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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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Dongelmans EJ, Sonneveld MJ, Janssen HLA. Letter to the Editor: Benefits of stopping therapy in patients with cirrhotic hepatitis B, true effect or residual confounding? Hepatology 2024; 79:E95-E96. [PMID: 37862458 DOI: 10.1097/hep.0000000000000639] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 09/14/2023] [Indexed: 10/22/2023]
Affiliation(s)
- Edo J Dongelmans
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Milan J Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Harry L A Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
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Varghese N, Majeed A, Nyalakonda S, Boortalary T, Halegoua-DeMarzio D, Hann HW. Review of Related Factors for Persistent Risk of Hepatitis B Virus-Associated Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:777. [PMID: 38398168 PMCID: PMC10887172 DOI: 10.3390/cancers16040777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 01/30/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Chronic hepatitis B virus (HBV) infection is the largest global cause of hepatocellular carcinoma (HCC). Current HBV treatment options include pegylated interferon-alpha and nucleos(t)ide analogues (NAs), which have been shown to be effective in reducing HBV DNA levels to become undetectable. However, the literature has shown that some patients have persistent risk of developing HCC. The mechanism in which this occurs has not been fully elucidated. However, it has been discovered that HBV's covalently closed circular DNA (cccDNA) integrates into the critical HCC driver genes in hepatocytes upon initial infection; additionally, these are not targets of current NA therapies. Some studies suggest that HBV undergoes compartmentalization in peripheral blood mononuclear cells that serve as a sanctuary for replication during antiviral therapy. The aim of this review is to expand on how patients with HBV may develop HCC despite years of HBV viral suppression and carry worse prognosis than treatment-naive HBV patients who develop HCC. Furthermore, HCC recurrence after initial surgical or locoregional treatment in this setting may cause carcinogenic cells to behave more aggressively during treatment. Curative novel therapies which target the life cycle of HBV, modulate host immune response, and inhibit HBV RNA translation are being investigated.
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Affiliation(s)
- Nevin Varghese
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Amry Majeed
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Suraj Nyalakonda
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Tina Boortalary
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Hie-Won Hann
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
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Mitchell T, Nayagam JS, Dusheiko G, Agarwal K. Health inequalities in the management of chronic hepatitis B virus infection in patients from sub-Saharan Africa in high-income countries. JHEP REPORTS : INNOVATION IN HEPATOLOGY 2022; 5:100623. [PMID: 36636709 PMCID: PMC9829705 DOI: 10.1016/j.jhepr.2022.100623] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 10/21/2022] [Accepted: 10/24/2022] [Indexed: 11/06/2022]
Abstract
Chronic hepatitis B virus disproportionately affects migrant communities in high-income countries, reflecting increased migration from sub-Saharan Africa. Chronic hepatitis B virus is endemic in sub-Saharan Africa, yet the natural history of chronic infection experienced by patients remains incompletely understood, with evidence of variability across genotypes and regions within sub-Saharan Africa. Clinical guidelines recommending treatment thresholds are not specific to sub-Saharan African patients and are based on natural history studies from Western Pacific Asian countries. Access to standard of care treatment is available for sub-Saharan African people with chronic hepatitis B virus infection in high-income countries; however, the evidence base for these treatments was not established in this cohort and areas of uncertainty remain, particularly regarding HCC surveillance and treatment discontinuation. Participation in phase III clinical trials for chronic hepatitis B therapies is almost non-existent amongst sub-Saharan African patients, even when residing in high-income countries that participate in multicentre trials. Engagement with sub-Saharan African patients with chronic hepatitis B in high-income countries is challenging because of the stigma associated with the diagnosis, absence of routine screening systems and the complexities involved in navigating the healthcare system. Nonetheless, improved engagement is critical if we are to achieve global hepatitis B virus elimination.
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Affiliation(s)
- Tim Mitchell
- Institute of Liver Studies, King’s College Hospital, London, United Kingdom,Gastroenterology and Hepatology Department, Royal Perth Hospital, Perth, Australia,Corresponding author. Address: Gastroenterology and Hepatology Department, Level 8 A Block, Royal Perth Hospital, 197 Wellington Street, Perth, Western Australia 6000, Australia; Tel.: +61 8 9224 2179.
| | - Jeremy S. Nayagam
- Institute of Liver Studies, King’s College Hospital, London, United Kingdom,Department of Inflammation Biology, King’s College London, London, UK
| | - Geoffrey Dusheiko
- Institute of Liver Studies, King’s College Hospital, London, United Kingdom,University College London Medical School, London, UK
| | - Kosh Agarwal
- Institute of Liver Studies, King’s College Hospital, London, United Kingdom
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Stella L, Santopaolo F, Gasbarrini A, Pompili M, Ponziani FR. Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment. World J Gastroenterol 2022; 28:2251-2281. [PMID: 35800182 PMCID: PMC9185215 DOI: 10.3748/wjg.v28.i21.2251] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/08/2021] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a global health challenge. Due to the high prevalence in low-income countries, hepatitis B virus (HBV) and hepatitis C virus infections remain the main risk factors for HCC occurrence, despite the increasing frequencies of non-viral etiologies. In addition, hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection. The molecular processes underlying HCC development are complex and various, either independent from liver disease etiology or etiology-related. The reciprocal interlinkage among non-viral and viral risk factors, the damaged cellular microenvironment, the dysregulation of the immune system and the alteration of gut-liver-axis are known to participate in liver cancer induction and progression. Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis. The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance, both through clinical-biochemical scores and periodic ultrasound assessment. This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC.
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Affiliation(s)
- Leonardo Stella
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
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Khoo T, Lam D, Olynyk JK. Impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes of liver disease. World J Gastroenterol 2021; 27:4831-4845. [PMID: 34447229 PMCID: PMC8371504 DOI: 10.3748/wjg.v27.i29.4831] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/14/2021] [Accepted: 07/21/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic infections with the hepatitis B and C viruses have significant worldwide health and economic impacts. Previous treatments for hepatitis C such as interferon and ribavirin therapy were ineffective and poorly tolerated by patients. The introduction of directly acting curative antiviral therapy for hepatitis C and the wider use of nucleos(t)ide analogues for suppression of chronic Hepatitis B infection have resulted in many positive developments. Decreasing the prevalence of hepatitis B and C have concurrently reduced transmission rates and hence, the number of new infections. Antiviral treatments have decreased the rates of liver decompensation and as a result, lowered hospitalisation and mortality rates for both chronic hepatitis B and C infection. The quality of life of chronically infected patients has also been improved significantly by modern treatment. Antiviral therapy has stopped the progression of liver disease to cirrhosis in certain patient cohorts and prevented ongoing hepatocellular damage in patients with existing cirrhosis. Longer term benefits of antiviral therapy include a reduced risk of developing hepatocellular carcinoma and decreased number of patients requiring liver transplantation. This review article assesses the literature and summarises the impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes from liver disease.
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Affiliation(s)
- Tiffany Khoo
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch 6150, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
| | - Danielle Lam
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch 6150, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
| | - John K Olynyk
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch 6150, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
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7
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Chon HY, Lee JS, Lee HW, Chun HS, Kim BK, Park JY, Kim DY, Ahn SH, Kim SU. Impact of antiviral therapy on risk prediction model for hepatocellular carcinoma development in patients with chronic hepatitis B. Hepatol Res 2021; 51:406-416. [PMID: 33242365 DOI: 10.1111/hepr.13600] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 10/27/2020] [Accepted: 11/08/2020] [Indexed: 02/08/2023]
Abstract
AIM Risk prediction models for hepatocellular carcinoma (HCC) development are available. However, the influence of antiviral therapy (AVT) on these models in patients with chronic hepatitis B is unknown. METHODS The dynamic changes in risk prediction models during AVT and the association between risk prediction model and the risk of chronic hepatitis B-related HCC development were investigated. Between 2005 and 2017, 4917 patients with chronic hepatitis B (3361 noncirrhotic, 1556 cirrhotic) were recruited. RESULTS The mean age of the study population was 49.3 years and 60.6% (n = 2980) of the patients were male. The mean Chinese University-HCC (CU-HCC) score was 12.7 at baseline in the overall study population, and decreased significantly (mean, 8.7) after 1 year of AVT (p < 0.001). The score was maintained throughout 5 years of AVT (mean, 8.4-8.8; p > 0.05). The proportion of high-risk patients (CU-HCC score ≥ 20) was 28.9% at baseline, and decreased significantly after 1 year of AVT (5.0%; p < 0.001), and remained stable through 5 years of AVT (2.2%-3.6%; p > 0.05). In addition to the score at baseline, the CU-HCC score at 1 year of AVT independently predicted the risk of HCC development (hazard ratio = 1.072; p < 0.001), together with male gender and platelet count (all p < 0.05). CONCLUSIONS The CU-HCC score significantly decreased at 1 year of AVT and was maintained thereafter. The CU-HCC score after 1 year of AVT independently predicted the risk of HCC development in patients with chronic hepatitis B.
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Affiliation(s)
- Hye Yeon Chon
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Jae Seung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ho Soo Chun
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
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Rigopoulou EI, Gatselis N, Arvaniti P, Koukoulis GK, Dalekos GN. Alcoholic liver disease and autoimmune hepatitis: Sometimes a closer look under the surface is needed. Eur J Intern Med 2021; 85:86-91. [PMID: 33451888 DOI: 10.1016/j.ejim.2020.12.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 12/25/2020] [Accepted: 12/27/2020] [Indexed: 02/07/2023]
Abstract
AIMS Differential diagnosis of autoimmune hepatitis (AIH) incorporates various liver diseases, including alcoholic liver disease (ALD). We report on clinical, laboratory and outcome characteristics of AIH patients who were initially referred as ALD based on increased alcohol consumption (AIH/ALD). METHODS From 2000-2019, we retrospectively identified 12 AIH/ALD patients [9 males, age: 61 (30-73) years] in our prospective data base of 317 AIH patients. RESULTS AIH diagnosis was based on aminotransferases elevation in 10 patients, high IgG in 8, compatible autoantibody profile in all and typical/compatible histology in all 9 with available biopsy. There were no significant differences of baseline demographics, presentation, cirrhosis at diagnosis, response to treatment and simplified score compared to 45 age- and sex-matched AIH patients without alcohol consumption and 44 age- and sex-matched ALD patients. However, the AIH/ALD cohort was characterized by more frequent progression to cirrhosis, higher liver-related deaths and overall mortality compared to AIH, though similar to the ALD group. AST/ALT ratio>1 seems to bear a good positive (0.84) and negative predictive value (0.88) for ALD and AIH diagnosis, respectively, but cannot help in discriminating the AIH/ALD variant. CONCLUSIONS AIH should not be forgotten in patients with alcohol use when clinical and laboratory features hint towards the diagnosis of AIH/ALD variant as this group seems to have worse outcome compared to those with AIH alone suggesting the need for closer follow-up and surveillance. Reliable autoantibody testing and cautious interpretation of liver histology appear mandatory for AIH diagnosis in these difficult to diagnose cases.
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Affiliation(s)
- Eirini I Rigopoulou
- Institute of Internal Medicine and Hepatology, 41447 Larissa, Greece; Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110 Larissa, Greece
| | - Nikolaos Gatselis
- Institute of Internal Medicine and Hepatology, 41447 Larissa, Greece; Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110 Larissa, Greece
| | - Pinelopi Arvaniti
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110 Larissa, Greece
| | - George K Koukoulis
- Department of Pathology, Medical School, University of Thessaly, 41110 Larissa, Greece
| | - George N Dalekos
- Institute of Internal Medicine and Hepatology, 41447 Larissa, Greece; Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110 Larissa, Greece.
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Rigopoulou EI, Gatselis NK, Galanis K, Lygoura V, Gabeta S, Zachou K, Dalekos GN. The changing epidemiology of hepatitis B in Greece. Ann Gastroenterol 2021; 34:431-437. [PMID: 33948070 PMCID: PMC8079866 DOI: 10.20524/aog.2021.0614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 01/04/2021] [Indexed: 11/11/2022] Open
Abstract
Background The epidemiology of hepatitis B virus (HBV) infection has changed in recent years as a result of various factors. Our aim was to assess the epidemiological characteristics and the evolution of the HBV infection in a well-defined area of Greece. Method Prospectively collected data from 1910 consecutive patients (60.8% male, age: 50.1 years) with chronic hepatitis B (CHB) followed from 1999-2016 were analyzed. Results Of the patients evaluated, 90.6% were of Greek and 8% of Albanian origin. Vertical/intrafamilial transmission during early childhood (56.8%) and traditional practices (17.2%) were the most common infection sources. Several areas with higher rates of CHB were identified. At first evaluation, 68.8% had chronic infection, 21.7% chronic hepatitis, 6.1% cirrhosis and 3.4% hepatocellular carcinoma (HCC). Comparison between 2 periods (1999-2010 and 2011-2016) revealed older age and longer disease duration at first presentation (P<0.001 for both) to be more common during 2011-2016, while patients of foreign nationality doubled during this period. There was a trend towards more advanced disease stage at first assessment during 2011-2016. Patients after 2011 had lower rates of virological and biochemical breakthrough (P<0.001 for both) during treatment with new antivirals. In addition, fewer patients progressed to cirrhosis (P=0.02) and HCC (P=0.04). Conclusions CHB continues to be a major health problem in Central Greece, as highlighted by the preservation of high prevalence areas and a tendency towards an increase of chronic liver disease burden longitudinally. Our data highlight the need for scaling-up prevention and treatment strategies, especially in at-risk populations.
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Affiliation(s)
- Eirini I Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece
| | - Nikolaos K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece
| | - Konstantinos Galanis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece
| | - Vasiliki Lygoura
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece
| | - Stella Gabeta
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece
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Wang X, Liu X, Dang Z, Yu L, Jiang Y, Wang X, Yan Z. Nucleos(t)ide Analogues for Reducing Hepatocellular Carcinoma in Chronic Hepatitis B Patients: A Systematic Review and Meta-Analysis. Gut Liver 2021. [PMID: 31158948 DOI: 10.5009/gnl18546.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Background/Aims Studies have shown that nucleos(t)ide analogue (NA) treatment can reduce the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients, but it is unclear which NA is most effective. We performed a meta-analysis and systematic review comparing the efficacies of NAs in CHB patients. Methods We searched literature databases for randomized controlled trials (RCTs) and observational studies that analyzed the hepatic biochemical response, virological response, seroconversion rate, drug resistance rate, and HCC incidence rate in CHB patients treated with NAs. Meta-analyses were performed with RevMan and Stata/SE software. Results Twelve cohort studies and one RCT were selected, in which entecavir (ETV), lamivudine (LAM), telbivudine (LdT), and/or tenofovir disoproxil fumarate (TDF) were evaluated in CHB patients. The meta-analysis showed that ETV was superior to LAM with regard to the HCC incidence (p<0.001), biochemical response (p=0.001), virological response (p=0.02), and drug resistance (p<0.001), and ETV was superior to LdT with regard to the virological response (p<0.001) and drug resistance (p<0.001). We found no significant difference between ETV and TDF with regard to the HCC incidence (p=0.08), biochemical response (p=0.39), virological response (p=0.31), serological conversion (p=0.38), or drug resistance (p=0.95). NA-treated patients with pre-existing cirrhosis had a 5.49 times greater incidence of HCC than those without cirrhosis (p<0.001). Conclusions ETV or TDF should be used for long-term first-line monotherapy in CHB patients according to the current guidelines. Standardized protocols are needed for future studies of ETV and TDF to facilitate conclusive comparisons. Patients with cirrhosis are at significantly elevated risk for HCC, despite the benefits of NA treatment.
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Affiliation(s)
- Xinhui Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoli Liu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Zhibo Dang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lihua Yu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuyong Jiang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xianbo Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Zhiyun Yan
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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Wang X, Liu X, Dang Z, Yu L, Jiang Y, Wang X, Yan Z. Nucleos(t)ide Analogues for Reducing Hepatocellular Carcinoma in Chronic Hepatitis B Patients: A Systematic Review and Meta-Analysis. Gut Liver 2021; 14:232-247. [PMID: 31158948 PMCID: PMC7096226 DOI: 10.5009/gnl18546] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 03/12/2019] [Accepted: 04/05/2019] [Indexed: 01/10/2023] Open
Abstract
Background/Aims Studies have shown that nucleos(t)ide analogue (NA) treatment can reduce the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients, but it is unclear which NA is most effective. We performed a meta-analysis and systematic review comparing the efficacies of NAs in CHB patients. Methods We searched literature databases for randomized controlled trials (RCTs) and observational studies that analyzed the hepatic biochemical response, virological response, seroconversion rate, drug resistance rate, and HCC incidence rate in CHB patients treated with NAs. Meta-analyses were performed with RevMan and Stata/SE software. Results Twelve cohort studies and one RCT were selected, in which entecavir (ETV), lamivudine (LAM), telbivudine (LdT), and/or tenofovir disoproxil fumarate (TDF) were evaluated in CHB patients. The meta-analysis showed that ETV was superior to LAM with regard to the HCC incidence (p<0.001), biochemical response (p=0.001), virological response (p=0.02), and drug resistance (p<0.001), and ETV was superior to LdT with regard to the virological response (p<0.001) and drug resistance (p<0.001). We found no significant difference between ETV and TDF with regard to the HCC incidence (p=0.08), biochemical response (p=0.39), virological response (p=0.31), serological conversion (p=0.38), or drug resistance (p=0.95). NA-treated patients with pre-existing cirrhosis had a 5.49 times greater incidence of HCC than those without cirrhosis (p<0.001). Conclusions ETV or TDF should be used for long-term first-line monotherapy in CHB patients according to the current guidelines. Standardized protocols are needed for future studies of ETV and TDF to facilitate conclusive comparisons. Patients with cirrhosis are at significantly elevated risk for HCC, despite the benefits of NA treatment.
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Affiliation(s)
- Xinhui Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoli Liu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Zhibo Dang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lihua Yu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuyong Jiang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xianbo Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Zhiyun Yan
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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Tarao K, Nozaki A, Chuma M, Taguri M, Maeda S. Effectiveness of entecavir in preventing hepatocellular carcinoma development is genotype-dependent in hepatitis B virus-associated liver cirrhosis. World J Hepatol 2021; 13:144-150. [PMID: 33584993 PMCID: PMC7856867 DOI: 10.4254/wjh.v13.i1.144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/16/2020] [Accepted: 11/29/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The oral nucleos(t)ide analogue, entecavir (ETV) was demonstrated to reduce the rate of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV)-associated liver cirrhosis. However, the reduction of HCC differs in various regions of the world.
AIM To investigate the reduction of HCC development due to ETV therapy by meta-analysis.
METHODS We surveyed the differences in HCC development following ETV treatment based on published articles using PubMed (2004-2019).
RESULTS The regions with the most marked reduction in HCC development due to ETV therapy were Spain (1.0%/year) and Canada (Southern part, 1.3%/year), and the most ineffective areas were South Korea (3.6%-3.8%/year), China (3.3%/year), Taiwan (2.4%-3.1%/year), and Hong Kong (2.8%/year). Following ETV administration, the incidence of HCC in genotype D regions (1.89% ± 0.28%/year, mean ± SE) was significantly lower than that in genotype C regions (2.91% ± 0.24%/year, P < 0.01). With regard to the initial HBV-DNA level, in genotype C patients (average: 5.61 Log10IU/mL) this was almost the same as that in genotype D patients (average: 5.46 Log10IU/mL). Moreover, there was no association between the prevalence ratio of HBV and the incidence of HCC on ETV treatment.
CONCLUSION The effectiveness of ETV in preventing HCC development in HBV-associated liver cirrhosis is genotype-dependent.
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Affiliation(s)
- Kazuo Tarao
- Department of Gastroenterology, Tarao’s Gastroenterological Clinic, Yokohama City 241-0821, Japan
| | - Akito Nozaki
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama 232-0024, Japan
| | - Makoto Chuma
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama 232-0024, Japan
| | - Masataka Taguri
- Department of Data Science, Yokohama City University School of Data Science, Yokohama 236-0004, Japan
| | - Shin Maeda
- Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
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Oh H, Yoon EL, Jun DW, Ahn SB, Lee HY, Jeong JY, Kim HS, Jeong SW, Kim SE, Shim JJ, Sohn JH, Cho YK. No Difference in Incidence of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Virus Infection Treated With Entecavir vs Tenofovir. Clin Gastroenterol Hepatol 2020; 18:2793-2802.e6. [PMID: 32135246 DOI: 10.1016/j.cgh.2020.02.046] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 02/14/2020] [Accepted: 02/22/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Studies to evaluate risks of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection treated with the nucelos(t)ide analogues entecavir or tenofovir have produced contradictory results. These differences are likely to be the result of censored data, insufficient observation periods, and different observation periods for patients treated with different drugs. We aimed to compare the incidence of HCC development between patients treated with oral entecavir or tenofovir and followed up for the same time periods. METHODS We performed a retrospective study, collecting data from 1560 treatment-naive patients with chronic HBV infection who were first treated with entecavir (n = 753) or tenofovir (n = 807) from 2011 through 2015 at 9 academic hospitals in Korea. Clinical outcomes were recorded over a mean time period of 4.7 ± 1.0 years, from 92.4% of patients treated with tenofovir and 92.7% of patients treated with entecavir. RESULTS Thirty-four patients in the entecavir group (4.5%) and 45 patients in the tenofovir group (5.6%) developed HCC during the follow-up period. The incidence of HCC did not differ significantly between groups, even in a 516-pair propensity score-matched population. CONCLUSIONS In a retrospective study of 1560 treatment-naive patients with chronic HBV infection, the incidence of HCC did not differ significantly between patients treated with entecavir vs tenofovir over the same observation period. CLINICAL TRIAL KCT0003487.
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Affiliation(s)
- Hyunwoo Oh
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Eileen L Yoon
- Department of Internal Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Republic of Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Republic of Korea.
| | - Sang Bong Ahn
- Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University College of Medicine, Seoul, Republic of Korea
| | - Hyo-Young Lee
- Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University College of Medicine, Seoul, Republic of Korea
| | - Jae Yoon Jeong
- Department of Gastroenterology and Hepatology, National Medical Center, Seoul, Korea
| | - Hyoung Su Kim
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Sung Eun Kim
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang-si, Republic of Korea
| | - Jae-Jun Shim
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea
| | - Joo Hyun Sohn
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri-si, Republic of Korea
| | - Yong Kyun Cho
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Adjuvant Fuzheng Huayu Capsule Reduces the Incidence of Hepatocellular Carcinoma in Patients with Hepatitis B-Caused Cirrhosis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:8826091. [PMID: 33178324 PMCID: PMC7644307 DOI: 10.1155/2020/8826091] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 09/28/2020] [Accepted: 10/16/2020] [Indexed: 12/28/2022]
Abstract
Aim Fuzhenghuayu (FZHY) capsule can inhibit the progression of cirrhosis. This study explored whether FZHY can reduce the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis B-caused cirrhosis (HBC) undergoing antiviral therapy. Methods A retrospective review of 842 patients with HBC between 2011 and 2015 was performed, including 270 treated with FZHY combined with nucleos (t) ide analogues (NAs) and 572 with NAs alone. The incidence of HCC was compared between the FZHY (n = 259) and control (n = 259) groups using 1 : 1 propensity score (PS) matching. The incidence of HCC in patients with HBC with different Child-Turcotte-Pugh (CTP) classifications and Toronto HCC risk index (THRI) scores was analyzed using Kaplan-Meier curves. Results The 5-year cumulative incidence of HCC before and after PS matching was 151 (17.9%) and 86 (16.6%), respectively. In PS-matched samples, the multivariate Cox proportional-hazards model indicated that the FZHY group demonstrated a significantly lower risk for HCC than the control group (adjusted hazard ratio [aHR] = 0.32, 95% CI 0.19-0.53 P < 0.001). The risk of HCC diminished with increased duration of FZHY use. The stratified analysis revealed that the FZHY group, regardless of CTP classification, benefited significantly from FZHY therapy. Patients in the medium- and high-THRI risk groups were the dominant population for FZHY. Conclusions FZHY combined with NAs was associated with a significantly lower risk of HCC than NAs alone in patients with HBC, which supports the integration of FZHY with antiviral treatment into clinical practice.
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Tseng CH, Tseng CM, Wu JL, Hsu YC, El-Serag HB. Magnitude of and prediction for risk of hepatocellular carcinoma in patients with chronic hepatitis B taking entecavir or tenofovir therapy: A systematic review. J Gastroenterol Hepatol 2020; 35:1684-1693. [PMID: 32343431 DOI: 10.1111/jgh.15078] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 04/01/2020] [Accepted: 04/23/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) have been shown to reduce incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This systematic review aims to evaluate the magnitude, change over time, and prediction of residual HCC risks in CHB patients treated with ETV/TDF therapy. METHODS Available literature was systematically reviewed through searches of PubMed and EMBASE databases from January 1, 2006 to September 1, 2019, to identify cohort studies that reported HCC incidence in CHB patients during ETV/TDF therapy. Studies were screened by title and abstract and then evaluated for eligibility in terms of full text. RESULTS We identified 141 studies for full-text review, and 34 were eligible for analysis. From 19 studies with data separated by cirrhosis status, the 5-year cumulative incidence of HCC was 0.5-6.9% in patients without cirrhosis, 4.5-21.6% in compensated cirrhosis, and 36.3-46.5% in decompensated cirrhosis. All four studies that addressed temporal changes in HCC risks consistently found the incidence rate decreased over time in patients with cirrhosis, although the findings were inconsistent in patients without cirrhosis. Six predictive scores were developed and validated to predict incident HCC during ETV/TDF therapy in CHB patients. Common scoring variables included age, sex, cirrhosis (fibrosis grade), and hepatic function. Conflicting results were reported in seven individual studies and two meta-analyses that compared ETV versus TDF. CONCLUSIONS The residual risk of HCC remains during ETV/TDF treatment in CHB patients with cirrhosis but declines over time. Risk stratification is attainable by validated predictive scores.
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Affiliation(s)
- Cheng-Hao Tseng
- Division of Gastroenterology and Hepatology, E-DA Cancer Hospital/I-Shou University, Kaohsiung, Taiwan.,Center for Liver Diseases and Division of Gastroenterology and Hepatology, E-DA Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Chao-Ming Tseng
- Division of Gastroenterology and Hepatology, E-DA Cancer Hospital/I-Shou University, Kaohsiung, Taiwan.,Center for Liver Diseases and Division of Gastroenterology and Hepatology, E-DA Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Jia-Ling Wu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, E-DA Cancer Hospital/I-Shou University, Kaohsiung, Taiwan.,Center for Liver Diseases and Division of Gastroenterology and Hepatology, E-DA Hospital/I-Shou University, Kaohsiung, Taiwan.,School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Hashem B El-Serag
- Michael E. DeBakey Veterans Affairs Medical Center and Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine Houston, Houston, Texas, USA
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16
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Gatselis NK, Tornai T, Shums Z, Zachou K, Saitis A, Gabeta S, Albesa R, Norman GL, Papp M, Dalekos GN. Golgi protein-73: A biomarker for assessing cirrhosis and prognosis of liver disease patients. World J Gastroenterol 2020; 26:5130-5145. [PMID: 32982114 PMCID: PMC7495033 DOI: 10.3748/wjg.v26.i34.5130] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/19/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Reliable biomarkers of cirrhosis, hepatocellular carcinoma (HCC), or progression of chronic liver diseases are missing. In this context, Golgi protein-73 (GP73) also called Golgi phosphoprotein-2, was originally defined as a resident Golgi type II transmembrane protein expressed in epithelial cells. As a result, GP73 expression was found primarily in biliary epithelial cells, with only slight detection in hepatocytes. However, in patients with acute or chronic liver diseases and especially in HCC, the expression of GP73 is significantly up-regulated in hepatocytes. So far, few studies have assessed GP73 as a diagnostic or prognostic marker of liver fibrosis and disease progression. AIM To assess serum GP73 efficacy as a diagnostic marker of cirrhosis and/or HCC or as predictor of liver disease progression. METHODS GP73 serum levels were retrospectively determined by a novel GP73 ELISA (QUANTA Lite® GP73, Inova Diagnostics, Inc., Research Use Only) in a large cohort of 632 consecutive patients with chronic viral and non-viral liver diseases collected from two tertiary Academic centers in Larissa, Greece (n = 366) and Debrecen, Hungary (n = 266). Aspartate aminotransferase (AST)/Platelets (PLT) ratio index (APRI) was also calculated at the relevant time points in all patients. Two hundred and three patients had chronic hepatitis B, 183 chronic hepatitis C, 198 alcoholic liver disease, 28 autoimmune cholestatic liver diseases, 15 autoimmune hepatitis, and 5 with other liver-related disorders. The duration of follow-up was 50 (57) mo [median (interquartile range)]. The development of cirrhosis, liver decompensation and/or HCC during follow-up were assessed according to internationally accepted guidelines. In particular, the surveillance for the development of HCC was performed regularly with ultrasound imaging and alpha-fetoprotein (AFP) determination every 6 mo in cirrhotic and every 12 mo in non-cirrhotic patients. RESULTS Increased serum levels of GP73 (> 20 units) were detected at initial evaluation in 277 out of 632 patients (43.8%). GP73-seropositivity correlated at baseline with the presence of cirrhosis (96.4% vs 51.5%, P < 0.001), decompensation of cirrhosis (60.3% vs 35.5%, P < 0.001), presence of HCC (18.4% vs 7.9%, P < 0.001) and advanced HCC stage (52.9% vs 14.8%, P = 0.002). GP73 had higher diagnostic accuracy for the presence of cirrhosis compared to APRI score [Area under the curve (AUC) (95%CI): 0.909 (0.885-0.934) vs 0.849 (0.813-0.886), P = 0.003]. Combination of GP73 with APRI improved further the accuracy (AUC: 0.925) compared to GP73 (AUC: 0.909, P = 0.005) or APRI alone (AUC: 0.849, P < 0.001). GP73 levels were significantly higher in HCC patients compared to non-HCC [22.5 (29.2) vs 16 (20.3) units, P < 0.001) and positively associated with BCLC stage [stage 0: 13.9 (10.8); stage A: 17.1 (16.8); stage B: 19.6 (22.3); stage C: 32.2 (30.8); stage D: 45.3 (86.6) units, P < 0.001] and tumor dimensions [very early: 13.9 (10.8); intermediate: 19.6 (18.4); advanced: 29.1 (33.6) units, P = 0.004]. However, the discriminative ability for HCC diagnosis was relatively low [AUC (95%CI): 0.623 (0.570-0.675)]. Kaplan-Meier analysis showed that the detection of GP73 in patients with compensated cirrhosis at baseline, was prognostic of higher rates of decompensation (P = 0.036), HCC development (P = 0.08), and liver-related deaths (P < 0.001) during follow-up. CONCLUSION GP73 alone appears efficient for detecting cirrhosis and superior to APRI determination. In combination with APRI, its diagnostic performance can be further improved. Most importantly, the simple GP73 measurement proved promising for predicting a worse outcome of patients with both viral and non-viral chronic liver diseases.
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Affiliation(s)
- Nikolaos K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa 41110, Greece
- Institute of Internal Medicine and Hepatology, Larissa 41447, Greece
| | - Tamás Tornai
- Department of Internal Medicine, Division of Gastroenterology, University of Debrecen, Faculty of Medicine, Debrecen H-4032, Hungary
| | - Zakera Shums
- Department of Research and Development, Inova Diagnostics, Inc., San Diego, CA 92131, United States
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa 41110, Greece
- Institute of Internal Medicine and Hepatology, Larissa 41447, Greece
| | - Asterios Saitis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa 41110, Greece
| | - Stella Gabeta
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa 41110, Greece
| | - Roger Albesa
- Department of Research and Development, Inova Diagnostics, Inc., San Diego, CA 92131, United States
| | - Gary L Norman
- Department of Research and Development, Inova Diagnostics, Inc., San Diego, CA 92131, United States
| | - Mária Papp
- Department of Internal Medicine, Division of Gastroenterology, University of Debrecen, Faculty of Medicine, Debrecen H-4032, Hungary
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa 41110, Greece
- Institute of Internal Medicine and Hepatology, Larissa 41447, Greece
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Wang HW, Lai HC, Hu TH, Su WP, Lu SN, Lin CH, Hung CH, Chuang PH, Wang JH, Lee MH, Chen CH, Peng CY. On-Treatment Changes in FIB-4 and 1-Year FIB-4 Values Help Identify Patients with Chronic Hepatitis B Receiving Entecavir Therapy Who Have the Lowest Risk of Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12051177. [PMID: 32392752 PMCID: PMC7281667 DOI: 10.3390/cancers12051177] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 05/05/2020] [Indexed: 02/08/2023] Open
Abstract
Noninvasive fibrosis indices can help stratify the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving nucleos(t)ide analogue (NA) therapy. We investigated the predictive performance of on-treatment changes in FIB-4 (△FIB-4) and 1-year FIB-4 values (FIB-4 12M) for HCC risk in patients with CHB receiving entecavir therapy. We included 1325 NA-naïve patients with CHB treated with entecavir, retrospectively, from January 2007 to August 2012. A combination of △FIB-4 and FIB-4 12M was used to stratify the cumulative risk of HCC into three subgroups each in the noncirrhotic and cirrhotic subgroups with p < 0.0001 by using the log-rank test (noncirrhotic: the highest risk (n = 88): FIB-4 12M ≥ 1.58/△FIB-4 ≥ 0 (hazard ratio (HR): 40.35; 95% confidence interval (CI): 5.107–318.7; p <0.0001) and cirrhotic: the highest risk (n = 89): FIB-4 12M ≥2.88/△FIB-4 ≥0 (HR: 9.576; 95% CI: 5.033–18.22; p < 0.0001)). Patients with noncirrhotic CHB treated with entecavir who had a FIB-4 12M < 1.58 or FIB-4 12M ≥ 1.58/△FIB-4 < 0 exhibited the lowest 5-year HCC risk (0.6%). A combination of on-treatment changes in FIB-4 and 1-year FIB-4 values may help identify patients with CHB receiving entecavir therapy with the lowest risk of HCC.
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Affiliation(s)
- Hung-Wei Wang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (H.-C.L.); (W.-P.S.); (C.-H.L.); (P.-H.C.)
| | - Hsueh-Chou Lai
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (H.-C.L.); (W.-P.S.); (C.-H.L.); (P.-H.C.)
- School of Chinese Medicine, China Medical University, Taichung 404, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; (T.-H.H.); (S.-N.L.); (C.-H.H.); (J.-H.W.)
| | - Wen-Pang Su
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (H.-C.L.); (W.-P.S.); (C.-H.L.); (P.-H.C.)
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; (T.-H.H.); (S.-N.L.); (C.-H.H.); (J.-H.W.)
| | - Chia-Hsin Lin
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (H.-C.L.); (W.-P.S.); (C.-H.L.); (P.-H.C.)
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; (T.-H.H.); (S.-N.L.); (C.-H.H.); (J.-H.W.)
| | - Po-Heng Chuang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (H.-C.L.); (W.-P.S.); (C.-H.L.); (P.-H.C.)
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; (T.-H.H.); (S.-N.L.); (C.-H.H.); (J.-H.W.)
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan;
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; (T.-H.H.); (S.-N.L.); (C.-H.H.); (J.-H.W.)
- Correspondence: (C.-H.C.); (C.-Y.P.); Tel.: +886-4-2205-2121 (ext. 2260) (C.-Y.P.)
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; (H.-W.W.); (H.-C.L.); (W.-P.S.); (C.-H.L.); (P.-H.C.)
- School of Medicine, China Medical University, Taichung 404, Taiwan
- Correspondence: (C.-H.C.); (C.-Y.P.); Tel.: +886-4-2205-2121 (ext. 2260) (C.-Y.P.)
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Ding Y, Liu K, Xu Y, Zhao Q, Lou S, Xiang X, Yan L, Cao Z, Xie Q, Zhu C, Bao S, Wang H. Combination of inflammatory score/liver function and AFP improves the diagnostic accuracy of HBV-related hepatocellular carcinoma. Cancer Med 2020; 9:3057-3069. [PMID: 32150664 PMCID: PMC7196063 DOI: 10.1002/cam4.2968] [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] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 01/23/2020] [Accepted: 02/19/2020] [Indexed: 02/06/2023] Open
Abstract
Background Alpha‐fetoprotein (AFP), routinely used for diagnosis of hepatocellular carcinoma (HCC), is limited with relatively low sensitivity and high false positivity in HBV‐related HCC (HBV‐HCC). Thus, an alternative approach was explored to improve specificity/sensitivity for diagnosis of HBV‐HCC, using the combination of AFP, inflammatory score, and liver function. Methods Chronic hepatitis B (CHB) (n = 510) and HBV‐HCC (n = 473) patients were identified retrospectively for this study. The diagnostic value of single vs combined biomarkers for HBV‐HCC was analyzed, using ROC curve. Results It was observed that elderliness, male sex, cirrhosis, HBeAg+ or no‐antiviral therapy, and elevation of ALT, AST, neutrophil‐lymphocyte ratio (NLR), and AFP were associated with developing HBV‐HCC. However, the cut‐off ALT defined by Chinese standard, but not by AASLD, was a risk factor. Interestingly, AFP of HBeAg‐ HBV‐HCC patients without cirrhosis was significantly higher than that of the HBeAg+ patients. AUC values for AFP, ALT, AST, or NLR were 0.84 (95% CI: 0.815‐0.862), 0.533 (95% CI: 0.501‐0.565), 0.696 (95% CI: 0.666‐0.725), or 0.684 (95% CI: 0.654‐0.713) with optimal cut‐off at 7.21 ng/mL, 43 IU/mL, 38 IU/mL, or 2.61, respectively. Combination of AFP with ALT, AST, and NLR improved the diagnostic performance for HBV‐HCC, compared to any of the single biomarkers or any other combinations among these patients (except no‐cirrhosis). Conclusions Elderliness, male sex, elevated ALT, AST, NLR, AFP, cirrhosis, HBeAg+, and no‐antiviral treatment were independent risk factors for HBV‐HCC. AASLD standard of ALT cut‐off value may not be suitable for the Chinese population. Regular monitoring of HCC among HBeAg‐ patients with abnormal AFP may improve the management of HBV‐HCC. The diagnostic performance of AFP combined with ALT, AST, and NLR for HBV‐HCC was superior to single biomarker or any other combinations among these patients, and its diagnostic equation can be used as useful tool for differentiation of HBV‐HCC from CHB.
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Affiliation(s)
- Yezhou Ding
- Department of Infectious Diseases and Hepatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kehui Liu
- Department of Infectious Diseases and Hepatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Infectious Diseases, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yumin Xu
- Department of Infectious Diseases and Hepatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qingqing Zhao
- Department of Infectious Diseases and Hepatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shike Lou
- Department of Infectious Diseases and Hepatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaogang Xiang
- Department of Infectious Diseases and Hepatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Yan
- Department of Infectious Diseases and Hepatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhujun Cao
- Department of Infectious Diseases and Hepatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing Xie
- Department of Infectious Diseases and Hepatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chuanwu Zhu
- Department of Infectious Diseases, The Fifth People's Hospital of Suzhou, Jiangsu, China
| | - Shisan Bao
- Discipline of Pathology, School of Medical Sciences and Bosch Institute, Charles Perkin Centre, The University of Sydney, New South Wales, Australia
| | - Hui Wang
- Department of Infectious Diseases and Hepatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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19
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Dynamic prediction of liver cirrhosis risk in chronic hepatitis B patients using longitudinal clinical data. Eur J Gastroenterol Hepatol 2020; 32:120-126. [PMID: 31688313 DOI: 10.1097/meg.0000000000001592] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
OBJECTIVES In longitudinal studies, serum biomarkers are often measured longitudinally which is valuable to predict the risk of disease progression. Previous risk prediction models for liver cirrhosis restrict data to baseline or baseline and a single follow-up time point, which failed to incorporate the time-dependent marker information. The aim of this study is to develop risk model in patients with chronic hepatitis B for dynamic prediction of cirrhosis by incorporating longitudinal clinical data. METHODS Data from the hospital-based retrospective cohort at the Third Affiliated Hospital of Sun Yat-sen University, from 2004 to 2016, were analyzed. Using the multilevel logistic regression model, the time-dependent marker information and individual characteristics were taken as input, and the risk of at different time as the output. RESULTS At the end of follow-up, 8.8% of patients progressed to cirrhosis, the average estimate values of hepatitis B virus DNA and alanine aminotransferase demonstrated a downward trend, the aspartate aminotransferase/alanine aminotransferase ratio showed a flat trend overall. The important predictors were as follows: age, oral antiviral treatment, hepatitis B virus DNA. This risk prediction model had an area under the receiver operator characteristic curve of 0.835 (95% confidence interval: 0.772-0.899) and 0.809 (95% confidence interval: 0.708-0.910) in the derivation and validation sets, respectively. CONCLUSION Longitudinal prediction model can be used for dynamic prediction of disease progression and identify changing high-risk patients.
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Wang HW, Lai HC, Hu TH, Su WP, Lu SN, Lin CH, Hung CH, Chuang PH, Wang JH, Lee MH, Chen CH, Peng CY. Stratification of hepatocellular carcinoma risk through modified FIB-4 index in chronic hepatitis B patients on entecavir therapy. J Gastroenterol Hepatol 2019; 34:442-449. [PMID: 29968933 DOI: 10.1111/jgh.14372] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 06/14/2018] [Accepted: 06/26/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Noninvasive fibrosis indices can predict the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Modified FIB-4 (mFIB-4) is a promising noninvasive index for predicting liver fibrosis. To investigate the predictive accuracy of several extant noninvasive fibrosis indices, including mFIB-4, for HCC incidence in CHB patients receiving long-term entecavir therapy. METHODS We enrolled 1325 nucleos(t)ide analogue-naïve CHB patients (noncirrhotic 844; cirrhotic 481) treated with entecavir. Baseline clinical features and fibrosis indices were collected and evaluated for predicting HCC risk through univariate and multivariate Cox regression analyses. RESULTS Of the 1325 patients, 105 (7.9%) developed HCC during a median follow-up period of 4.1 years. Age (hazard ratio [HR], 1.039; 95% confidence interval [CI], 1.020-1.059; P < 0.0001), diabetes mellitus (DM) (HR, 1.902; 95% CI, 1.185-3.052; P = 0.0077), and mFIB-4 (HR, 4.619; 95% CI, 1.810-11.789; P = 0.0014) were independent predictors of HCC in all patients (mFIB-4 ≥ 1.5 for the noncirrhotic cohort; DM and mFIB-4 ≥ 2.0 for the cirrhotic cohort). A combination of mFIB-4 and the DM status stratified the cumulative risk of HCC into three subgroups in all patients (high: mFIB-4 ≥ 1.5/DM; intermediate: mFIB-4 ≥ 1.5/non-DM; and low: mFIB-4 < 1.5, P < 0.0001) and in the cirrhotic cohort (high: mFIB-4 ≥ 2.0/DM; intermediate: mFIB-4 ≥ 2.0/non-DM; and low: mFIB-4 < 2.0, P = 0.0007). An mFIB-4 cutoff value of 1.5 stratified the cumulative risk of HCC in the noncirrhotic cohort (P = 0.015). CONCLUSIONS The mFIB-4 index alone or in combination with DM is the optimal noninvasive predictor of HCC risk in CHB patients receiving entecavir therapy.
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Affiliation(s)
- Hung-Wei Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Hsueh-Chou Lai
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Wen-Pang Su
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chia-Hsin Lin
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Po-Heng Chuang
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Cheng-Yuan Peng
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Medicine, China Medical University, Taichung, Taiwan
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21
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Stournaras E, Neokosmidis G, Stogiannou D, Protopapas A, Tziomalos K. Effects of antiviral treatment on the risk of hepatocellular cancer in patients with chronic viral hepatitis. Eur J Gastroenterol Hepatol 2018; 30:1277-1282. [PMID: 30179906 DOI: 10.1097/meg.0000000000001254] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a major complication of chronic hepatitis B (CHB) and chronic hepatitis C (CHC). Accumulating data suggest that antiviral treatment in both CHB and CHC reduces the incidence of HCC. Evidence is more consistent for interferon-based treatment in both CHB and CHC and for lamivudine in patients with CHB. However, more limited data suggest that other nucleos(t)ide analogues might also reduce the risk of HCC. In contrast, conflicting data have been reported on the effects of direct-acting antivirals on the incidence of HCC.
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MESH Headings
- Antiviral Agents/therapeutic use
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/prevention & control
- Carcinoma, Hepatocellular/virology
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/drug therapy
- Hepatitis B, Chronic/epidemiology
- Hepatitis B, Chronic/virology
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/epidemiology
- Hepatitis C, Chronic/virology
- Humans
- Incidence
- Liver Neoplasms/diagnosis
- Liver Neoplasms/epidemiology
- Liver Neoplasms/prevention & control
- Liver Neoplasms/virology
- Protective Factors
- Risk Factors
- Treatment Outcome
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Affiliation(s)
- Evangelos Stournaras
- First Propaedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
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22
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Papatheodoridis GV, Sypsa V, Dalekos G, Yurdaydin C, van Boemmel F, Buti M, Goulis J, Calleja JL, Chi H, Manolakopoulos S, Loglio A, Siakavellas S, Gatselis N, Keskın O, Lehretz M, Savvidou S, de la Revilla J, Hansen BE, Kourikou A, Vlachogiannakos I, Galanis K, Idilman R, Colombo M, Esteban R, Janssen HLA, Berg T, Lampertico P. Eight-year survival in chronic hepatitis B patients under long-term entecavir or tenofovir therapy is similar to the general population. J Hepatol 2018; 68:1129-1136. [PMID: 29427727 DOI: 10.1016/j.jhep.2018.01.031] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 01/21/2018] [Accepted: 01/28/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS The effects of long-term antiviral therapy on survival have not been adequately assessed in chronic hepatitis B (CHB). In this 10-centre, ongoing cohort study, we evaluated the probability of survival and factors affecting survival in Caucasian CHB patients who received long-term entecavir/tenofovir therapy. METHODS We included 1,951 adult Caucasians with CHB, with or without compensated cirrhosis and without hepatocellular carcinoma (HCC) at baseline, who received entecavir/tenofovir for ≥12 months (median, six years). Kaplan-Meier estimates of cumulative survival over time were obtained. Standardized mortality ratios (SMRs) were calculated by comparing death rates with those in the Human Mortality Database. RESULTS The one-, five-, and eight-year cumulative probabilities were 99.7, 95.9, and 94.1% for overall survival, 99.9, 98.3, and 97.4% for liver-related survival, and 99.9, 97.8, and 95.8% for transplantation-free liver-related survival, respectively. Overall mortality was independently associated with older age and HCC development, liver-related mortality was associated with HCC development only, and transplantation-free liver-related mortality was independently associated with HCC development and lower platelet levels at baseline. Baseline cirrhosis was not independently associated with any type of mortality. Compared with the general population, in all CHB patients mortality was not significantly different (SMR 0.82), whereas it was lower in patients without HCC regardless of baseline cirrhosis (SMR 0.58) and was higher in patients who developed HCC (SMR 3.09). CONCLUSION Caucasian patients with CHB and compensated liver disease who receive long-term entecavir/tenofovir therapy have excellent overall and liver-related eight-year survival, which is similar to that of the general population. HCC is the main factor affecting their overall mortality, and is the only factor affecting their liver-related mortality. LAY SUMMARY Caucasian patients with chronic hepatitis B with or without compensated cirrhosis who receive long-term entecavir or tenofovir therapy have excellent overall eight-year survival, which is similar to that of the general population. Hepatocellular carcinoma is the main factor affecting their overall mortality, and is the only factor affecting liver-related mortality in this setting.
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Affiliation(s)
- George V Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.
| | - Vana Sypsa
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - George Dalekos
- Department of Internal Medicine, Thessalia University Medical School, Larissa, Greece
| | - Cihan Yurdaydin
- Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey
| | - Florian van Boemmel
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Maria Buti
- Liver Unit, Hospital General Universitario Valle Hebron and Ciberehd, Barcelona, Spain
| | - John Goulis
- 4th Department of Internal Medicine, Αristotle University of Thessaloniki Medical School, Thessaloniki, Greece
| | - Jose Luis Calleja
- Department of Gastroenterology, Hospital U Puerta de Hierro, IDIPHIM CIBERehd, Madrid, Spain
| | - Heng Chi
- Department of Gastroenterology & Hepatology, Erasmus MC, University Medical Center, Rotterdam, Netherlands
| | - Spilios Manolakopoulos
- 2nd Department of Internal Medicine, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Alessandro Loglio
- CRC "AM e A Migliavacca" Center for Liver Disease, Division of Gastrotnerology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Spyros Siakavellas
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Nikolaos Gatselis
- Department of Internal Medicine, Thessalia University Medical School, Larissa, Greece
| | - Onur Keskın
- Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey
| | - Maria Lehretz
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Savvoula Savvidou
- 4th Department of Internal Medicine, Αristotle University of Thessaloniki Medical School, Thessaloniki, Greece
| | - Juan de la Revilla
- Department of Gastroenterology, Hospital U Puerta de Hierro, IDIPHIM CIBERehd, Madrid, Spain
| | - Bettina E Hansen
- Department of Gastroenterology & Hepatology, Erasmus MC, University Medical Center, Rotterdam, Netherlands
| | - Anastasia Kourikou
- 2nd Department of Internal Medicine, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Ioannis Vlachogiannakos
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Kostantinos Galanis
- Department of Internal Medicine, Thessalia University Medical School, Larissa, Greece
| | - Ramazan Idilman
- Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey
| | - Massimo Colombo
- Hepatology Translational Research Center, Humanitas Clinical and Research Centre, Rozzano, Italy
| | - Rafael Esteban
- Liver Unit, Hospital General Universitario Valle Hebron and Ciberehd, Barcelona, Spain
| | - Harry L A Janssen
- Department of Gastroenterology & Hepatology, Erasmus MC, University Medical Center, Rotterdam, Netherlands; Liver Clinic, Toronto Western and General Hospital, University Health Network, Toronto, ON, Canada
| | - Thomas Berg
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Pietro Lampertico
- CRC "AM e A Migliavacca" Center for Liver Disease, Division of Gastrotnerology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
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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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24
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Chen CH, Lee CM, Lai HC, Hu TH, Su WP, Lu SN, Lin CH, Hung CH, Wang JH, Lee MH, Peng CY. Prediction model of hepatocellular carcinoma risk in Asian patients with chronic hepatitis B treated with entecavir. Oncotarget 2017; 8:92431-92441. [PMID: 29190928 PMCID: PMC5696194 DOI: 10.18632/oncotarget.21369] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 08/28/2017] [Indexed: 12/15/2022] Open
Abstract
Background Until now, no risk score could predict hepatocellular carcinoma (HCC) in nucleos(t)ide analog (NA)-treated Asian patients. Methods We enrolled 1325 NA-naïve chronic hepatitis B patients with entecavir monotherapy for >12 months, with 883 and 442 patients randomly assigned to the development and validation groups, respectively, in the risk model. Results The cumulative probabilities of HCC were 2.4%, 4.1%, and 9.9% after 2, 3, and 5 years of treatment, respectively. In the development group, age, platelet counts, and alpha-fetoprotein levels after 12 months of treatment were the independent predictors of HCC. We converted the Cox proportional hazards regression coefficients for these predictors into risk scores and developed the APA-B model, with the total risk scores ranging from 0 to 15. The risk scores accurately categorized patients with low (0–5), medium (6–9), and high (10–15) risks in the validation group (P <0.001). The areas under the receiver operating characteristic curve for predicting HCC risk after 2, 3, and 5 years were 0.877, 0.842, and 0.827, respectively, in the development group and 0.939, 0.892, and 0.862, respectively, in the validation group. Conclusion The proposed HCC risk prediction model exhibited excellent predictive accuracy in NA-naïve Asian patients receiving entecavir therapy.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chuan-Mo Lee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hsueh-Chou Lai
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Wen-Pang Su
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chia-Hsin Lin
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Cheng-Yuan Peng
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Medicine, China Medical University, Taichung, Taiwan
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25
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Sohn W, Cho JY, Kim JH, Lee JI, Kim HJ, Woo MA, Jung SH, Paik YH. Risk score model for the development of hepatocellular carcinoma in treatment-naïve patients receiving oral antiviral treatment for chronic hepatitis B. Clin Mol Hepatol 2017; 23:170-178. [PMID: 28506056 PMCID: PMC5497662 DOI: 10.3350/cmh.2016.0086] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 03/20/2017] [Accepted: 03/21/2017] [Indexed: 12/12/2022] Open
Abstract
Background/Aims This study aimed to develop and validate a risk prediction model for the development of hepatocellular carcinoma (HCC) in treatment-naïve patients receiving oral antiviral treatment for chronic hepatitis B (CHB). Methods We investigated 2,061 Korean treatment-naïve patients with CHB treated with entecavir as an initial therapy. A risk score model for HCC development was developed based on multivariable Cox regression model in a single center (n=990) and was validated using the time-dependent area under the receiver operating characteristic curve (AUROC) in three other centers (n=1,071). The difference of HCC development among risk groups (low, intermediate, and high) categorized by risk score was also investigated. Results The cumulative incidence rates of HCC at 5 years were 11.2% and 8.9% in the testing and validation cohorts, respectively. HCC-Risk Estimating Score in CHB patients Under Entecavir (HCC-RESCUE) is formulated as (age+15×gender [female=0 / male=1]+23×cirrhosis [absence=0 / presence=1]). The AUROCs at 1 year, 3 years, and 5 years were 0.82, 0.81, and 0.81, respectively, in the validation cohort. A significant difference of HCC development in each risk group was determined by the 5-year HCC risk score in the validation cohort (low risk group, 2.1%; intermediate risk group, 9.3%; high risk group, 41.2%, p<0.001). Conclusions The study presents a new risk score model with a good ability to predict HCC development and determine high risk patients for HCC development consisting of readily available clinical factors in treatment-naïve CHB patients receiving entecavir.
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Affiliation(s)
- Won Sohn
- Department of Gastroenterology, Wonkwang University Sanbon Hospital, Gunpo, Korea
| | - Ju-Yeon Cho
- Department of Medicine, Chosun University Hospital, Gwangju, Korea
| | - Ji Hoon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Jung Il Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Hyung Joon Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Min-Ah Woo
- Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.,Department of Health Science and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea
| | - Sin-Ho Jung
- Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.,Department of Health Science and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea
| | - Yong-Han Paik
- Department of Health Science and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.,Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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26
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Zheng NQ, Zheng ZH, Xu HX, Huang MX, Peng XM. Glucose-regulated protein 78 demonstrates antiviral effects but is more suitable for hepatocellular carcinoma prevention in hepatitis B. Virol J 2017; 14:77. [PMID: 28407787 PMCID: PMC5390389 DOI: 10.1186/s12985-017-0747-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 04/06/2017] [Indexed: 02/07/2023] Open
Abstract
Background Hepatitis B virus (HBV) is the leading cause of liver cirrhosis and hepatocellular carcinoma in Asia and Africa. Existing antivirals cannot cure HBV or eliminate risk of hepatocellular carcinoma. Glucose-regulated protein 78 (GRP78) can inhibit HBV replication, but promote virion secretion and hepatocellular cancer cell invasion. For these reasons, the overall effect of GRP78 on HBV production and whether to utilize the HBV replication-inhibitory effect of GRP78 up-regulation or the hepatocellular cancer cell invasion-inhibitory effect of its down-regulation were further investigated in order to improve the efficacy of current antiviral therapy. Methods GRP78 regulations in HepG2.2.15 cells were conducted by transfections of expressing vector and small interfering RNA, respectively. The changes in HBV replication, hepatitis B e antigen (HBeAg) synthesis and hepatoma cell motility were monitored. Results GRP78 overall decreased HBV production due to its HBV replication-inhibitory effect time-dependently overwhelming virion secretion-promoting effect in HepG2.2.15 cells. Unlike the parental cells (HepG2), HepG2.2.15 cells demonstrated decreased expressions of the major genes in the interferon-β1-dependent pathway. Moreover, the expressions of these genes were not affected by GRP78 regulations. However, GRP78 was found to inhibit HBeAg secretion and to increase the retro-transportation of capsid assembly-interfering HBeAg precursor from the endoplasmic reticulum into the cytosol where new viral nucleocapsids formed. Furthermore, GRP78 overexpression promoted wound healing process (the motility) of HepG2.2.15 cells. In contrast, GRP78 knockdown enhanced HBV replication and HBeAg secretion, but they were abolished by entecavir and furin inhibitor, respectively. Conclusions GRP78 mainly demonstrates anti-HBV effects, reducing HBV production and HBeAg secretion. With due regard to the hepatocellular cancer invasion risk of the overexpression and the rectifiability of the unpleasant effects of the knockdown, GRP78 down-regulation may be more suitable to serve as an additive strategy to cover the hepatocellular cancer prevention shortage of current antiviral therapy in the future.
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Affiliation(s)
- Nai Q Zheng
- Department of Infectious Diseases, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zi H Zheng
- Jinan University Clinic, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Hai X Xu
- Department of Infectious Diseases, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ming X Huang
- Center of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-Sen University, 52 Meihua East Road, Zhuhai, 519000, Guangdong, China
| | - Xiao M Peng
- Center of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-Sen University, 52 Meihua East Road, Zhuhai, 519000, Guangdong, China.
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27
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Zhang L, Zhang FK. Recent advances in treatment of chronic hepatitis B with entecavir. Shijie Huaren Xiaohua Zazhi 2017; 25:7-16. [DOI: 10.11569/wcjd.v25.i1.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Entecavir (ETV) is a potent hepatitis B virus inhibitor with a high barrier to resistance, and it has been recommended as one of the first-line drugs for treating chronic hepatitis B (CHB) by guidelines from several international and national societies. This paper reviews the recent advances in the treatment of CHB with ETV, in terms of treatment adherence, efficacy in the treatment of various kinds of patients with CHB, management of patients with partial virological response, viral resistance or treatment failure to ETV, treatment cessation, sequential or combination therapy with ETV and pegylated interferon, as well as the surveillance of hepatocellular carcinoma.
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Lee HW, Park JY, Ahn SH. An evaluation of entecavir for the treatment of chronic hepatitis B infection in adults. Expert Rev Gastroenterol Hepatol 2016; 10:177-86. [PMID: 26610256 DOI: 10.1586/17474124.2016.1125781] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Entecavir is a nucleoside analogue of 2'-deoxyguanosine whose intracellular triphosphate form inhibits replication of the hepatitis B virus. Entecavir is recommended as a first-line monotherapy option for nucleos(t)ide-naïve patients with HBeAg-positive or -negative chronic hepatitis B infection. Entecavir has a three-step mechanism of action: It maintains viral suppression with a greater than 90% chance of undetectable hepatitis B virus DNA during continuous therapy, improves liver histology, and reduces the risk of liver failure or hepatocellular carcinoma development. The safety profile of long-term entecavir therapy is favorable; however, its optimal treatment duration is unknown. Entecavir monotherapy is not a rescue option for patients with lamivudine/adefovir resistance or baseline lamivudine-resistant mutants; rather, combination treatment is recommended for patients with lamivudine/adefovir resistance.
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Affiliation(s)
- Hye Won Lee
- a Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Korea.,b Yonsei Liver Center , Severance hospital , Seoul , Korea
| | - Jun Yong Park
- a Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Korea.,b Yonsei Liver Center , Severance hospital , Seoul , Korea.,c Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Korea
| | - Sang Hoon Ahn
- a Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Korea.,b Yonsei Liver Center , Severance hospital , Seoul , Korea.,c Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Korea.,d Brain Korea 21 Project for Medical Science , Seoul , Korea
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29
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Kim HS, Kim BK, Kim SU, Park JY, Kim DY, Song KJ, Park JW, Kim YJ, Baatarkhuu O, Han KH, Ahn SH. Association Between Level of Fibrosis, Rather Than Antiviral Regimen, and Outcomes of Patients With Chronic Hepatitis B. Clin Gastroenterol Hepatol 2016; 14:1647-1656.e6. [PMID: 27305847 DOI: 10.1016/j.cgh.2016.05.039] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 05/27/2016] [Accepted: 05/27/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We performed a propensity-score matched analysis to investigate whether entecavir, compared with lamivudine, can reduce risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B after adjusting for level of fibrosis. METHODS We performed a retrospective study of 1079 patients with chronic hepatitis B who received first-line therapy with lamivudine (n = 435) or entecavir (n = 644) from 2006 through 2013. Only patients with available liver stiffness value measured by transient elastography were recruited. Liver cirrhosis was diagnosed by ultrasonography. To adjust for the imbalance of patients treated with lamivudine versus entecavir, we performed propensity-score matching (PSM), at a ratio of 1:1, using 7 factors (age, sex, hepatitis B e antigen, alanine aminotransferase, serum albumin, platelet count, and liver stiffness; PSM1) or 8 factors (variables of PSM1 plus ultrasonography measurements of cirrhosis; PSM2). Patients with virologic breakthrough or resistance mutations received rescue therapy. RESULTS Over the 7-year period, 91 patients developed HCC and 104 had liver-related events in the entire cohort. In multivariate analyses, level of fibrosis, but not antiviral regimen, was independently associated with risk of HCC (P < .05). The PSM1 group included 342 pairs of patients and the PSM2 group included 338 pairs. Similar proportions of patients given lamivudine versus entecavir developed HCC in each model (10.5% given lamivudine vs 9.9% given entecavir in PSM1 and 11.9% vs 12.6% in PSM2; all P > .05). When PSM was applied to patients with liver stiffness value ≤13 kPa or >13 kPa, patients given lamivudine versus entecavir still had similar cumulative rates of HCC development (all P > .05). CONCLUSIONS In a PSM analysis, we associated level of fibrosis, rather than antiviral regimen, with risk of HCC, when patients received appropriate rescue therapy in case of virologic breakthrough or resistance mutations.
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Affiliation(s)
- Hye Soo Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ki Jun Song
- Department of Biostatistics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jung Won Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yeong Jin Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Oidov Baatarkhuu
- Department of Infectious Diseases, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.
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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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31
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Nayagam S, Conteh L, Sicuri E, Shimakawa Y, Suso P, Tamba S, Njie R, Njai H, Lemoine M, Hallett TB, Thursz M. Cost-effectiveness of community-based screening and treatment for chronic hepatitis B in The Gambia: an economic modelling analysis. Lancet Glob Health 2016; 4:e568-78. [PMID: 27443782 DOI: 10.1016/s2214-109x(16)30101-2] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 05/05/2016] [Accepted: 05/23/2016] [Indexed: 12/23/2022]
Abstract
BACKGROUND Despite the high burden of hepatitis B virus (HBV) infection in sub-Saharan Africa, absence of widespread screening and poor access to treatment leads to most people remaining undiagnosed until later stages of disease when prognosis is poor and treatment options are limited. We examined the cost-effectiveness of community-based screening and early treatment with antiviral therapy for HBV in The Gambia. METHODS In this economic evaluation, we combined a decision tree with a Markov state transition model to compare a screen and treat intervention consisting of adult community-based screening using a hepatitis B surface antigen (HBsAg) rapid test and subsequent HBV antiviral therapy versus current practice, in which there is an absence of publicly provided screening or treatment for HBV. We used data from the PROLIFICA study to parameterise epidemiological, primary screening, and cost information, and other model parameter inputs were obtained from a literature search. Outcome measures were cost per disability-adjusted life-year (DALY) averted; cost per life-year saved; and cost per quality-adjusted life-year (QALY) gained. We calculated the incremental cost-effectiveness ratios (ICERs) between current practice and the screen and treat intervention. Costs were assessed from a health provider perspective. Costs (expressed in 2013 US$) and health outcomes were discounted at 3% per year. FINDINGS In The Gambia, where the prevalence of HBsAg is 8·8% in people older than 30 years, adult screening and treatment for HBV has an incremental cost-effectiveness ratio (ICER) of $540 per DALY averted, $645 per life-year saved, and $511 per QALY gained, compared with current practice. These ICERs are in line with willingness-to-pay levels of one times the country's gross domestic product per capita ($487) per DALY averted, and remain robust over a wide range of epidemiological and cost parameter inputs. INTERPRETATION Adult community-based screening and treatment for HBV in The Gambia is likely to be a cost-effective intervention. Higher cost-effectiveness might be achievable with targeted facility-based screening, price reductions of drugs and diagnostics, and integration of HBV screening with other public health interventions. FUNDING European Commission.
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Affiliation(s)
- Shevanthi Nayagam
- Division of Digestive Diseases, St Mary's Hospital, Imperial College, London, UK; Department of Infectious Disease Epidemiology, School of Public Health, Imperial College, London, UK.
| | - Lesong Conteh
- Health Economics Group, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College, London, UK
| | - Elisa Sicuri
- Health Economics Group, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College, London, UK; ISGlobal, Barcelona Centre for International Health Research (CRESIB), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain
| | - Yusuke Shimakawa
- Medical Research Council Laboratories, The Gambia Unit, Fajara, The Gambia; Unité d'Épidémiologie des Maladies Émergentes, Institut Pasteur, Paris, France
| | - Penda Suso
- Medical Research Council Laboratories, The Gambia Unit, Fajara, The Gambia
| | - Saydiba Tamba
- Medical Research Council Laboratories, The Gambia Unit, Fajara, The Gambia
| | - Ramou Njie
- International Agency for Research on Cancer (IARC), Lyon, France
| | - Harr Njai
- Medical Research Council Laboratories, The Gambia Unit, Fajara, The Gambia
| | - Maud Lemoine
- Division of Digestive Diseases, St Mary's Hospital, Imperial College, London, UK; Medical Research Council Laboratories, The Gambia Unit, Fajara, The Gambia
| | - Timothy B Hallett
- Department of Infectious Disease Epidemiology, School of Public Health, Imperial College, London, UK
| | - Mark Thursz
- Division of Digestive Diseases, St Mary's Hospital, Imperial College, London, UK
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Kim SU, Kim BK, Park JY, Kim DY, Ahn SH, Song K, Han KH. Transient Elastography is Superior to FIB-4 in Assessing the Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B. Medicine (Baltimore) 2016; 95:e3434. [PMID: 27196449 PMCID: PMC4902391 DOI: 10.1097/md.0000000000003434] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Liver stiffness (LS), assessed using transient elastography (TE), and (FIB-4) can both estimate the risk of developing hepatocellular carcinoma (HCC). We compared prognostic performances of LS and FIB-4 to predict HCC development in patients with chronic hepatitis B (CHB).Data from 1308 patients with CHB, who underwent TE, were retrospectively analyzed. FIB-4 was calculated for all patients. The cumulative rate of HCC development was assessed using Kaplan-Meier curves. The predictive performances of LS and FIB-4 were evaluated using time-dependent receiver-operating characteristic (ROC) curves.The mean age (883 men) was 50 years. During follow-up (median 6.1 years), 119 patients developed HCC. The areas under the ROC curves (AUROCs) predicting HCC risk at 3, 5, and 7 years were consistently greater for LS than for FIB-4 (0.791-0.807 vs 0.691-0.725; all P < 0.05). Similarly, when the respective AUROCs for LS and FIB-4 at every time point during the 7-year follow-up were plotted, LS also showed consistently better performance than FIB-4 after 1 year of enrollment. The combined use of LS and FIB-4 significantly enhanced the prognostic performance compared with the use of FIB-4 alone (P < 0.05), but the performance of the combined scores was statistically similar to that of LS alone (P > 0.05).LS showed significantly better performance than FIB-4 in assessing the risk of HCC development, and the combined use of LS and FIB-4 did not provide additional benefit compared with the use of LS alone. Hence, LS assessed using TE might be helpful for optimizing HCC surveillance strategies.
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Affiliation(s)
- Seung Up Kim
- From the Department of Internal Medicine (SUK, BKK, JYP, DYK, SHA, K-HH); Institute of Gastroenterology (SUK, BKK, JYP, DYK, SHA, K-HH); Department of Biostatistics (KS), Yonsei University College of Medicine, Seoul, Republic of Korea; and Translational Research Informatics Center (KS, K-HH), Japan
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Roderburg C, Tacke F, Trautwein C. Antiviral Therapy in Patients with Viral Hepatitis and Hepatocellular Carcinoma: Indications and Prognosis. Visc Med 2016; 32:121-6. [PMID: 27413730 PMCID: PMC4926886 DOI: 10.1159/000444990] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Chronic hepatitis B and C infections represent major risk factors for the development of hepatocellular carcinoma (HCC). Recently, the management of patients with viral hepatitis has dramatically changed. In the present review we discuss the impact of these developments on the prevention of HCC as well as the treatment of patients with HCC. METHODS Studies indexed in Medline between 1990 and 2015 (November) were reviewed. The terms 'hepatocellular carcinoma', 'HCC', 'hepatitis B', 'hepatitis C', 'viral hepatitis', and combinations of these terms were used. RESULTS Patients with chronic hepatitis B or hepatitis C without HCC should be evaluated for antiviral therapy, since antiviral therapy was suggested to reduce the risk of HCC development. Cirrhotic patients infected with hepatitis B virus (HBV) require antiviral therapy, while cirrhotics infected with hepatitis C virus (HCV) need to be prioritized for therapy with interferon (IFN)-free regimens. Antiviral therapy should be considered in HBV-infected patients with HCC, especially to prevent tumor recurrence after curative-intended therapy or to prevent hepatic decompensation. HCV-infected patients with HCC should be considered in similar intention for IFN-free antiviral therapy, depending on the tumor stage and life expectancy. CONCLUSION Patients with viral hepatitis should be considered for antiviral treatment for the prevention of HCC development as well as during HCC treatment.
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Affiliation(s)
| | | | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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34
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Oral antiviral therapy reduces the risk of hepatocellular carcinoma in persons with chronic hepatitis B infection: combining evidence and common sense. Hepatol Int 2016; 10:239-41. [DOI: 10.1007/s12072-016-9714-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 02/05/2016] [Indexed: 02/07/2023]
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Jung KS, Kim SU, Song K, Park JY, Kim DY, Ahn SH, Kim BK, Han KH. Validation of hepatitis B virus-related hepatocellular carcinoma prediction models in the era of antiviral therapy. Hepatology 2015; 62:1757-66. [PMID: 26249025 DOI: 10.1002/hep.28115] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Accepted: 08/04/2015] [Indexed: 12/15/2022]
Abstract
UNLABELLED Several risk prediction models have been created to predict hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) occurrence, with promising results. However, their prognostic performances need to be validated in the era of antiviral therapy. From 2006 to 2011, patients with chronic HBV infection were recruited and those with a history of HCC or hepatic decompensation were excluded. At enrollment, liver stiffness (LS) was measured using transient elastography. We assessed the performances of conventional HCC prediction models (CU-HCC, GAG-HCC, REACH-B, and LSM-HCC scores) and the modified REACH-B (mREACH-B) score where LS values were incorporated into REACH-B score instead of serum HBV-DNA levels. Of 1,308 subjects analyzed, the median age was 50.0 years (883 men). During the follow-up (median, 75.3 months), HCC developed in 125 (9.6%) patients. mREACH-B score had the highest areas under the receiver operating characteristic curves (AUROCs) for the prediction of HCC development at 3/5 years (0.828/0.806), compared with LSM-HCC (0.777/0.759), GAG-HCC (0.751/0.757), REACH-B (0.717/0.699), and CU-HCC (0.698/0.700) scores, respectively, with statistical significances (all P values <0.05 vs. mREACH-B). When serum HBV-DNA levels were excluded from the formula for REACH-B score, AUROCs for HCC development at 3/5 years improved paradoxically (from 0.717/0.699 to 0.757/0.732, respectively). In patients with antiviral therapy (n = 848), mREACH-B score had the better prognostic performances for HCC development at 3/5 years, compared to other prediction models. However, in patients without antiviral therapy (n = 460), it had the prognostic performances comparable to those of other prediction models. CONCLUSIONS Prognostic performances of mREACH-B score seemed better compared to conventional models. In the era of antiviral therapy, incorporation of serum HBV-DNA level should be applied cautiously and individual risks should be assessed effectively based on the fibrotic burden.
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Affiliation(s)
- Kyu Sik Jung
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kijun Song
- Department of Biostatistics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Brain Korea 21 Project of Medical Science, Seoul, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Brain Korea 21 Project of Medical Science, Seoul, Republic of Korea
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Rapti I, Hadziyannis S. Risk for hepatocellular carcinoma in the course of chronic hepatitis B virus infection and the protective effect of therapy with nucleos(t)ide analogues. World J Hepatol 2015; 7:1064-1073. [PMID: 26052395 PMCID: PMC4450183 DOI: 10.4254/wjh.v7.i8.1064] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2014] [Revised: 02/10/2015] [Accepted: 03/18/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a major health problem worldwide, representing one of the leading causes of death. Chronic hepatitis B virus (HBV) infection (CHB) is the most important etiologic factor of this tumor, accounting for the development of more than 50% of the cases in the world. Primary prevention of HCC is possible by hepatitis B vaccination conferring protection from HBV infection. However, according to the World Health Organization Hepatitis B Fact sheet N° 204 (update of July 2014) globally there exists a large pool of > 240 million people chronically infected with HBV who are at risk for development of HCC. These individuals represent a target population for secondary prevention both of cirrhosis and of HCC. Since ongoing HBV replication in CHB is linked with the progression of the underlying liver disease to cirrhosis as well as with the development of HCC, effective antiviral treatment in CHB has also been evaluated in terms of secondary prevention of HCC. Currently, most patients with active CHB are subjected to long term treatment with the first line nucleos(t)ide analogues entecavir and tenofovir. These compounds are of high antiviral potency and have a high barrier to HBV resistance compared to lamivudine, adefovir dipivoxil and even telbivudine. Many studies have shown that patients under antiviral treatment, especially those in virological remission, develop less frequently HCC compared to the untreated ones. However, the risk for development of HCC cannot be eliminated. Therefore, surveillance for the development of HCC of patients with chronic hepatitis B must be lifelong or until a time in the future when new treatments will be able to completely eradicate HBV from the liver particularly in the early stages of CHB infection. In this context, the aim of this review is to outline the magnitude of the risk for development of HCC among patients with CHB, in the various phases of the infection and in relation to virus, host and environmental factors as evaluated in the world literature. Moreover, the benefits of antiviral treatment of CHB with nucleos/tide analogs, which have changed the natural history of the disease and have reduced but not eliminated the risk of HCC are also reviewed.
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Russo FP, Rodríguez-Castro K, Scribano L, Gottardo G, Vanin V, Farinati F. Role of antiviral therapy in the natural history of hepatitis B virus-related chronic liver disease. World J Hepatol 2015; 7:1097-1104. [PMID: 26052398 PMCID: PMC4450186 DOI: 10.4254/wjh.v7.i8.1097] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 10/21/2014] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a dynamic state of interactions among HBV, hepatocytes, and the host immune system. Natural history studies of chronic hepatitis B (CHB) infection have shown an association between active viral replication and adverse clinical outcomes such as cirrhosis and hepatocellular carcinoma. The goal of therapy for CHB is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensation, end-stage liver disease, hepatocellular carcinoma (HCC) and death. This goal can be achieved if HBV replication is suppressed in a sustained manner. The accompanying reduction in histological activity of CHB lessens the risk of cirrhosis and of HCC, particularly in non-cirrhotic patients. However, CHB infection cannot be completely eradicated, due to the persistence of covalently closed circular DNA in the nucleus of infected hepatocytes, which may explain HBV reactivation. Moreover, the integration of the HBV genome into the host genome may favour oncogenesis, development of HCC and may also contribute to HBV reactivation.
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Abstract
About 80% of hepatocellular carcinoma (HCC) is caused by hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections especially in the setting of established cirrhosis or advanced fibrosis, making HCC prevention a major goal of antiviral therapy. HCC tumors are highly complex and heterogeneous resulting from the aberrant function of multiple molecular pathways. The roles of HCV or HBV in promoting HCC development are still either directly or indirectly are still speculative, but the evidence for both effects is compelling. In patients with chronic hepatitis viral infection, cirrhosis is not a prerequisite for tumorigenesis.
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Affiliation(s)
- Ziv Ben Ari
- Liver Disease Center, Sheba Medical Center, Derech Sheba No 1, Ramat Gan 52621, Israel; Liver Research Laboratory, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
| | - Ella Weitzman
- Liver Disease Center, Sheba Medical Center, Derech Sheba No 1, Ramat Gan 52621, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Michal Safran
- Liver Disease Center, Sheba Medical Center, Derech Sheba No 1, Ramat Gan 52621, Israel; Liver Research Laboratory, Sheba Medical Center, Ramat Gan, Israel
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Kondo Y, Kimura O, Shimosegawa T. Significant biomarkers for the management of hepatocellular carcinoma. Clin J Gastroenterol 2015; 8:109-15. [PMID: 25855582 DOI: 10.1007/s12328-015-0568-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 03/30/2015] [Indexed: 02/07/2023]
Abstract
Surveillance of hepatocellular carcinoma (HCC) is important for early detection. Imaging tests including computed tomography, magnetic resonance imaging and ultrasonography with or without various kinds of contrast medium are important options for detecting HCC. In addition to the imaging tests, various kinds of biomarkers including alpha-fetoprotein (AFP), lectin-bound AFP (AFP-L3) and protein induced by vitamin K absence or antagonist II (PIVKA-II) have been widely used to detect HCC and analyze treatment response. Recently, various kinds of novel biomarkers (proteins and miRNA) have been found to predict the malignancy potential of HCC and treatment response to specific therapies. Moreover, various combinations of well-established biomarkers and novel biomarkers have been tested to improve sensitivity and specificity. In practical terms, biomarkers that can be analyzed using peripheral blood samples might be more useful than immunohistochemical techniques. It has been reported that quantification of cytokines in peripheral blood and the analysis of peripheral immune subsets could be good biomarkers for managing HCC. Here, we describe the usefulness of and update well-established and novel biomarkers for the management of HCC.
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Affiliation(s)
- Yasuteru Kondo
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo, Aoba, Sendai City, Miyagi, 980-8574, Japan,
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