased HBV promoter transactivation, FGF11 decreased the FXRα-mediated gene induction of the HBV promoter by the FXRα agonist. Reduced endogenous levels of FXRα by siRNA and the dominant negative mutant protein (aa 1-187 without ligand binding domain) of FXRα expression indicated that HBV gene suppression by FGF11 is dependent on FXRα inhibition. In addition, FGF11 interacts with FXRα protein and reduces FXRα protein stability. These results indicate that FGF11 inhibits HBV replicative expression through the liver cell-specific transcription factor, FXRα, and suppresses HBV promoter activity. Our findings may contribute to the establishment of better regimens for the treatment of chronic HBV infections by including FGF11 to alter the bile acid mediated FXR pathway.
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Affiliation(s)
- Mi So Seong
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Jeong Ah Jang
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Ye Rim Jeong
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Ye Bin Kim
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Yi Yi Kyaw
- Advanced Molecular Research Centre, Department of Medical Research, Republic of Union of Myanmar, Yangon, 11191, Myanmar
| | - Hee Jeong Kong
- Biotechnology Research Division, National Institute of Fisheries Science, Busan, 46083, Republic of Korea
| | - Jung-Hyun Lee
- Marine Biotechnology Research Center, Korea Institute of Ocean Science and Technology, Busan, 49111, Republic of Korea
| | - JaeHun Cheong
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea.
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5
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Wang P, Wang X, Liu X, Yan F, Yan H, Zhou D, Yu L, Wang X, Yang Z. Primary non-response to antiviral therapy affects the prognosis of hepatitis B virus-related hepatocellular carcinoma. BMC Cancer 2023; 23:564. [PMID: 37340357 PMCID: PMC10280839 DOI: 10.1186/s12885-023-11059-y] [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: 12/02/2022] [Accepted: 06/12/2023] [Indexed: 06/22/2023] Open
Abstract
BACKGROUND AND AIM Although antiviral treatments have been shown to affect the recurrence and long-term survival of patients with hepatocellular carcinoma (HCC) who have high viral loads, the effect of different responses to antiviral therapy on the clinical outcomes remains unclear. This study aimed to assess the effect of primary non-response (no-PR) to antiviral therapy on the survival or prognosis of patients with HCC with a high load of hepatitis B virus (HBV) DNA. METHODS A total of 493 HBV-HCC patients hospitalized at Beijing Ditan Hospital of Capital Medical University were admitted to this retrospective study. Patients were divided into two groups based on viral response (no-PR and primary response). Kaplan-Meier (KM) curves were used to compare the overall survival of the two cohorts. Serum viral load comparison and subgroup analysis were performed. Additionally, risk factors were screened and the risk score chart was created. RESULTS This study consisted of 101 patients with no-PR and 392 patients with primary response. In the different categories based on hepatitis B e antigen and HBV DNA, no-PR group had a poor 1-year overall survival (OS). In addition, in the alanine aminotransferase < 50 IU/L and cirrhosis groups, primary nonresponse was related to poor overall survival and progression-free survival. Based on multivariate risk analysis, primary non-response (hazard ratio (HR) = 1.883, 95% CI 1.289-2.751, P = 0.001), tumor multiplicity (HR = 1.488, 95% CI 1.036-2.136, P = 0.031), portal vein tumor thrombus (HR = 2.732, 95% CI 1.859-4.015, P < 0.001), hemoglobin < 120 g/L (HR = 2.211, 95% CI 1.548-3.158, P < 0.001) and tumor size ≥ 5 cm (HR = 2.202, 95% CI 1.533-3.163, P < 0.001) were independent risk factors for 1-year OS. According to the scoring chart, patients were divided into three risk groups (high-, medium-, and low-risk groups) with mortality rates of 61.7%, 30.5%, and 14.1%, respectively. CONCLUSIONS The level of viral decline at 3 months post-antiviral treatment may predict the OS of patients with HBV-related HCC, and primary non-response may shorten the median survival time of patients with high HBV-DNA levels.
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Affiliation(s)
- Peng Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Xinhui Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Xiaoli Liu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Fengna Yan
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Huiwen Yan
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Dongdong Zhou
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Lihua Yu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Xianbo Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Zhiyun Yang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China.
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6
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The Baveno VII concept of cirrhosis recompensation. Dig Liver Dis 2023; 55:431-441. [PMID: 36646527 DOI: 10.1016/j.dld.2022.12.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 12/02/2022] [Accepted: 12/18/2022] [Indexed: 01/18/2023]
Abstract
Traditionally, the progression from compensated to decompensated cirrhosis has been regarded as a point of no return in the natural history of the disease. However, this point of view is increasingly being challenged by new evidence on disease regression and hepatic recompensation upon suppression/cure of the underlying aetiology. In order to create a uniform definition of recompensated cirrhosis, standardised criteria have been set out by the Baveno VII consensus, which include the removal of the primary aetiological factor, the resolution of any decompensating events and a sustained improvement in hepatic function. Initial insights into the concept of hepatic recompensation come from previous studies, which have demonstrated that a cure/suppression of the underlying aetiology in patients with prior decompensation leads to significant clinical improvements and favourable outcomes and can even enable the delisting of transplant candidates. Nevertheless, future studies are required to shed light on the natural history of hepatic recompensation, assess modifying factors and potential non-invasive biomarkers of recompensation and explore the molecular mechanisms of disease regression.
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7
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Davidov Y, Abu Baker F, Israel A, Ben Ari Z. Real-world hepatitis B antiviral treatment trends and adherence to practice guidelines: a large cohort study. Acta Clin Belg 2022:1-7. [PMID: 36448668 DOI: 10.1080/17843286.2022.2152566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Affiliation(s)
- Yana Davidov
- Liver Diseases Center, Sheba Medical Center, Tel Aviv, Israel
| | - Fadi Abu Baker
- Department of Gastroenterology and Hepatology, Hillel Yaffe Medical Center, Hadera, Israel
- Technion Faculty of Medicine, Haifa, Israel
| | - Ariel Israel
- Leumit Research Institute & Department of Family Medicine, Leumit Health Services, Israel
| | - Ziv Ben Ari
- Liver Diseases Center, Sheba Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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8
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Xu X, Wu C, Jiang L, Peng C, Pan L, Zhang X, Shen W, Chen L, Lou Z, Xu K, Li L, Dong Y, Ruan B. Cost-Effectiveness of Hepatitis B Mass Screening and Management in High-Prevalent Rural China: A Model Study From 2020 to 2049. Int J Health Policy Manag 2022; 11:2115-2123. [PMID: 34664496 PMCID: PMC9808295 DOI: 10.34172/ijhpm.2021.126] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 09/04/2021] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Chronic hepatitis B (CHB) is highly prevalent among adults in rural China and better management of those populations is of vital importance for viral hepatitis elimination. Adult immunization has been the subject of much controversy in previous studies. This study estimates the cost-effectiveness of population-based hepatitis B screening, treatment, and immunization strategy (comprehensive strategy) in rural areas with high prevalence under the national policy of sharp-drop drug prices. METHODS We constructed a Markov model comparing 4 strategies in a 30-year horizon from the healthcare payer perspective: (1) the conventional pattern; (2) screening and treating infected (treatment); (3) screening and immunizing susceptible individuals (immunization); and (4) the comprehensive strategy. Screening intensity ranged from 50% to 100%. Outcomes were measured by costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and clinical outcomes. RESULTS The costs for the conventional pattern, treatment strategy, immunization strategy, and comprehensive strategy were US$ 341, 351, 318, and 323, respectively. In addition, effects were 17.45, 17.57, 17.46, and 17.58 QALYs, respectively. The ICER of the comprehensive strategy was US$ 35/QALY gained at 50% screening intensity and 420 US$/QALY gained at 100%. The net monetary benefit increased with increasing screening intensity and declined after 90%, with the highest value of US$40 693. All new infections and 52.5% mortality could be avoided from 2020 to 2049 if all patients were properly treated and all susceptible individuals were immunized. The results were stable within a wide range of parameters. CONCLUSION It was cost-effective to implement the mass hepatitis B screening, treatment, and immunization strategy in areas of rural China with high prevalence, and the strategy gained the most net monetary benefit at a screening intensity of 90%. Although it was impractical to fulfill 100% coverage, efforts should be made to obtain more people screened.
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Affiliation(s)
- Xiaolan Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Chensi Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lushun Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Chunting Peng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Liya Pan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xue Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Wei Shen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lin Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhuoqi Lou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Kaijin Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yin Dong
- People’s Hospital Medical Community of Yuhuan County, Taizhou, China
| | - Bing Ruan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Noverati N, Bashir-Hamidu R, Halegoua-DeMarzio D, Hann HW. Hepatitis B Virus-Associated Hepatocellular Carcinoma and Chronic Stress. Int J Mol Sci 2022; 23:ijms23073917. [PMID: 35409275 PMCID: PMC8999024 DOI: 10.3390/ijms23073917] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 01/27/2023] Open
Abstract
The Hepatitis B virus is one of the most significant hepatocarcinogens globally. The carcinogenic mechanisms of this virus are complex, and may include interactions with the host’s immune system. Certain factors, such as stress on the body, can also potentiate these mechanisms. Stress, although adaptive in an acute form, is deleterious to health when chronic and can both suppress and activate the host’s defense system. In hepatocellular carcinoma, this can lead to tumor initiation and progression. Those that are more prone to stress, or exposed to situations that incite stress, may be at higher risk of developing cancer. Racial disparities, for example, are a source of chronic psychosocial stress in America and predispose minorities to poorer outcomes. As it remains perplexing why some individuals with chronic hepatitis B develop feared complications while others do not, it is important to recognize as many risk factors as possible, including those often overlooked such as chronic stress.
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Affiliation(s)
- Nicholas Noverati
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.N.); (R.B.-H.); (D.H.-D.)
| | - Rukaiya Bashir-Hamidu
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.N.); (R.B.-H.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.N.); (R.B.-H.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Hie-Won Hann
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.N.); (R.B.-H.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
- Correspondence:
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10
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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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11
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Wang X, Liu X, Wang P, Yu L, Yan F, Yan H, Zhou D, Yang Z. Antiviral Therapy Reduces Mortality in Hepatocellular Carcinoma Patients with Low-Level Hepatitis B Viremia. J Hepatocell Carcinoma 2021; 8:1253-1267. [PMID: 34708007 PMCID: PMC8544274 DOI: 10.2147/jhc.s330301] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 10/04/2021] [Indexed: 12/14/2022] Open
Abstract
Background and Aims Although antiviral treatment has been shown to reduce mortality in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients with high HBV-DNA levels, it is still unclear whether it is useful in reducing mortality in patients with low HBV-DNA levels. Methods A retrospective analysis of 756 HBV-associated HCC patients at the Beijing Ditan Hospital with HBV-DNA levels < 500 IU/mL was conducted between January 2008 and June 2017. Patients were divided into antiviral and non-antiviral groups based on whether they received nucleos(t)ide analogue (NA) treatment when they were diagnosed with HCC in our hospital for the first time. We used 1:4 frequency matching by age, gender, tumor size, Barcelona Clinic Liver Cancer (BCLC) staging, anti-tumor therapy, cirrhosis, diabetes, and hyperlipoidemia to compare the antiviral (n = 366) and non-antiviral (n = 100) groups. A Cox multivariate regression analysis was employed to evaluate the effects of NA therapy on the hazard ratio (HR), and the Kaplan–Meier survival curve was used to determine the mortality risk in patients with HCC. A Log rank test was performed to analyze the effects of NA therapy on the survival rate of patients with HCC. Results After propensity score matching, the 1-, 3-, and 5-year overall survival (OS) rates for the antiviral and non-antiviral groups were 82.5%, 68.6%, and 52.2%, and 61.0%, 51.0%, and 38.0%, respectively. The l-year progression-free survival (PFS) rates for the two groups were 68.0% and 47.0%, respectively. The OS of the antiviral group was significantly higher than that of the control group (P < 0.001, P = 0.001, and P = 0.013, respectively). The 1-year PFS for the antiviral group was also significantly better than that for the non-antiviral groups (P = 0.005). After adjusting for confounding prognostic factors in the Cox model, the HR of 5-year death after antiviral treatment was 0.721 (95% confidence interval [CI], 0.530–0.980, P = 0.037). Antiviral therapy is an independent protective factor for 5-year mortality in patients with HCC and low-level viremia. Conclusion Antiviral therapy significantly reduced mortality in HCC patients with low HBV-DNA levels.
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Affiliation(s)
- Xinhui Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Xiaoli Liu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Peng Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Lihua Yu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Fengna Yan
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Huiwen Yan
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Dongdong Zhou
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
| | - Zhiyun Yang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China
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12
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Su TH, Peng CY, Chang SH, Tseng TC, Liu CJ, Chen CL, Liu CH, Yang HC, Chen PJ, Kao JH. Serum PIVKA-II and alpha-fetoprotein at virological remission predicts hepatocellular carcinoma in chronic hepatitis B related cirrhosis. J Formos Med Assoc 2021; 121:703-711. [PMID: 34452785 DOI: 10.1016/j.jfma.2021.08.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 07/18/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The risk of hepatocellular carcinoma (HCC) is reduced but not eliminated after nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB). We aimed to investigate the role of serum Prothrombin Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) and alpha-fetoprotein in predicting HCC and mortality in cirrhotic CHB patients at virological remission (VR) following NA therapy. METHODS Patients with CHB-related cirrhosis undergoing NA therapy from two medical centers in Taiwan were retrospectively included. Serum PIVKA-II were quantified by an automated chemiluminescence assay. Multivariable Cox proportional hazards regression models were used to identify predictors for HCC and death. Serial on-treatment PIVKA-II levels after VR were investigated. RESULTS Overall, 293 CHB-related cirrhosis patients were included. At VR, the mean age was 55, and the mean PIVKA-II level was 35 mAU/mL. After a mean follow-up of 78 months, 76 patients developed HCC and 19 died. After adjustment for confounding factors, alpha-fetoprotein >7 ng/mL (hazard ratio [HR]: 2.84, 95% confidence interval [CI]: 1.73-4.67) and PIVKA-II >50 mAU/mL (HR: 2.46, 95%CI: 1.35-4.49) at VR significantly predicted HCC development. In patients with alpha-fetoprotein ≤10 ng/mL or ≤20 ng/mL at VR, PIVKA-II >50 mAU/mL increased 2.45 or 3.16-fold risk of HCC, respectively. PIVKA-II levels after VR increased serially in patients who developed HCC afterwards. CONCLUSIONS In patients with CHB-related cirrhosis, serum alpha-fetoprotein >7 ng/mL and PIVKA-II >50 mAU/mL at the time of antiviral therapy-induced VR is associated with a greater risk of HCC. PIVKA-II is a predictive marker for HCC in patients with low normal alpha-fetoprotein level.
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Affiliation(s)
- Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Cheng-Yuan Peng
- School of Medicine, China Medical University, Taichung, Taiwan; Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Shan-Han Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan
| | - Tai-Chung Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - 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
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chen-Hua Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-Chih Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan; Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
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13
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Bashir Hamidu R, Chalikonda DM, Hann HW. Gender Disparity in Host Responses to Hepatitis B-Related Hepatocellular Carcinoma: A Case Series. Vaccines (Basel) 2021; 9:vaccines9080838. [PMID: 34451963 PMCID: PMC8402514 DOI: 10.3390/vaccines9080838] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/25/2021] [Accepted: 07/26/2021] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is one of the most common causes of hepatocellular carcinoma (HCC), a malignant tumor with high mortality worldwide. One remarkable clinical feature of HBV-related HCC is that the risk of development is higher in males and postmenopausal females compared to other females. Increasing evidence also indicates that the prognosis of HBV-associated HCC may involve gender disparity, with females having more favorable outcomes. The proposed mechanism of this gender disparity is thought to be complex and multifactorial. Attributions have been made to gender differences in behavioral risk factors, host stress, immune response, psychology, metabolic risk factors, tumor biology, and hormonal factors. Gender disparities in hormonal factors and stress with consequent incited inflammation and hepatocarcinogenesis in HBV-related HCC is a particularly burgeoning area of investigation. Clarifying these mechanisms could provide insight into HBV-related HCC pathogenesis, and potentially provide a target for prevention and treatment of this disease. Reported herein is a case series involving two families affected by vertically transmitted chronic hepatitis B, longitudinally observed over multiple decades, with family members demonstrating discordant outcomes related to HCC, with worse outcomes among affected males. As a supplement to this case, we review the currently available literature on gender differences in outcomes from HBV-related HCC. In reporting this case series, we aim to add our important observation to the current literature and highlight the need for further research in the mechanisms involved in gender disparity in the prognosis of HBV-related HCC.
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Affiliation(s)
- Rukaiya Bashir Hamidu
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA;
| | - Divya M. Chalikonda
- Department of Medicine, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA;
| | - Hie-Won Hann
- Liver Disease Prevention Center, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
- Correspondence:
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14
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Abd El Aziz MA, Sacco R, Facciorusso A. Nucleos(t)ide analogues and Hepatitis B virus-related hepatocellular carcinoma: A literature review. Antivir Chem Chemother 2021; 28:2040206620921331. [PMID: 32418480 PMCID: PMC7232045 DOI: 10.1177/2040206620921331] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Hepatitis B virus is mainly considered to cause hepatocellular carcinoma which is
the fourth leading cause of cancer-related mortality worldwide. Treatment of
Hepatitis B virus with nucleos(t)ide analogues can decrease the progression of
the disease and subsequently decreases the incidence of hepatocellular
carcinoma. In this review, we have discussed the different classes of
nucleos(t)ide analogues used in the treatment of Hepatitis B virus and their
relationship with the development of hepatocellular carcinoma. Furthermore, we
discussed the effect of treatment of Hepatitis B virus with Nucleoside analogues
(NAs) before, during and after surgery, chemoembolization, radiofrequency
ablation, and chemotherapy for the treatment of hepatocellular carcinoma.
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Affiliation(s)
| | - Rodolfo Sacco
- Department of Medical Sciences, Section of Gastroenterology, University of Foggia, Foggia Italy
| | - Antonio Facciorusso
- Department of Medical Sciences, Section of Gastroenterology, University of Foggia, Foggia Italy
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15
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Prifti GM, Moianos D, Giannakopoulou E, Pardali V, Tavis JE, Zoidis G. Recent Advances in Hepatitis B Treatment. Pharmaceuticals (Basel) 2021; 14:417. [PMID: 34062711 PMCID: PMC8147224 DOI: 10.3390/ph14050417] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 01/10/2023] Open
Abstract
Hepatitis B virus infection affects over 250 million chronic carriers, causing more than 800,000 deaths annually, although a safe and effective vaccine is available. Currently used antiviral agents, pegylated interferon and nucleos(t)ide analogues, have major drawbacks and fail to completely eradicate the virus from infected cells. Thus, achieving a "functional cure" of the infection remains a real challenge. Recent findings concerning the viral replication cycle have led to development of novel therapeutic approaches including viral entry inhibitors, epigenetic control of cccDNA, immune modulators, RNA interference techniques, ribonuclease H inhibitors, and capsid assembly modulators. Promising preclinical results have been obtained, and the leading molecules under development have entered clinical evaluation. This review summarizes the key steps of the HBV life cycle, examines the currently approved anti-HBV drugs, and analyzes novel HBV treatment regimens.
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Affiliation(s)
- Georgia-Myrto Prifti
- Department of Pharmacy, Division of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece; (G.-M.P.); (D.M.); (E.G.); (V.P.)
| | - Dimitrios Moianos
- Department of Pharmacy, Division of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece; (G.-M.P.); (D.M.); (E.G.); (V.P.)
| | - Erofili Giannakopoulou
- Department of Pharmacy, Division of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece; (G.-M.P.); (D.M.); (E.G.); (V.P.)
| | - Vasiliki Pardali
- Department of Pharmacy, Division of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece; (G.-M.P.); (D.M.); (E.G.); (V.P.)
| | - John E. Tavis
- Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, MO 63104, USA;
| | - Grigoris Zoidis
- Department of Pharmacy, Division of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece; (G.-M.P.); (D.M.); (E.G.); (V.P.)
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16
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Kumada T, Toyoda H, Yasuda S, Miyake N, Ito T, Tanaka J. Long-term prognosis with or without nucleot(s)ide analogue therapy in hepatitis B virus-related decompensated cirrhosis. J Viral Hepat 2021; 28:508-516. [PMID: 33306854 DOI: 10.1111/jvh.13457] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/04/2020] [Accepted: 11/22/2020] [Indexed: 12/14/2022]
Abstract
The development of nuleos(t)ide analogues (NAs) has dramatically changed the natural history of chronic hepatitis B virus (HBV) infection. In this study, we compared patients with HBV-related decompensated cirrhosis with and without NA therapy in terms of hepatocarcinogenesis and all-cause, liver-related, and non-liver-related mortality. This study enrolled 160 patients with decompensated cirrhosis, 78 of whom were treated with NA therapy (NA group) and 82 of whom were not (non-NA group). Propensity score matching and inverse probability weighting were performed to adjust the baseline characteristics in the NA and non-NA groups. Liver-related and non-liver-related mortality were analysed using the competing risks IPW cumulative incidence functions estimator. The Cox proportional hazards model and the Fine and Gray proportional hazards model were used to analyse factors associated with hepatocarcinogenesis and all-cause, liver-related, and non-liver-related mortality. HBV DNA ≥20,000 IU/ml (adjusted hazard ratio [aHR], 8.440) and dyslipidemia (aHR, 0.178) were independently associated with hepatocarcinogenesis. HBV DNA ≥20,000 IU/ml (aHR, 4.360) and non-NA group (aHR, 4.802) were independently associated with all-cause mortality. Diabetes mellitus (aHR, 4.925), FIB-4 score >3.6 (aHR, 4.151), non-NA group (aHR, 9.180), presence of dyslipidemia (aHR, 0.182) and male gender (aHR, 3.045) were independently associated with liver-related mortality. HBV DNA ≥20,000 IU/ml (aHR, 3.216) and high age (aHR, 2.692) were independently associated with non-liver-related mortality. Although the cumulative incidence rate of hepatocarcinogenesis and non-liver-related mortality was not reduced by NA therapy, viral suppression reduced liver-related mortality in patients with DC.
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Affiliation(s)
- Takashi Kumada
- Department of Nursing, Faculty of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Nozomi Miyake
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Junko Tanaka
- Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan
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17
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Block PD, Shinn B, Kim JH, Hann HW. Hepatitis B-related hepatocellular carcinoma and stress: untangling the host immune response from clinical outcomes. Hepat Oncol 2020; 8:HEP35. [PMID: 33680431 PMCID: PMC7907965 DOI: 10.2217/hep-2020-0028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 12/01/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major public health challenge on the global scale. Affecting hundreds of millions worldwide, HBV is a leading risk factor for hepatocellular carcinoma (HCC). Clinical outcomes from chronic HBV infection are varied and appear to be influenced by a complex and dysregulated host immune response. In turn, much attention has been given to the immunologic response to HBV in an effort to identify host factors that lead to the development of HCC. However, the role of nonimmunologic host factors, such as chronic stress, in HBV-related HCC is poorly defined. Indeed, a growing appreciation for the effects of stress on chronic liver diseases raises the question of its role in chronic HBV infection. In this light, the present review will untangle the roles of key host factors in HBV-related HCC with an emphasis on chronic stress as a viable contributor. First discussed is the interplay of stress, inflammation and chronic liver disease. The host immune response's role as a driver of HBV-related HCC is then reviewed, allowing for a close exploration of the effects of stress on immune function in chronic hepatitis B and as a potential risk factor for HBV-related HCC.
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Affiliation(s)
- Peter D Block
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Brianna Shinn
- Department of Gastroenterology & Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Jin Hyang Kim
- Bristol-Myers Squibb, 3401 Princeton Pike, Lawrenceville, NJ 08648, USA
| | - Hie-Won Hann
- Department of Gastroenterology & Hepatology, Liver Disease Prevention Center, Philadelphia, PA 19107, USA
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18
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Li S, Saviano A, Erstad DJ, Hoshida Y, Fuchs BC, Baumert T, Tanabe KK. Risk Factors, Pathogenesis, and Strategies for Hepatocellular Carcinoma Prevention: Emphasis on Secondary Prevention and Its Translational Challenges. J Clin Med 2020; 9:E3817. [PMID: 33255794 PMCID: PMC7760293 DOI: 10.3390/jcm9123817] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 11/11/2020] [Accepted: 11/17/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality globally. Given the limited therapeutic efficacy in advanced HCC, prevention of HCC carcinogenesis could serve as an effective strategy. Patients with chronic fibrosis due to viral or metabolic etiologies are at a high risk of developing HCC. Primary prevention seeks to eliminate cancer predisposing risk factors while tertiary prevention aims to prevent HCC recurrence. Secondary prevention targets patients with baseline chronic liver disease. Various epidemiological and experimental studies have identified candidates for secondary prevention-both etiology-specific and generic prevention strategies-including statins, aspirin, and anti-diabetic drugs. The introduction of multi-cell based omics analysis along with better characterization of the hepatic microenvironment will further facilitate the identification of targets for prevention. In this review, we will summarize HCC risk factors, pathogenesis, and discuss strategies of HCC prevention. We will focus on secondary prevention and also discuss current challenges in translating experimental work into clinical practice.
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Affiliation(s)
- Shen Li
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA; (S.L.); (D.J.E.); (B.C.F.)
| | - Antonio Saviano
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, 67000 Strasbourg, France;
| | - Derek J. Erstad
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA; (S.L.); (D.J.E.); (B.C.F.)
| | - Yujin Hoshida
- Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Department of Internal Medicine, Dallas, TX 75390, USA;
| | - Bryan C. Fuchs
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA; (S.L.); (D.J.E.); (B.C.F.)
| | - Thomas Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, 67000 Strasbourg, France;
| | - Kenneth K. Tanabe
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA; (S.L.); (D.J.E.); (B.C.F.)
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19
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Lee SB, Jeong J, Park JH, Jung SW, Jeong ID, Bang SJ, Shin JW, Park BR, Park EJ, Park NH. Low-level viremia and cirrhotic complications in patients with chronic hepatitis B according to adherence to entecavir. Clin Mol Hepatol 2020; 26:364-375. [PMID: 32466635 PMCID: PMC7364359 DOI: 10.3350/cmh.2020.0012] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 04/09/2020] [Indexed: 02/06/2023] Open
Abstract
Background/Aims Low-level viremia (LLV) after nucleos(t)ide analog treatment was presented as a possible cause of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). However, detailed information on patients’ adherence in the real world was lacking. This study aimed to evaluate the effects of LLV on HCC development, mortality, and cirrhotic complications among patients according to their adherence to entecavir (ETV) treatment. Methods We performed a retrospective observational analysis of data from 894 consecutive adult patients with treatment-naïve CHB undergoing ETV treatment. LLV was defined according to either persistent or intermittent episodes of <2,000 IU/mL detectable hepatitis B virus DNA during the follow-up period. Good adherence to medication was defined as a cumulative adherence ≥90% per study period. Results Without considering adherence in the entire cohort (n=894), multivariate analysis of the HCC incidence showed that LLV was an independent prognostic factor in addition to other traditional risk factors in the entire cohort (P=0.031). Good adherence group comprised 617 patients (69.0%). No significant difference was found between maintained virologic response and LLV groups in terms of the incidence of liver-related death or transplantation, HCC, and hepatic decompensation in good adherence group, according to multivariate analyses. Conclusions In patients with treatment-naïve CHB and good adherence to ETV treatment in the real world, LLV during treatment is not a predictive factor for HCC and cirrhotic complications. It may be unnecessary to adjust their antiviral agent for patients with good adherence who experience LLV during ETV treatment.
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Affiliation(s)
- Seung Bum Lee
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Joonho Jeong
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Jae Ho Park
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Seok Won Jung
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - In Du Jeong
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Sung-Jo Bang
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Jung Woo Shin
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Bo Ryung Park
- Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Eun Ji Park
- Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Neung Hwa Park
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.,Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
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20
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Woo HY, Park JY, Bae SH, Kim CW, Jang JY, Tak WY, Kim DJ, Kim IH, Heo J, Ahn SH. Entecavir+tenofovir vs. lamivudine/telbivudine+adefovir in chronic hepatitis B patients with prior suboptimal response. Clin Mol Hepatol 2020; 26:352-363. [PMID: 32460460 PMCID: PMC7364362 DOI: 10.3350/cmh.2019.0044n] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 04/07/2020] [Indexed: 12/12/2022] Open
Abstract
Background/Aims Suboptimal responses to lamivudine or telbivudine plus adefovir (LAM/LdT+ADV) rescue therapy are common in patients with LAM-resistant hepatitis B virus (HBV) infections. We compared patients switched to entecavir plus tenofovir (ETV+TDF) to those maintained on LAM/LdT+ADV. Methods This prospective randomized controlled trial examined 91 patients whose serum HBV DNA levels were greater than 60 IU/mL after at least 24 weeks of treatment with LAM/LdT+ADV for LAM-resistant HBV. Patients were randomized to receive a new treatment (ETV+TDF, n=45) or maintained on the same treatment (LAM/LdT+ADV, n=46) for 48 weeks. Patients with baseline ADV resistance were excluded. Results Compared to LAM/LdT+ADV group, ETV+TDF group had more patients with a virologic response (42/45 [93.33%] vs. 3/46 [6.52%], P<0.001) and had a greater mean reduction in serum HBV DNA level from baseline (-4.16 vs. -0.37 log10 IU/mL, P<0.001). Multivariate analysis indicated that high baseline HBV DNA level (P=0.005) and LAM/LdT+ADV maintenance therapy (P=0.001) were negatively associated with virologic response. At week 48, additional ADV- or ETV-associated mutations were cleared in ETV+TDF group, but such mutations were present in 4.3% of patients in LAM/LdT+ADV group (P=0.106). The two groups had similar rates of adverse events. Conclusions ETV+TDF combination treatment led to a significantly higher rate of virologic response compared to LAM/LdT+ADV combination treatment in patients with LAM-resistant HBV who had suboptimal responses to LAM/LdT+ADV regardless of HBV genotypic resistance profile (NCT01597934).
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Affiliation(s)
- Hyun Young Woo
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea.,Medical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Si Hyun Bae
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chang Wook Kim
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jae Young Jang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Won Young Tak
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea.,Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Korea
| | - In Hee Kim
- Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University College of Medicine, Chonju, Korea
| | - Jeong Heo
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Korea.,Medical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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21
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Lee HW. [Long Term Efficacy of Antiviral Therapy: Mortality and Incidence of Hepatocellular Carcinoma]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2020; 74:251-257. [PMID: 31765553 DOI: 10.4166/kjg.2019.74.5.251] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 11/14/2019] [Accepted: 11/15/2019] [Indexed: 01/27/2023]
Abstract
Multiple studies have shown that oral antiviral therapies reduced the incidence of hepatocellular carcinoma (HCC) and improved the survival of patients with chronic hepatitis B when compared with that of untreated patients. In particular, entecavir and tenofovir share the qualities of high efficacy in reducing the HBV DNA levels, and they have excellent tolerability and safety. These drugs modified the natural history of liver fibrosis, improve liver function, decrease the incidence of HCC, decrease the need for liver transplantation, and improve survival. Many studies have suggested that long-term antiviral therapy reduces the risk of HCC and liver cirrhosis in patients with chronic hepatitis. The mechanism of these drugs in reducing the risk of HCC is not clear. This article reviews the mechanisms of carcinogenic HBV by conducting a review of the literature on the efficacy of therapy for reducing the risk of HCC. A few recent articles have suggested that tenofovir offers advantages over entecavir in terms of HCC prevention, but these articles have the inherent limitations of observational data. No other head-to-head randomized trials exist. Further randomized studies would help provide stronger evidence of the association between the type of antiviral agent and the HCC outcomes. Only achieving complete viral eradication from the liver will truly decrease the mortality and incidence of HCC.
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Affiliation(s)
- Hyun Woong Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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22
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Association of virological breakthrough and clinical outcomes in entecavir-treated HBeAg-positive chronic hepatitis B. PLoS One 2019; 14:e0221958. [PMID: 31469875 PMCID: PMC6716625 DOI: 10.1371/journal.pone.0221958] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 08/19/2019] [Indexed: 12/15/2022] Open
Abstract
Background & aims To evaluate virological breakthrough (VBT) and the risk of hepatocellular carcinoma (HCC) in HBeAg-positive chronic hepatitis B (CHB) patients receiving entecavir (ETV) treatment. Methods A retrospective cohort study was conducted in a tertiary referral hospital and a total of 228 HBeAg-positive CHB patients treated with ETV for more than 48 weeks were enrolled. Clinical outcome measures included HBeAg seroclearance, maintained virological response and the development of HCC. Results During a median follow-up period of 197 weeks, VBT developed in 26 (11.4%) patients (VBT group), and the other 202 patients without VBT (non-VBT group). The overall cumulative rate of HBeAg seroclearance in the VBT group and non-VBT group were 23.1% and 23.8%, 27.1% and 37.9%, 27.1% and 55.1%, 27.1% and 74.1%, 27.1% and 76.7% from week 48 to 240, respectively(p = 0.013). The cumulative probability of maintained virological responses from week 48 to 240 were 7.69% and 21.78%, 7.69% in the VBT groups and 36.85%, 7.69% and 51.68%, 7.69% and 64.97%, 7.69% and 72.1% in the non-VBT groups, respectively (p<0.001). In the multivariate analysis, age (p<0.001) and virological response at week 24 (p = 0.005) were independently associated with VBT. Cox regression analysis showed that cirrhosis had carried the highest risk for HCC (HR = 4.99, CI = 1.14–21.81, p = 0.033). Subgroup survival analysis by Kaplan–Meier method showed that patients with VBT had higher incidence of developing HCC than without VBT in cirrhotic patients (50% (95%CI = 1–99%) vs 9% (95% CI = 1–9%); p = 0.048). Conclusions VBT was associated with adverse clinical outcomes, including a low probability of HBeAg seroclearance, failure to achieve maintained virological responses, and a risk of developing HCC. Patients, particularly with cirrhosis, who had experienced VBT during ETV treatment, more likely developed HCC.
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23
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Kim MN, Hwang SG, Kim BK, Park JY, Kim DY, Han KH, Kim SU, Ahn SH. Liver Cirrhosis, Not Antiviral Therapy, Predicts Clinical Outcome in Cohorts with Heterogeneous Hepatitis B Viral Status. Gut Liver 2019; 13:197-205. [PMID: 30602075 PMCID: PMC6430437 DOI: 10.5009/gnl18204] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 08/23/2018] [Accepted: 08/24/2018] [Indexed: 12/16/2022] Open
Abstract
Background/Aims Antiviral therapy (AVT) reduces the risk of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B (CHB). This multicenter retrospective study investigated the effects of AVT and hepatitis B virus (HBV)-related factors on the risk of HCC development in a cohort with heterogeneous HBV status. Methods A total of 1,843 patients with CHB from two institutions were included in this study. Ultrasound and laboratory tests, including the α-fetoprotein test, were conducted regularly to detect HCC development. Results The mean age of our study population (1,063 men and 780 women) was 49.4 years. Cirrhosis was identified in 617 patients (33.5%). During follow-up (median, 42.5 months), 81 patients developed HCC (1.39% per person-year). A total of 645 patients (35.0%) received ongoing AVT at enrollment. Ongoing AVT was not significantly associated with the risk of HCC development (all p>0.05). HBV-related variables (HBV DNA level, hepatitis B e antigen status, and alanine aminotransferase level) were also not significantly associated with the risk of HCC development (all p>0.05). In contrast, cirrhosis was significantly associated with the risk of HCC development, regardless of adjustment (adjusted hazard ratio=4.098 to 7.020; all p<0.05). Cirrhosis significantly predicted the risk of HCC development in subgroups with and without ongoing AVT at enrollment, regardless of adjustment. Conclusions Our study showed that cirrhosis, not AVT and HBV-related variables, was associated with HCC development in a cohort of patients with heterogeneous HBV status. Our results may help clinicians apply individualized surveillance strategies according to fibrotic status in patients with CHB.
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Affiliation(s)
- Mi Na Kim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Seong Gyu Hwang
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Up 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
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24
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Shinn BJ, Martin A, Coben RM, Conn MI, Prieto J, Kroop H, DiMarino AJ, Hann HW. Persistent risk for new, subsequent new and recurrent hepatocellular carcinoma despite successful anti-hepatitis B virus therapy and tumor ablation: The need for hepatitis B virus cure. World J Hepatol 2019; 11:65-73. [PMID: 30705719 PMCID: PMC6354125 DOI: 10.4254/wjh.v11.i1.65] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 11/14/2018] [Accepted: 01/01/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) is one of the most significant hepatocarcinogens. The ultimate goal of anti-HBV treatment is to prevent the development of hepatocellular carcinoma (HCC). During the last two decades, with the use of currently available anti-HBV therapies (lamivudine, entecavir and tenofovir disoproxil fumatate), there has been a decrease in the incidence of HBV-associated HCC (HBV-HCC). Furthermore, several studies have demonstrated a reduction in recurrent or new HCC development after initial HCC tumor ablation. However, during an observation period spanning 10 to 20 years, several case reports have demonstrated the development of new, subsequent new and recurrent HCC even in patients with undetectable serum HBV DNA. The persistent risk for HCC is attributed to the presence of covalently closed circular DNA (cccDNA) in the hepatocyte nucleus which continues to work as a template for HBV replication. While a functional cure (loss of hepatitis B surface antigen and undetectable viral DNA) can be attained with nucleos(t)ide analogues, these therapies do not eliminate cccDNA. Of utmost importance is successful eradication of the transcriptionally active HBV cccDNA from hepatocyte nuclei which would be considered a complete cure. The unpredictable nature of HCC development in patients with chronic HBV infection shows the need for a complete cure. Continued support and encouragement for research efforts aimed at developing curative therapies is imperative. The aims of this minireview are to highlight these observations and emphasize the need for a cure for HBV.
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Affiliation(s)
- Brianna J Shinn
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
| | - Aaron Martin
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
| | - Robert M Coben
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
| | - Mitchell I Conn
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
| | - Jorge Prieto
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
| | - Howard Kroop
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
| | - Anthony J DiMarino
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
| | - Hie-Won Hann
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
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25
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Kim HS, Baatarkhuu O, Lee HW, Park JY, Kim DY, Ahn SH, Song K, Han KH, Kim BK, Kim SU. Fibrosis-matched outcomes between chronic hepatitis B patients with drug-induced virological response and inactive carriers. Liver Int 2019; 39:81-89. [PMID: 30280461 DOI: 10.1111/liv.13948] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Revised: 08/12/2018] [Accepted: 08/21/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS We compared the risk of hepatocellular carcinoma (HCC) development between patients with chronic hepatitis B (CHB) who achieved virological response (VR; HBV-DNA < 2000 IU/mL) with nucleos(t)ide analogues (NUCs) treatment (NUC-VR group) and patients with inactive CHB phase (ICHBP group). METHODS To adjust for imbalances between NUC-VR and ICHBP groups, propensity score matching (PSM) models with 1:1 ratios were performed. RESULTS This study included 2032 patients (n = 1291 in NUC-VR group and n = 741 in ICHBP group). Before PSM, NUC-VR group was at higher risk of HCC development than ICHBP group at 7 years (9.4% in NUC-VR group vs 3.3% in ICHBP group; P < 0.001). However, after PSM, the cumulative HCC development rates at 7 years were similar in NUC-VR and ICHBP groups using the three PSM models [2.0% vs 4.3%, PSM model-1 (612 pairs); 3.7% vs 4.4%, PSM model-2 (618 pairs); and 2.4% vs 4.3%, PSM model-3 (610 pairs)] (all P > 0.05). CONCLUSIONS After adjusting heavier hepatic fibrosis burden in NUC-VR group, overall clinical outcomes between 2 groups had become comparable. Therefore, if appropriate, NUCs to prevent viral replication and hepatic inflammation are required for achieving better prognosis.
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Affiliation(s)
- Hye Soo Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Oidov Baatarkhuu
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Department of Infectious Diseases, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Kijun Song
- Department of Biostatistics, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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26
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Kim BG, Park NH, Lee SB, Jeon S, Park JH, Jung SW, Jeong ID, Bang SJ, Shin JW. The risk of hepatocellular carcinoma within and beyond the first 5 years of entecavir in Korean patients with chronic hepatitis B. Liver Int 2018; 38:2269-2276. [PMID: 30052303 DOI: 10.1111/liv.13938] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Revised: 07/05/2018] [Accepted: 07/23/2018] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS The development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) has decreased due to potent antiviral agents. However, it remains uncertain whether the risk of HCC will diminish after long-term antiviral therapy in Asia, where CHB is endemic and vertical transmission is common. This study aimed to compare the incidence of HCC within and beyond the first 5 years of entecavir (ETV) in treatment-naïve Korean patients with CHB. METHODS We performed a retrospective observational analysis of data from 894 consecutive, adult patients with CHB undergoing ETV treatment at a tertiary referral hospital in Ulsan, Korea from January 1, 2007 through April 31, 2017. We compared the HCC incidence rates per 100 person-years within and beyond the first 5 years. Univariate and multivariate analyses for factors predictive of HCC were performed. RESULTS The incidence rate of HCC in patients with CHB did not differ statistically when we compared within and beyond the first 5 years of ETV therapy (2.29% vs 1.66% per person-year, P = 0.217). Failure to achieve maintained virological response (MVR) was a major independent risk factor for HCC in patients at a follow-up of <5 years. In contrast, in patients with a follow-up of ≥5 years, achieving MVR was not significantly associated with HCC development. CONCLUSIONS The incidence rate of HCC may not change significantly before and after 5 years of ETV therapy in Korean CHB patients. The risk of HCC in Asian CHB patients may remain in the long-term.
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Affiliation(s)
- Byung Gyu Kim
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Neung Hwa Park
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Seung Bum Lee
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Soyoung Jeon
- Statistical Consulting Laboratory, Department of Mathematical Sciences, University of Texas at El Paso, El Paso, Texas
| | - Jae Ho Park
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Seok Won Jung
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - In Du Jeong
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Sung-Jo Bang
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Jung Woo Shin
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
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27
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Kim BG, Park NH, Lee SB, Lee H, Lee BU, Park JH, Jung SW, Jeong ID, Bang SJ, Shin JW. Mortality, liver transplantation and hepatic complications in patients with treatment-naïve chronic hepatitis B treated with entecavir vs tenofovir. J Viral Hepat 2018; 25:1565-1575. [PMID: 29998592 DOI: 10.1111/jvh.12971] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 06/02/2018] [Accepted: 06/07/2018] [Indexed: 12/12/2022]
Abstract
Few studies have directly compared the long-term clinical outcomes of entecavir (ETV) and tenofovir disoproxil fumarate (TDF). This study aimed to compare the risk of mortality, liver transplantation and hepatic complications including hepatocellular carcinoma (HCC) and hepatic decompensation between these drugs in treatment-naïve chronic hepatitis B (CHB). We performed a longitudinal observational analysis of data from 1325 consecutive adult CHB patients with a cumulative adherence of ≥80% to treatment with ETV (n = 721) or TDF (n = 604) at a tertiary referral hospital in Ulsan, Korea, from 1 January 2007 through 31 April 2017. Among the patients, 708 were analysed using propensity score matching with a ratio of 1:1. In the follow-up period of up to 5 years, five patients (0.4%) died, three patients (0.2%) underwent liver transplantation (LT) and 54 patients (4.1%) developed HCC. Hepatic decompensation occurred in 24 (1.8%) patients. ETV therapy did not significantly differ from TDF therapy regarding the risk of liver-related death or LT (HR 0.96; 95% CI, 0.23-4.07; log-rank P = 0.955), HCC (HR, 1.36; 95% CI, 0.72-2.56; log-rank P = 0.340) and hepatic decompensation (HR, 1.64; 95% CI, 0.67-4.00; log-rank P = 0.276). In the 708 propensity-matched pairs, ETV and TDF were also not significantly different with respect to the risk of mortality, LT and hepatic complications. In this longitudinal observational study of 1325 patients with CHB, ETV and TDF therapies were not significantly different regarding the risk of mortality, HCC, LT and hepatic decompensation.
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Affiliation(s)
- Byung Gyu Kim
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Neung Hwa Park
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Seung Bum Lee
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Hojune Lee
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Byung Uk Lee
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Jae Ho Park
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Seok Won Jung
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - In Du Jeong
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Sung-Jo Bang
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Jung Woo Shin
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
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28
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Shin JW, Jung SW, Lee SB, Lee BU, Park BR, Park EJ, Park NH. Medication Nonadherence Increases Hepatocellular Carcinoma, Cirrhotic Complications, and Mortality in Chronic Hepatitis B Patients Treated With Entecavir. Am J Gastroenterol 2018; 113:998-1008. [PMID: 29880971 DOI: 10.1038/s41395-018-0093-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 04/04/2018] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Optimal adherence to nucleoside analogue treatment is necessary to achieve undetectable levels of hepatitis B virus (HBV) DNA in patients with chronic hepatitis B (CHB), and to prevent cirrhotic complications. However, any large long-term follow-up study has not been investigated the effect of adherence to entecavir (ETV) treatment on specific liver-related events (LREs), namely, hepatocellular carcinoma (HCC), cirrhotic complications, and mortality. METHODS This was a 10-year longitudinal observational study of treatment-naïve patients with CHB who received ETV treatment. The primary outcome was the cumulative probability of LREs. The cumulative level of adherence to medication was categorized as good (≥90%) or poor (<90%). RESULTS Data from 894 treatment-naïve CHB patients who received ETV were analyzed. Overall mean adherence rates were 89.1%. Patients with poor adherence had a higher risk of virologic breakthrough (VBT) (HR, 22.42; 95% CI, 19.57-52.52; P < 0.001) than those with good adherence. Multivariate analyses showed a higher risk of liver-related (HR, 14.29; 95% CI, 3.49-58.47; P < 0.001) or all-cause (HR, 4.96; 95% CI, 2.19-11.27; P < 0.001) mortality, HCC (HR, 2.86; 95% CI, 1.76-4.64; P < 0.001), and cirrhotic complications (HR, 2.86; 95% CI, 1.93-4.25; P < 0.001) with poor adherence. Medication adherence was further stratified into three groups according to adherence rates of <70%, ≥70 to <90%, and ≥90%. The dose-response analyses of adherence rates showed that the risk of LREs increased progressively as medication adherence declined. In particular, the unfavorable effects of nonadherence were more pronounced in patients with cirrhosis. CONCLUSIONS Poor adherence to medication was associated with a higher mortality and greater risk of HCC and cirrhotic complications, particularly among patients with liver cirrhosis.
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Affiliation(s)
- Jung Woo Shin
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea. Biomedical Research Center, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea. These authors share co-first authorship: Jung Woo Shin and Seok Won Jung
| | - Seok Won Jung
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea. Biomedical Research Center, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea. These authors share co-first authorship: Jung Woo Shin and Seok Won Jung
| | - Seung Bum Lee
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea. Biomedical Research Center, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea. These authors share co-first authorship: Jung Woo Shin and Seok Won Jung
| | - Byung Uk Lee
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea. Biomedical Research Center, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea. These authors share co-first authorship: Jung Woo Shin and Seok Won Jung
| | - Bo Ryung Park
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea. Biomedical Research Center, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea. These authors share co-first authorship: Jung Woo Shin and Seok Won Jung
| | - Eun Ji Park
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea. Biomedical Research Center, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea. These authors share co-first authorship: Jung Woo Shin and Seok Won Jung
| | - Neung Hwa Park
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea. Biomedical Research Center, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea. These authors share co-first authorship: Jung Woo Shin and Seok Won Jung.,Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea. Biomedical Research Center, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea. These authors share co-first authorship: Jung Woo Shin and Seok Won Jung
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29
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Cho H, Ahn H, Lee DH, Lee JH, Jung YJ, Chang Y, Nam JY, Cho YY, Lee DH, Cho EJ, Yu SJ, Lee JM, Kim YJ, Yoon JH. Entecavir and tenofovir reduce hepatitis B virus-related hepatocellular carcinoma recurrence more effectively than other antivirals. J Viral Hepat 2018; 25:707-717. [PMID: 29316069 DOI: 10.1111/jvh.12855] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 11/13/2017] [Indexed: 12/15/2022]
Abstract
Nucleos(t)ide analogues (NAs) have been shown to decrease the risk of hepatocellular carcinoma (HCC) recurrence. This study evaluated whether high-potency NAs (entecavir and tenofovir disoproxil fumarate [TDF]) reduce the risk of tumour recurrence more potently than low-potency NAs after curative treatment of hepatitis B virus (HBV)-related HCC. This study included 607 consecutive HBV-related HCC patients treated with surgical resection or radiofrequency ablation. The patients were categorized into three groups according to antiviral treatment: group A (no antiviral; n = 261), group B (low-potency NA; n = 90) and group C (high-potency NA; n = 256). The primary end-point was recurrence-free survival (RFS). During the duration of follow-up, the median RFS was 29.4, 25.1, and 88.2 months in groups A, B and C, respectively (P < .001, log-rank test). The multivariate Cox analysis indicated that group C had a significantly longer RFS than both group A (adjusted hazard ratio [HR] = 0.39, P < .001) and group B (adjusted HR = 0.47, P < .001). When baseline characteristics were balanced using inverse probability weighting, group C still had a significantly longer RFS than group A (adjusted HR = 0.46, P < .001) and group B (adjusted HR = 0.59, P = .007). Group C had significantly lower risk of viral breakthrough than group B (HR = 0.19, P < .001). Viral breakthrough was an independent risk factor for shorter RFS among groups B and C (adjusted HR = 2.03, P = .007, time-dependent Cox analysis). Antiviral agents with high genetic barrier to resistance (entecavir and TDF) reduced the risk of HCC recurrence compared with other antivirals and no antiviral treatment, especially in patients with high baseline viral load.
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Affiliation(s)
- H Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - H Ahn
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - D H Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - J-H Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Y J Jung
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Y Chang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - J Y Nam
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Y Y Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - D H Lee
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - E J Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - S J Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - J M Lee
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Y J Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - J-H Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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30
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Colombo M, Lleo A. The impact of antiviral therapy on hepatocellular carcinoma epidemiology. Hepat Oncol 2018; 5:HEP03. [PMID: 30302194 PMCID: PMC6168041 DOI: 10.2217/hep-2017-0024] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 02/13/2018] [Indexed: 02/06/2023] Open
Abstract
The development of nucleos(t)ide analogs and direct antiviral agents has revolutionized the management of chronic infection with HBV and HCV, respectively. These regimens allow to expand treatment to virtually all infected, including those with poor hepatic reserve and those with severe comorbidities. As a result, permanent suppression of HBV and eradication of HCV has been achieved in almost all treated patients, resulting in substantial clinical benefits. In several cohorts, these successes have translated into a reduction of the incidence of hepatocellular carcinoma that was more frequently observed in patients with less advanced hepatitis, whereas liver cancer was more often associated with male gender, cirrhosis, alcohol abuse and diabetes.
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Affiliation(s)
- Massimo Colombo
- Department of Internal Medicine, Center for Translational Research in Hepatology, Humanitas Clinical and Research Center, 20089 Rozzano (MI), Italy.,Department of Internal Medicine, Center for Translational Research in Hepatology, Humanitas Clinical and Research Center, 20089 Rozzano (MI), Italy
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Via R. Levi Montalcini 4, 20090 Pieve Emanuele (MI), Italy.,Hepatology, Department of Internal Medicine, Humanitas Clinical & Research Center, Rozzano (MI), Italy.,Department of Biomedical Sciences, Humanitas University, Via R. Levi Montalcini 4, 20090 Pieve Emanuele (MI), Italy.,Hepatology, Department of Internal Medicine, Humanitas Clinical & Research Center, Rozzano (MI), Italy
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31
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Okada M, Enomoto M, Kawada N, Nguyen MH. Effects of antiviral therapy in patients with chronic hepatitis B and cirrhosis. Expert Rev Gastroenterol Hepatol 2017; 11:1095-1104. [PMID: 28752768 DOI: 10.1080/17474124.2017.1361822] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hepatitis B virus (HBV) infection is the major cause of cirrhosis worldwide. The ultimate goal of current antiviral treatments for chronic hepatitis B (nucleos(t)ide analogs and interferon-α) is to prevent the development of end-stage liver diseases. Areas covered: We present a review of the current literature on antiviral therapy in patients with chronic hepatitis B and cirrhosis. Medline search was performed to identify relevant literature from 1993 through January of 2017. Expert commentary: One randomized controlled trial and a number of observational studies have shown that nucleos(t)ide analogs can decrease the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis B patients with advanced fibrosis. Data from clinical trials of entecavir and tenofovir have shown that histological improvement and regression of fibrosis can be achieved in the majority of patients with chronic hepatitis B by successful viral suppression. Entecavir and tenofovir are the preferred antiviral agents for treatment of chronic hepatitis B in patients with cirrhosis due to their high antiviral potency and high genetic barrier to resistance. Pegylated interferon-α is another therapeutic option for chronic hepatitis B patients with well-compensated cirrhosis. However, interferon therapy is contraindicated in patients with decompensated cirrhosis, and evidence for reduced HCC is currently insufficient.
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Affiliation(s)
- Masako Okada
- a Department of Hepatology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Masaru Enomoto
- a Department of Hepatology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Norifumi Kawada
- a Department of Hepatology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Mindie H Nguyen
- b Division of Gastroenterology and Hepatology , Stanford University Medical Center , Palo Alto , CA , USA
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32
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Zhang W, Wang X, Wang Y, Zhao X, Duan W, Wang Q, Wu X, Kong Y, Ma H, You H, Ou X, Jia J. Effective viral suppression is necessary to reduce hepatocellular carcinoma development in cirrhotic patients with chronic hepatitis B: Results of a 10-year follow up. Medicine (Baltimore) 2017; 96:e8454. [PMID: 29095292 PMCID: PMC5682811 DOI: 10.1097/md.0000000000008454] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
High viral load is an independent risk factor for development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Antiviral therapy can reduce but not eliminate the risk of HCC. The aim of this study was to identify the risk factors for HCC development in CHB patients during antiviral therapy.CHB patients with HBV DNA level ≥10 copies/mL, with or without compensated cirrhosis receiving adefovir were followed up every 6 months for 10 years (2004-2014). The primary endpoint was the development of HCC. The cumulative incidence and risk factors of HCC were evaluated by the Kaplan-Meier method and multivariate Cox proportional hazards models.At baseline, 28 of the 120 patients (23.3%) were cirrhotic. One patient developed HCC within 1 year, and therefore 119 patients were analyzed. At the end-point of follow-up, 59.7% (71/119) patients achieved virological remission (VR). Overall, 16 patients developed HCC, giving a 10-year cumulative incidence of 15.73%. Multivariate analysis showed that cirrhosis at baseline and failure to achieve VR were significant risk factors for HCC. The 10-year incidence of HCC was significantly higher in cirrhotic than noncirrhotic patients (43.16% vs. 7.05%, P < .0001). For cirrhotic patients, the 10-year incidence of HCC was significantly higher in patients without VR than those with VR (62.24% vs. 27.78%, P = .0139).Cirrhosis at baseline and failure to achieve VR during antiviral therapy were significant risk factors for HCC development in CHB patients. Effective viral suppression is necessary to reduce HCC development in cirrhotic CHB patients.
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Affiliation(s)
- Wei Zhang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Xiaoming Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Yu Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Xinyan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Weijia Duan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Qianyi Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Xiaoning Wu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Yuanyuan Kong
- Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University; National Clinical Research Center for Digestive Disease, Beijing, China
| | - Hong Ma
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis & National Clinical Research Center for Digestive Diseases
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Abstract
There is great geographical variation in the distribution of hepatocellular carcinoma (HCC), with the majority of all cases worldwide found in the Asia–Pacific region, where HCC is one of the leading public health problems. Since the “Toward Revision of the Asian Pacific Association for the Study of the Liver (APASL) HCC Guidelines” meeting held at the 25th annual conference of the APASL in Tokyo, the newest guidelines for the treatment of HCC published by the APASL has been discussed. This latest guidelines recommend evidence-based management of HCC and are considered suitable for universal use in the Asia–Pacific region, which has a diversity of medical environments.
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Bi J, Zhang Z, Qin E, Hou J, Liu S, Liu Z, Li S, Wei Z, Zhong Y. Nucleoside analogs treatment delay the onset of hepatocellular carcinoma in patients with HBV-related cirrhosis. Oncotarget 2017; 8:96725-96731. [PMID: 29228565 PMCID: PMC5722517 DOI: 10.18632/oncotarget.18075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 05/06/2017] [Indexed: 02/06/2023] Open
Abstract
Whether Nucleos(t)ide analogs(NA) treatment can delay the onset of HCC remains unclear. We retrospectively analyzed the clinical data of patients with HBV-related cirrhosis and HCC from 2000 to 2012. Cox proportional hazards model was used to explore the association between NA treatment and postponement of HCC development, the dependent variable was time interval from cirrhosis treatment towards the onset of HCC, and the covariates included age, sex, family history, compensation status at baseline. A total of 1155 HCC patients treated with NAs (n = 528, lamivudine, adefovir, entecavir) and non NA (n = 627) for more than 24 months before the occurrence of HCC were incorporated into the cohort. Compared with the non-NA group, NAs therapy was associated with delaying the onset of HCC in patients with cirrhosis. Significant factors were: adefovir treatment (n = 181; p = 0.0072; HR: 0.792; 90% CI: 0.687–0.914), entecavir treatment (n = 83; p = 0.0068; HR: 0.716; 90% CI: 0.585-0.877), lamivudine switched to adefovir treatment (n = 95, p = 0.0808; HR: 0.822; 90% CI: 0.684 to 0.989). But Lamivudine monotherapy was not a significant factor (n = 102; p = 0.6877; HR: 1.045; 90% CI: 0.873–1.250). Long-term NA treatment (> 6 months, except for lamivudine monotherapy) can delay the onset of HCC in patients with HBV-related cirrhosis, and applying high barrier NA to resistance is important in these patients.
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Affiliation(s)
- Jingfeng Bi
- Research Center for Clinical and Translational Medicine, 302 Hospital, Beijing, 100039, China
| | - Zheng Zhang
- Research Center for Clinical and Translational Medicine, 302 Hospital, Beijing, 100039, China
| | - Enqiang Qin
- Infectious Disease Treatment Center, 302 Hospital, Beijing, 100039, China
| | - Jun Hou
- Research Center for Clinical and Translational Medicine, 302 Hospital, Beijing, 100039, China
| | - Shuiwen Liu
- Medical Department, 302 Hospital, Beijing, 100039, China
| | - Zengmin Liu
- Medical Department, XingLong Hospital of TCM, Beijing, 100039, China
| | - Shuo Li
- Medical Department, 302 Hospital, Beijing, 100039, China
| | - Zhenman Wei
- Research Center for Clinical and Translational Medicine, 302 Hospital, Beijing, 100039, China
| | - Yanwei Zhong
- Institute of Infectious Disease, Pediatric Liver Disease Therapy and Research Center, 302 Hospital, Beijing, 100039, China
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35
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Abdul Basit S, Dawood A, Ryan J, Gish R. Tenofovir alafenamide for the treatment of chronic hepatitis B virus infection. Expert Rev Clin Pharmacol 2017; 10:707-716. [PMID: 28460547 DOI: 10.1080/17512433.2017.1323633] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
INTRODUCTION In April 2017 tenofovir alafenamide (TAF) was added to the list of first-line therapies recommended for chronic hepatitis B (CHB). TAF has pharmacology similar to tenofovir disoproxil fumarate (TDF) with higher cell delivery to the hepatocytes but less systemic exposure. Areas covered: We review here studies leading to TAF's approval and comparing it to TDF. In two major clinical trials, TAF was non-inferior to TDF in achieving HBV DNA levels below 29 IU/ml. TAF-treated patients had significantly smaller decreases in bone mineral density (BMD) at the hip and spine in both HBeAg-positive and HBeAg-negative patients, and smaller mean increases in serum creatinine, although the difference was only statistically significant in HBeAg-positive patients. Patients treated with TDF for 96 weeks and then switched to TAF had improvements in renal and BMD measures only 24 weeks after switching. Expert commentary: With clear evidence from major studies showing that TAF is safe, tolerable, and non-inferior to TDF, its recommendation as a first-line therapy is appropriate. Longer term follow up will be required to determine if the differences in adverse bone and kidney effects seen with TAF in comparison to TDF will be clinically relevant.
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Affiliation(s)
- Syed Abdul Basit
- a Department of Internal Medicine, Division of Gastroenterology and Hepatology , University of Nevada School of Medicine , Las Vegas , NV , USA
| | - Altaf Dawood
- a Department of Internal Medicine, Division of Gastroenterology and Hepatology , University of Nevada School of Medicine , Las Vegas , NV , USA
| | - John Ryan
- b Comprehensive Digestive Institute of Nevada (CDIN) , Las Vegas , NV , USA.,c Roseman University of Health Sciences , Henderson , NV , USA
| | - Robert Gish
- a Department of Internal Medicine, Division of Gastroenterology and Hepatology , University of Nevada School of Medicine , Las Vegas , NV , USA.,d Division of Gastroenterology and Hepatology, Department of Medicine , Stanford University Medical Center , Stanford , CA , USA.,e Hepatitis B Foundation , Doylestown , PA , USA.,f Asian Pacific Health Foundation , San Diego , CA , USA.,g National Viral Hepatitis Roundtable , Washington , D.C , USA
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36
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Cost-Effectiveness and Clinical Impact of Antiviral Strategies of HBeAg-Positive and -Negative Chronic Hepatitis B. Ann Hepatol 2017. [DOI: 10.5604/01.3001.0009.8590] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/22/2023]
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37
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Abstract
The primary goal of therapy for chronic hepatitis B (CHB) is to prevent liver disease progression. Hepatitis B surface antigen (HBsAg) seroclearance or seroconversion is regarded as an optimal endpoint to discontinue treatment. However, HBsAg seroclearance occurs very rarely with nucleos(t)ide analog (NUC) treatment, and long-term, almost indefinite, NUC treatment is required for the majority of patients. In patients with drug-resistant hepatitis B virus (HBV), a combination of tenofovir disoproxil fumarate (TDF) and entecavir (ETV), which is currently regarded as the strongest combination therapy against HBV, would be potentially safe to prevent the emergence of additional HBV resistance mutations. However, long-term tolerance data are lacking, and cost may be an issue for combination therapies. Several recent, well-designed, randomized controlled trials have shown that TDF monotherapy provides similar antiviral efficacy compared with the combination of TDF and ETV. Furthermore, no additional HBV resistance mutations emerged during TDF monotherapy for up to 96 weeks. Considering a comparable antiviral efficacy, extremely low risk of TDF-resistance, lower cost, and better safety potential, TDF monotherapy would be a reasonable choice for the treatment of drug-resistant patients with CHB.
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Affiliation(s)
- Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
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38
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Abstract
The goal in patients with immune active hepatitis B virus (HBV) infection is to significantly suppress viral replication and prevent progression of fibrosis to cirrhosis and liver decompensation and decrease the incidence of hepatocellular carcinoma. This is achievable by the highly active antivirals, entecavir and tenofovir, which are considered first-line therapy in most patients with immune active hepatitis C virus and after liver transplantation to prevent HBV recurrence. Patients with decompensated cirrhosis should be referred for liver transplantation and treated with first-line antivirals as early as possible, with the goal of achieving complete viral suppression in the shortest time possible.
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Affiliation(s)
| | - Tarek I Hassanein
- Southern California Research Center, Coronado, CA 92118, USA; University of California, San Diego School of Medicine, San Diego, CA, USA.
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39
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Cai QC, Zhao SQ, Shi TD, Ren H. Relationship between hepatitis B virus infection and chronic kidney disease in Asian populations: a meta-analysis. Ren Fail 2016; 38:1581-1588. [PMID: 27756165 DOI: 10.1080/0886022x.2016.1229548] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
PURPOSE To evaluate the association of Chronic hepatitis B virus (HBV) infection and chronic kidney disease (CKD). METHODS We searched Embase, Grateful Med, Ovid, PubMed, and the China Biological Medicine Database. A meta-analysis was performed to assess whether HBV infection plays an independent impact on the development of CKD in the general population. Relative risks of CKD (defined as reduced glomerular filtration rate or proteinuria) according to HBsAg serologic status were studied. RESULTS Six eligible clinical studies (189,709 individuals in total) were included in the analysis. There was no association between HBsAg seropositive status and prevalence of CKD, the summary estimate for adjusted relative risk (RR) was 1.16 (95% confidence interval (CI), 0.78, 1.71; p = .46) according to the random-effects model, and between studies heterogeneity was noted (p values by Q test <0.001). Also, there were no significant associations between positive HBV serologic status and low eGFR (adjusted relative risk, 0.95; 95% CI, 0.72, 1.26; p = .72) or proteinuria (adjusted relative risk, 1.00; 95% CI, 0.83, 1.20; p = .99). CONCLUSIONS This meta-analysis shows that there was no association between exposure to HBV and the risk of developing CKD in Asian populations.
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Affiliation(s)
- Qing-Chun Cai
- a Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases , The Second Affiliated Hospital, Chongqing Medical University , Chongqing , PR China
| | - Shu-Qi Zhao
- a Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases , The Second Affiliated Hospital, Chongqing Medical University , Chongqing , PR China
| | - Tong-Dong Shi
- a Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases , The Second Affiliated Hospital, Chongqing Medical University , Chongqing , PR China
| | - Hong Ren
- a Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases , The Second Affiliated Hospital, Chongqing Medical University , Chongqing , PR China
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40
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Kim HJ, Park SK, Yang HJ, Jung YS, Park JH, Park DI, Cho YK, Sohn CI, Jeon WK, Kim BI, Choi KY. Comparison of the clinical outcomes between antiviral-naïve patients treated with entecavir and lamivudine-resistant patients receiving adefovir add-on lamivudine combination treatment. Clin Mol Hepatol 2016; 22:350-358. [PMID: 27729626 PMCID: PMC5066373 DOI: 10.3350/cmh.2016.0019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 07/08/2016] [Accepted: 07/13/2016] [Indexed: 12/22/2022] Open
Abstract
Background/Aims To analyze the effects of preexisting lamivudine (LAM) resistance and applying antiviral treatment (adefovir [ADV] add-on LAM combination treatment) on long-term treatment outcomes, and comparing the clinical outcomes of antiviral-naïve chronic hepatitis B patients receiving entecavir (ETV) monotherapy. Methods This study enrolled 73 antiviral-naïve patients who received 0.5-mg ETV as an initial therapy and 54 patients who received ADV add-on LAM combination treatment as a rescue therapy from July 2006 to July 2010. Results During 24-month treatments, the decreases in serum log10HBV-DNA values (copies/mL) were significantly greater in the antiviral-naïve patients treated with ETV than the patients receiving ADV add-on LAM combination treatment. The biochemical response rates for alanine aminotransferase normalization at 6 months (ETV) and 12 months (ADV add-on LAM) were 90.4% (66/73) and 77.8% (42/54), respectively (P=0.048). A Kaplan-Meier analysis indicated that the rates of serologic response, viral breakthrough, and emergence of genotypic resistance did not differ significantly between the two patient groups. There were also no significant intergroup differences in the rates of disease progression (PD) and new development of hepatocellular carcinoma (HCC). Conclusion The long-term clinical outcomes of antiviral-naïve patients treated with ETV and LAM-resistant patients receiving ADV add-on LAM combination treatment were comparable in terms of the emergence of HCC and disease progression.
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Affiliation(s)
- Hong Joo Kim
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Soo Kyung Park
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyo Joon Yang
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yoon Suk Jung
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jung Ho Park
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dong Il Park
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yong Kyun Cho
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Chong Il Sohn
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Woo Kyu Jeon
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Byung Ik Kim
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyu Yong Choi
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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41
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Varbobitis I, Papatheodoridis GV. The assessment of hepatocellular carcinoma risk in patients with chronic hepatitis B under antiviral therapy. Clin Mol Hepatol 2016; 22:319-326. [PMID: 27729632 PMCID: PMC5066383 DOI: 10.3350/cmh.2016.0045] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 07/21/2016] [Accepted: 08/11/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary concern for patients with chronic hepatitis B (CHB). Antiviral therapy has been reasonably the focus of interest for HCC prevention, with most studies reporting on the role of the chronologically preceding agents, interferon-alfa and lamivudine. The impact of interferon-alfa on the incidence of HCC is clearer in Asian patients and those with compensated cirrhosis, as several meta-analyses have consistently shown HCC risk reduction, compared to untreated patients. Nucleos(t)ide analogues also seem to have a favorable impact on the HCC incidence when data from randomized or matched controlled studies are considered. Given that the high-genetic barrier agents, entecavir and tenofovir, are mainly used in CHB because of their favorable effects on the overall long-term outcome of such patients, the most clinically important challenge is the identification of patients who require close HCC surveillance despite on-therapy virological remission. Several risk scores have been developed for HCC prediction in CHB patients. Most of them, such as GAG-HCC, CU-HCC and REACH-B, have been developed and validated in Asian untreated and treated CHB patients, but they do not seem to offer good predictability in Caucasian CHB patients for whom a newer score, PAGE-B, has been recently developed.
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Affiliation(s)
- Ioannis Varbobitis
- Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - George V. Papatheodoridis
- Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
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42
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Keshavarz K, Kebriaeezadeh A, Alavian SM, Akbari Sari A, Rezaei Hemami M, Lotfi F, Hashemi Meshkini A, Javanbakht M, Keshvari M, Nikfar S. A Cost-Utility and Cost-Effectiveness Analysis of Different Oral Antiviral Medications in Patients With HBeAg-Negative Chronic Hepatitis B in Iran: An Economic Microsimulation Decision Model. HEPATITIS MONTHLY 2016; 16:e37435. [PMID: 27822262 PMCID: PMC5091008 DOI: 10.5812/hepatmon.37435] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Revised: 07/02/2016] [Accepted: 08/07/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Although hepatitis B infection is the major cause of chronic liver disease in Iran, no studies have employed economic evaluations of the medications used to treat Iranian patients with chronic hepatitis B (CHB). Therefore, the cost-effectiveness of the different treatment options for this disease in Iran is unknown. OBJECTIVES The aim of this study was to compare the cost utility and cost-effectiveness of medication strategies tailored to local conditions in patients with HB e antigen (HBeAg)-negative CHB infection in Iran. METHODS An economic evaluation of the cost utility of the following five oral medication strategies was conducted: adefovir (ADV), lamivudine (LAM), ADV + LAM, entecavir (ETV), and tenofovir (TDF). A Markov microsimulation model was used to estimate the clinical and economic outcomes over the course of the patient's lifetime and based on a societal perspective. Medical and nonmedical direct costs and indirect costs were included in the study and life-years gained (LYG) and quality-adjusted life-years (QALY) were determined as measures of effectiveness. The results are presented in terms of the incremental cost-effectiveness ratio (ICER) per QALY or LYG. The model consisted of nine stages of the disease. The transition probabilities for the movement between the different stages were based on clinical evidence and international expert opinion. A probabilistic sensitivity analysis (PSA) was used to measure the effects of uncertainty in the model parameters. RESULTS The results revealed that the TDF treatment strategy was more effective and less costly than the other options. In addition, TDF had the highest QALY and LYG in the HBeAg-negative CHB patients, with 13.58 and 21.26 (discounted) in all comparisons. The PSA proved the robustness of the model results. The cost-effectiveness acceptability curves showed that TDF was the most cost-effective treatment in 59% - 78% of the simulations of HBeAg-negative patients, with WTP thresholds less than $14010 (maximum WTP per QALY). CONCLUSIONS The use of TDF in patients with HBeAg-negative CHB seemed to be a highly cost-effective strategy. Compared with the other available medication options, TDF was the most cost-saving strategy. Thus, TDF may be the best option as a first-line medication. Patients can also be switched from other medications to TDF.
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Affiliation(s)
- Khosro Keshavarz
- Health Human Resource Research Center, School of Management and Information Sciences, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Abbas Kebriaeezadeh
- Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Ali Akbari Sari
- Department of Health Management and Economics, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Mohsen Rezaei Hemami
- Institute of Health & Wellbeing, Health Economics & Health Technology Assessment, University of Glasgow, Glasgow, United Kingdom
| | - Farhad Lotfi
- Health Human Resource Research Center, School of Management and Information Sciences, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Amir Hashemi Meshkini
- Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Mehdi Javanbakht
- Health Economics Research Unit, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK
| | - Maryam Keshvari
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, IR Iran
| | - Shekoufeh Nikfar
- Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IR Iran
- Corresponding Author: Shekoufeh Nikfar, Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IR Iran. Tel: +98-09123271200, Fax: +98-2188611883, E-mail:
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Lim YS, Yoo BC, Byun KS, Kwon SY, Kim YJ, An J, Lee HC, Lee YS. Tenofovir monotherapy versus tenofovir and entecavir combination therapy in adefovir-resistant chronic hepatitis B patients with multiple drug failure: results of a randomised trial. Gut 2016; 65:1042-51. [PMID: 25800784 DOI: 10.1136/gutjnl-2014-308435] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2014] [Accepted: 03/05/2015] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Little clinical data are available regarding the optimal treatment of patients who harbour adefovir-resistant HBV. DESIGN In this multicentre trial, patients who had adefovir-resistant HBV with serum HBV DNA levels >60 IU/mL were randomised to receive tenofovir disoproxil fumarate (TDF, 300 mg/day) monotherapy (n=50) or TDF and entecavir (ETV, 1 mg/day) combination therapy (TDF/ETV, n=52) for 48 weeks. All who completed 48 weeks in either group received TDF monotherapy for 48 additional weeks. RESULTS Baseline characteristics were comparable between groups, including HBV DNA levels (median, 3.38 log10 IU/mL). All patients had adefovir-resistant HBV mutations; rtA181V/T and/or rtN236T. The proportion of patients with HBV DNA <15 IU/mL was not significantly different between the TDF-TDF and TDF/ETV-TDF groups at weeks 48 (62% vs 63.5%; p=0.88) and 96 (64% vs 63.5%; p=0.96). The mean change in HBV DNA levels from baseline was not significantly different between groups at week 48 (-3.03 log10 IU/mL vs -3.31 log10 IU/mL; p=0.38). Virological breakthrough occurred in one patient on TDF-TDF and two patients on TDF/ETV-TDF over 96 weeks; all were attributed to poor drug adherence. At week 96, five and two patients in the TDF-TDF and TDF/ETV-TDF groups, respectively, retained some of their baseline resistance mutations (p=0.44). None developed additional resistance mutations. Safety profiles were comparable in the two groups. CONCLUSIONS In patients with adefovir-resistant HBV and multiple-drug failure, TDF monotherapy provided a virological response comparable to that of TDF and ETV combination therapy, and was safe up to 96 weeks. TRIAL REGISTRATION NUMBER NCT01639066.
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Affiliation(s)
- Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Byung Chul Yoo
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Kwan Soo Byun
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - So Young Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jihyun An
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Han Chu Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yung Sang Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Lim YS, Byun KS, Yoo BC, Kwon SY, Kim YJ, An J, Lee HC, Lee YS. Tenofovir monotherapy versus tenofovir and entecavir combination therapy in patients with entecavir-resistant chronic hepatitis B with multiple drug failure: results of a randomised trial. Gut 2016; 65:852-60. [PMID: 25596179 DOI: 10.1136/gutjnl-2014-308353] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Accepted: 12/27/2014] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Little clinical data are available regarding the optimal treatment of patients who harbour entecavir (ETV)-resistant HBV. DESIGN In this multicentre randomised trial, patients who had HBV with ETV resistance-associated mutations and serum HBV DNA concentrations >60 IU/mL were randomised to receive tenofovir disoproxil fumarate (TDF, 300 mg/day) monotherapy (n=45) or TDF and ETV (1 mg/day) combination therapy (n=45) for 48 weeks. RESULTS Baseline characteristics were comparable between groups, including HBV DNA levels (median, 4.02 log10 IU/mL) and hepatitis B e antigen-positivity (89%). All patients had at least one ETV-resistance mutation: rtT184A/C/F/G/I/L/S (n=49), rtS202G (n=43) and rtM250L/V (n=7), in addition to rtM204V/I (n=90). All except one patient in the TDF group completed 48 weeks of treatment. At week 48, the proportion of patients with HBV DNA <15 IU/mL, the primary efficacy endpoint, was not significantly different between the TDF and TDF+ETV groups (71% vs. 73%; p>0.99). The mean change in HBV DNA levels from baseline was not significantly different between groups (-3.66 vs. -3.74 log10 IU/mL; p=0.81). Virological breakthrough occurred in one patient on TDF, which was attributed to poor drug adherence. At week 48, six and three patients in the TDF and TDF+ETV groups, respectively, retained their baseline resistance mutations (p>0.99). None developed additional resistance mutations. Safety profiles were comparable in the two groups. CONCLUSIONS TDF monotherapy for 48 weeks provided a virological response comparable to that of TDF and ETV combination therapy in patients infected with ETV-resistant HBV. TRIAL REGISTRATION NUMBER ClinicalTrials.gov ID NCT01639092.
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Affiliation(s)
- Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kwan Soo Byun
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Byung Chul Yoo
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - So Young Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - Yoon Jun Kim
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jihyun An
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yung Sang Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Höner Zu Siederdissen C, Cornberg M. Management of HBV and HBV/HDV-Associated Liver Cirrhosis. Visc Med 2016; 32:86-94. [PMID: 27413725 DOI: 10.1159/000445518] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection and hepatitis delta virus (HDV) co-infection lead to liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). METHODS We review the current knowledge of the management of HBV mono-infection and HBV/HDV co-infection with a special emphasis on liver cirrhosis. RESULTS Treatment options for chronic hepatitis B are pegylated interferon (PEG-IFN) alfa and nucleos(t)ide analogues (NUC). PEG-IFN is a finite option to achieve hepatitis B surface antigen loss in compensated cirrhosis. However, this goal is rare. NUC are potent to achieve HBV DNA suppression but long-term treatment is mandatory in most cases. Long-term treatment with NUC can lead to reversion of liver cirrhosis, improve liver function, prevent liver transplantation, and reduces but does not eliminate the risk for development of HCC. Treatment options for hepatitis D are limited to PEG-IFN. Although late relapse is common, treatment with PEG-IFN reduces disease progression. However, new treatments are urgently needed for HDV infection. CONCLUSION Early treatment of chronic hepatitis B and D is important to prevent complications of cirrhosis. HCC surveillance remains important in patients with cirrhosis.
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Affiliation(s)
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hanover, Germany
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46
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Prevention of hepatitis B virus-associated liver diseases by antiviral therapy. Hepatol Int 2016; 10:574-93. [PMID: 27026375 DOI: 10.1007/s12072-016-9720-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Accepted: 02/28/2016] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) is a major cause of acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma, particularly in Asia-Pacific countries. The major complications in HBV carriers are hepatocellular carcinoma (HCC), liver failure and esophageal varices following the progression to cirrhosis, while some develop HCC without cirrhosis. The progression to liver fibrosis and these other complications could be prevented by treatment with nucleos(t)ide analogues (NUCs); however, NUCs must be continuously administered for a long time. Peginterferon could lead to HBV surface antigen loss. It is difficult to use peginterferon in HBV-infected patients with decompensated cirrhosis. Acute liver failure due to HBV infection and acute exacerbation of chronic hepatitis B could be treated by NUCs. Universal vaccination programs against HBV could prevent new HBV infections globally. Here, we review the currently available treatments for HBV infection.
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Hiramatsu N, Yamada R, Takehara T. The suppressive effect of nucleos(t)ide analogue treatment on the incidence of hepatocellular carcinoma in chronic hepatitis B patients. J Gastroenterol Hepatol 2016; 31:546-52. [PMID: 26574149 DOI: 10.1111/jgh.13229] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 11/10/2015] [Indexed: 12/25/2022]
Abstract
The development of nucleos(t)ide analogues (NA) has influenced hepatitis B virus management. However, the annual incidence rate during NA treatment has been reported to be 0.3-1.2% in non-cirrhosis cases and 1.8-6.0% in cirrhosis cases, indicating that the suppressive effect of NA treatment on hepatocellular carcinoma (HCC) would be insufficient. Past studies, including one randomized control trial that compared lamivudine treatment with placebo, have revealed that NA treatment could suppress the incidence of HCC in patients with advanced fibrosis. However, it remains unknown whether NA treatment can suppress the incidence of HCC in chronic hepatitis patients without advanced fibrosis. The HCC incidence in patients treated with entecavir was similar to that of those treated with lamivudine, although entecavir exhibits a stronger viral suppression than lamivudine. The following risk factors related to the incidence of HCC during NA treatment have been identified: older age, male gender, pre-existing cirrhosis, a family clustering of hepatitis B virus, lower platelet counts, and higher hepatitis B core-related antigens as baseline factors and higher alpha fetoprotein levels as an on-treatment factor. Conversely, the loss of the hepatitis B surface antigen (HBsAg) by interferon or NA was correlated with a lower HCC incidence rate. Because interferon treatment has much more effects on reducing HBsAg levels compared with NA treatment, a combination treatment with NA and pegylated interferon can bring additional reduction of HBsAg levels compared with NA monotherapy. Further study is needed to clarify this.
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Affiliation(s)
- Naoki Hiramatsu
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan
| | - Ryoko Yamada
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan
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48
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49
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Lok ASF, McMahon BJ, Brown RS, Wong JB, Ahmed AT, Farah W, Almasri J, Alahdab F, Benkhadra K, Mouchli MA, Singh S, Mohamed EA, Abu Dabrh AM, Prokop LJ, Wang Z, Murad MH, Mohammed K. Antiviral therapy for chronic hepatitis B viral infection in adults: A systematic review and meta-analysis. Hepatology 2016; 63:284-306. [PMID: 26566246 DOI: 10.1002/hep.28280] [Citation(s) in RCA: 412] [Impact Index Per Article: 45.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 09/23/2015] [Indexed: 01/10/2023]
Abstract
UNLABELLED Chronic hepatitis B viral (HBV) infection remains a significant global health problem. Evidence-based guidelines are needed to help providers determine when treatment should be initiated, which medication is most appropriate, and when treatment can safely be stopped. The American Association for the Study of Liver Diseases HBV guideline methodology and writing committees developed a protocol a priori for this systematic review. We searched multiple databases for randomized controlled trials and controlled observational studies that enrolled adults ≥18 years old diagnosed with chronic HBV infection who received antiviral therapy. Data extraction was done by pairs of independent reviewers. We included 73 studies, of which 59 (15 randomized controlled trials and 44 observational studies) reported clinical outcomes. Moderate-quality evidence supported the effectiveness of antiviral therapy in patients with immune active chronic HBV infection in reducing the risk of cirrhosis, decompensated liver disease, and hepatocellular carcinoma. In immune tolerant patients, moderate-quality evidence supports improved intermediate outcomes with antiviral therapy. Only very low-quality evidence informed the questions about discontinuing versus continuing antiviral therapy in hepatitis B e antigen-positive patients who seroconverted from hepatitis B e antigen to hepatitis B e antibody and about the safety of entecavir versus tenofovir. Noncomparative and indirect evidence was available for questions about stopping versus continuing antiviral therapy in hepatitis B e antigen-negative patients, monotherapy versus adding a second agent in patients with persistent viremia during treatment, and the effectiveness of antivirals in compensated cirrhosis with low-level viremia. CONCLUSION Most of the current literature focuses on the immune active phases of chronic HBV infection; decision-making in other commonly encountered and challenging clinical settings depends on indirect evidence.
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Affiliation(s)
- Anna S F Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI
| | - Brian J McMahon
- Liver Diseases and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY
| | - John B Wong
- Division of Clinical Decision Making, Tufts Medical Center, Boston, MA
| | - Ahmed T Ahmed
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN
| | - Wigdan Farah
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN
| | - Jehad Almasri
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN
| | - Fares Alahdab
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN
| | - Khalid Benkhadra
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN
| | | | - Siddharth Singh
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Essa A Mohamed
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | | | | | - Zhen Wang
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN
| | - Mohammad Hassan Murad
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN.,Division of Preventive, Occupational and Aerospace Medicine, Mayo Clinic, Rochester, MN
| | - Khaled Mohammed
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN.,Division of Preventive, Occupational and Aerospace Medicine, Mayo Clinic, Rochester, MN
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Honda K, Seike M, Murakami K. Benefits of nucleos(t)ide analog treatments for hepatitis B virus-related cirrhosis. World J Hepatol 2015; 7:2404-2410. [PMID: 26464756 PMCID: PMC4598611 DOI: 10.4254/wjh.v7.i22.2404] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 08/02/2015] [Accepted: 09/08/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B infection induces progressive liver disease. Before nucleos(t)ide analogs (NUCs) became established as a safe and effective treatment for hepatitis B, it was difficult to suppress the activity of the hepatitis B virus (HBV). Currently, many patients with hepatitis or cirrhosis associated with HBV are treated with NUCs for an extended period of time, and the effects, benefits, and limitations of these treatments have been apparent. This article reviews HBV-related cirrhosis, its natural course and survival, histological improvement after NUC treatments, treatment effects for decompensated cirrhosis, the incidence of hepatocellular carcinoma (HCC) after NUC treatments, and the efficacy of NUC treatments before and after the treatment of patients for HBV-related HCC. Of particular interest are the histological improvements, including regression of fibrosis, that have been achieved with NUC treatments. Liver function of patients with decompensated cirrhosis has significantly improved regardless of the type of NUC applied, and treatment with NUCs has reduced the incidence of HCC in cirrhotic patients. However, cirrhosis remains the strongest risk factor for HCC occurrence following NUC treatments, and the long-term cumulative incidence of HCC after NUC treatments remains high. When recurrence does occur, it is important to reconsider the treatment modality according to the degree of improved liver function that was achieved.
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