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Broquetas T, Carrión JA. Past, present, and future of long-term treatment for hepatitis B virus. World J Gastroenterol 2023; 29:3964-3983. [PMID: 37476586 PMCID: PMC10354584 DOI: 10.3748/wjg.v29.i25.3964] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
The estimated world prevalence of hepatitis B virus (HBV) infection is 316 million. HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma (HCC) despite universal vaccination programs, and effective antiviral therapy. Long-term administration of nucleos(t)ide analogues (NA) has been the treatment of choice for chronic hepatitis B during the last decades. The NA has shown a good safety profile and high efficacy in controlling viral replication, improving histology, and decreasing the HCC incidence, decompensation, and mortality. However, the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment. The knowledge, in recent years, about the different phases of the viral cycle, and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches. Consequently, several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results. This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B, the present of NA treatment and withdrawal, and the future perspectives with combined molecules to achieve a functional cure.
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Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
- Universitat Pompeu Fabra, Facultat de Ciències de la Salut i de la Vida, Barcelona 08003, Spain
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2
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Khanam A, Ghosh A, Chua JV, Kottilil S. Blockade of CCR4 breaks immune tolerance in chronic hepatitis B patients by modulating regulatory pathways. J Transl Med 2023; 21:271. [PMID: 37081509 PMCID: PMC10120209 DOI: 10.1186/s12967-023-04104-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 04/04/2023] [Indexed: 04/22/2023] Open
Abstract
BACKGROUND Immunotargets including checkpoint inhibitors and toll-like receptor 8 agonists have recently gained attention for the recovery of hepatitis B virus (HBV)-specific T cell exhaustion in chronic hepatitis B(CHB). Chemokine receptors have a similar significant role during viral infections; however, their role in CHB remains poorly understood. Therefore, in this study we evaluated the role of chemokine receptor 4 (CCR4) in deriving immunosuppression during CHB. METHODS We characterized CCR4+CD8+ T cells in CHB and identified their involvement in immunosuppression. Further, we examined if CCR4 blockade with mogamulizumab antibody can recover the functional exhaustion in HBsAg-specific T cells. RESULTS CHB patients exhibit higher frequency of CCR4+CD8+ T cells that increase with higher HBsAg levels and fibrosis scores. In vitro, HBs antigen triggers CCR4 expression. These cells express multiple inhibitory receptors and exhibit immunosuppressive functions by producing excessive immunoregulatory cytokines IL-4, IL-5, IL-10 and TGF-β1. CCR4 Blockade significantly boosted HBsAg-specific antiviral-cytokine production(IFN-γ, TNF-α and IL-21) in T cells through enhancing their proliferation capacity and polarizing these cells towards T helper 1(Th1) and T follicular helper cells(TFH) in case of CD4 cells, and cytotoxic T cell 1(TC1) and cytotoxic T follicular(TCF) cells in case of CD8. Cytotoxic potential was improved, while no induction of immunosuppressive-cytokines was seen after anti-CCR4 treatment thereby eliminating the risk of treatment-induced immunosuppression. CCR4 blockade inhibited the development and effector function of Tregs by controlling their expansion and TGF-β1 production preventing Tregs-induced immunotolearance. CONCLUSIONS CCR4 blockade reconstitutes antiviral immune response in T cells and limits the immunosuppressive functions of Tregs, representing them as a promising immunotherapeutic target for functional cure of CHB.
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Affiliation(s)
- Arshi Khanam
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - Alip Ghosh
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Joel V Chua
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
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Roade L, Riveiro-Barciela M, Esteban R, Buti M. Long-term efficacy and safety of nucleos(t)ides analogues in patients with chronic hepatitis B. Ther Adv Infect Dis 2021; 8:2049936120985954. [PMID: 33614029 PMCID: PMC7871062 DOI: 10.1177/2049936120985954] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 12/07/2020] [Indexed: 12/11/2022] Open
Abstract
Nucleos(t)ide analogues with high barrier to resistance are regarded as the principal therapeutic option for chronic hepatitis B (CHB). Treatment with entecavir (ETV), tenofovir disoproxil (TDF) and the later released tenofovir alafenamide (TAF) is highly effective at controlling hepatitis B virus (HBV) infection and, in the vast majority of patients, is well tolerated. No significant differences in viral suppression have been described among the different regimens, although an earlier achievement in biochemical response has been suggested first under TDF and recently under TAF. High barrier to resistance NAs rarely achieve hepatitis B surface antigen sero-clearance, and therefore should be maintained life-long in most cases. This has increased concerns about treatment-related toxicity, especially in patients under TDF with additional risk factors for kidney and bone impairment. TAF has shown a better bone and kidney safety profile than TDF, although it is not yet available worldwide due to its higher cost. Emergence of adverse events should be monitored since treatment-switch to ETV/TAF seems to be effective and safe in HBV mono-infected subjects. Finally, although an effective antiviral treatment leads to a clear improvement in clinical outcome of CHB patients; the risk of developing hepatocellular carcinoma (HCC) is not completely avoided with viral suppression. Whether tenofovir-based regimens provide any additional benefit over ETV in HCC prevention remains unclear and requires further investigation.
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Affiliation(s)
- Luisa Roade
- Liver Unit, Internal Medicine Department, Hospital Universitario Vall d'Hebrón, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Carlos III, Madrid, Spain
| | - Mar Riveiro-Barciela
- Liver Unit, Internal Medicine Department, Hospital Universitario Vall d'Hebrón, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Carlos III, Madrid, Spain
| | - Rafael Esteban
- Liver Unit, Internal Medicine Department, Hospital Universitario Vall d'Hebrón, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Carlos III, Madrid, Spain
| | - Maria Buti
- Liver Unit, Internal Medicine Department, Hospital Universitario Vall d'Hebrón, Vall d'Hebron Barcelona Hospital Campus, Barcelona, 119-129, Spain. Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Carlos III, Madrid, Spain
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4
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Kong LN, Zhu WF, He S, Wang T, Guo Y. Development and preliminary validation of the chronic hepatitis B self-management scale. Appl Nurs Res 2018; 41:46-51. [PMID: 29853213 DOI: 10.1016/j.apnr.2018.03.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 12/26/2017] [Accepted: 03/22/2018] [Indexed: 01/16/2023]
Abstract
BACKGROUNDS Chronic hepatitis B (CHB) patients may face many problems resulted from their conditions. To delay the progress of CHB, patients should be responsible for the management of their conditions. There is no dedicated scale for assessing self-management behaviors of CHB patients. OBJECTIVES This study aimed to develop and validate a self-report measure designed to assess the self-management behaviors for CHB patients (CHBSMS). DESIGN A cross-sectional descriptive study design. SETTING Participants were recruited from the infectious disease department of two hospitals in China. PARTICIPANTS A sample of 248 and 346 CHB patients for item analysis and test for validity and reliability, respectively. METHODS An initial 45-item scale developed based on item generation and a two-round Delphi survey was assessed by CHB patients for item analysis to develop a final scale. Construct validity was evaluated by exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). The Chronic Disease Self-Management Behavior Scale (CDSMBS) was used to test the criterion validity. Internal consistency and test-retest reliability were assessed by Cronbach's α coefficient and intraclass correlation coefficient (ICC), respectively. RESULTS A 25-item scale was developed. EFA indicated a four-factor structure (symptom management, lifestyle management, psychosocial coping and disease information management), which accounted for 58.149% of the total variance. CFA indicated appropriate fit of the four-factor model. The total scores of CHBSMS was correlated with that of CDSMBS (r = 0.634, P < 0.01). The Cronbach's α coefficient (α = 0.887) and the test-retest correlation coefficient (ICC = 0.871) showed good internal consistency and stability of the scale. CONCLUSIONS The 25-item CHBSMS is a reliable and valid measure that can be used to assess the self-management behaviors of CHB patients for improving patient education and health-related outcomes.
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Affiliation(s)
- Ling-Na Kong
- School of Nursing, Chongqing Medical University, Chongqing, PR China.
| | - Wen-Fen Zhu
- School of Nursing, Chongqing Medical University, Chongqing, PR China
| | - Shan He
- School of Nursing, Chongqing Medical University, Chongqing, PR China
| | - Tian Wang
- Department of Infectious Diseases, The first Affiliated Hospital of Chongqing Medical University, Chongqing, PR China
| | - Ying Guo
- Department of Internal Medicine, Outpatient Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, PR China
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Kim MN, Hwang SG, Rim KS, Kim BK, Park JY, Kim DY, Ahn SH, Han KH, Kim SU. Validation of PAGE-B model in Asian chronic hepatitis B patients receiving entecavir or tenofovir. Liver Int 2017; 37:1788-1795. [PMID: 28418595 DOI: 10.1111/liv.13450] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 04/07/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS A new hepatocellular carcinoma risk prediction model, PAGE-B, which includes age, gender and platelet count as constituent variables, has recently been proposed in Caucasian chronic hepatitis B patients. We validated PAGE-B model and compared its accuracy with that of conventional risk prediction models in Asian chronic hepatitis B patients. METHODS Chronic hepatitis B patients treated with entecavir or tenofovir were consecutively recruited. The performance of PAGE-B and three conventional risk prediction models (CU-HCC, GAG-HCC and REACH-B) were analysed. RESULTS A total of 1092 chronic hepatitis B patients (668 men, 61.2%) were selected between August 2006 and January 2015. The mean age was 48 years. During the follow-up period (median, 43.6 months), 36 (3.3%) patients developed hepatocellular carcinoma. Older age (hazard ratio [HR]=1.077), male gender (HR=3.676) and lower platelet count (HR=0.984) were independent predictors of hepatocellular carcinoma development. The PAGE-B showed similar area under receiver operating characteristic curves (AUROCs) to GAG-HCC and CU-HCC at 3 years (0.777 vs 0.793 and 0.743, respectively; all P>.05) and 5 years (0.799 vs 0.803 and 0.744, respectively; all P>.05), whereas the AUROCs of PAGE-B were significantly higher than those of the REACH-B (0.602 at 3 years and 0.572 at 5 years, P<.05). CONCLUSIONS Our study demonstrated that PAGE-B is applicable to Asian chronic hepatitis B patients receiving ETV or TDF therapy. The PAGE-B showed similar predictive performance to GAG-HCC and CU-HCC.
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Affiliation(s)
- Mi Na Kim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Seong Gyu Hwang
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Kyu Sung Rim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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Kayaaslan B, Guner R. Adverse effects of oral antiviral therapy in chronic hepatitis B. World J Hepatol 2017; 9:227-241. [PMID: 28261380 PMCID: PMC5316843 DOI: 10.4254/wjh.v9.i5.227] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 11/29/2016] [Accepted: 12/07/2016] [Indexed: 02/06/2023] Open
Abstract
Oral nucleoside/nucleotide analogues (NAs) are currently the backbone of chronic hepatitis B (CHB) infection treatment. They are generally well-tolerated by patients and safe to use. To date, a significant number of patients have been treated with NAs. Safety data has accumulated over the years. The aim of this article is to review and update the adverse effects of oral NAs. NAs can cause class adverse effects (i.e., myopathy, neuropathy, lactic acidosis) and dissimilar adverse effects. All NAs carry a "Black Box" warning because of the potential risk for mitochondrial dysfunction. However, these adverse effects are rarely reported. The majority of cases are associated with lamivudine and telbivudine. Adefovir can lead to dose- and time-dependent nephrotoxicity, even at low doses. Tenofovir has significant renal and bone toxicity in patients with human immunodeficiency virus (HIV) infection. However, bone and renal toxicity in patients with CHB are not as prominent as in HIV infection. Entecavir and lamivudine are not generally associated with renal adverse events. Entecavir has been claimed to increase the risk of lactic acidosis in decompensated liver disease and high Model for End-Stage Liver Disease scores. However, current studies reported that entecavir could be safely used in decompensated cirrhosis. An increase in fetal adverse events has not been reported with lamivudine, telbivudine and tenofovir use in pregnant women, while there is no adequate data regarding entecavir and adefovir. Further long-term experience is required to highlight the adverse effects of NAs, especially in special patient populations, including pregnant women, elderly and patients with renal impairment.
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Affiliation(s)
- Bircan Kayaaslan
- Bircan Kayaaslan, Rahmet Guner, Department of Infectious Disease and Clinical Microbiology, Yildirim Beyazit University Faculty of Medicine, Ataturk Education and Research Hospital, 06800 Ankara, Turkey
| | - Rahmet Guner
- Bircan Kayaaslan, Rahmet Guner, Department of Infectious Disease and Clinical Microbiology, Yildirim Beyazit University Faculty of Medicine, Ataturk Education and Research Hospital, 06800 Ankara, Turkey
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Kao JH, Asselah T, Dou XG, Hamed K. Telbivudine therapy for chronic hepatitis B: A journey to identify super-responders and to optimize treatment using the roadmap model. J Gastroenterol Hepatol 2017; 32:73-81. [PMID: 27515408 DOI: 10.1111/jgh.13512] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/03/2016] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) infection is one of the most serious health problems worldwide with a high risk for cirrhosis and liver cancer. Several antiviral agents have been approved for the treatment of chronic hepatitis B, leading to a rapid reduction in HBV DNA and normalization of serum alanine aminotransferase levels. Telbivudine, a potent inhibitor of HBV replication, has been shown to be well tolerated. Because of the emergence of drug resistance, optimization strategies for telbivudine therapy have been shown to improve patient responses. Optimal baseline characteristics in so-called super-responders have been used to predict the virological response. Baseline HBV DNA levels < 9 log10 copies/mL (2 × 108 IU/mL) or alanine aminotransferase levels of more than or equal to twofold the upper limit of normal in HBeAg-positive patients and HBV DNA < 7 log10 copies/mL (2 × 106 IU/mL) in HBeAg-negative patients were strong predictors for virological response. In addition, the roadmap model, based on early virological response at week 24 of therapy, is considered as a powerful tool to identify patients at risk of treatment failure (HBV DNA ≥ 300 copies/mL, i.e. 60 IU/mL) and to reduce the risk of antiviral resistance. When considering pre-treatment characteristics and on-treatment responses, telbivudine may provide physicians with a wide choice of options to effectively treat patients with chronic hepatitis B, especially those with or at risk of renal impairment, or women of childbearing age.
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Affiliation(s)
- Jia-Horng Kao
- Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Tarik Asselah
- Hepatology Department, AP-HP, Beaujon Hospital, University Paris Diderot and INSERM UMR1149, Centre de Recherche sur l'inflammation, Labex INFLAMEX, Clichy, France
| | - Xiao-Guang Dou
- Department of Infectious Disease, Shengjing Hospital, China Medical University, Shenyang, China
| | - Kamal Hamed
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
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8
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Lomonosova E, Tavis JE. In Vitro Enzymatic and Cell Culture-Based Assays for Measuring Activity of HBV RNaseH Inhibitors. Methods Mol Biol 2017; 1540:179-192. [PMID: 27975316 PMCID: PMC10591453 DOI: 10.1007/978-1-4939-6700-1_14] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
HBV is a small, enveloped DNA virus that replicates by reverse transcription via an RNA intermediate. Current anti-HBV treatment regiments that include interferon α and nucleos(t)ide analogs have insufficient efficiency, are of long duration and can be accompanied by systemic side effects. Though HBV RNaseH is essential for viral replication, it is unexploited as a drug target against HBV. RNaseH inhibitors that actively block viral replication would represent an important addition to the potential new drugs for treating HBV infection. Here we describe two methods to measure the activity of RNaseH inhibitors. DNA oligonucleotide-directed RNA cleavage assay allows low-throughput screening of compounds for potential anti-HBV RNaseH activity in vitro. Analysis of preferential inhibition of plus-polarity DNA strand synthesis by HBV RNaseH inhibitors in a cell culture model of HBV replication can be used to validate the efficiency of these compounds to block viral replication.
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Affiliation(s)
- Elena Lomonosova
- Department of Molecular Microbiology and Immunology, Saint Louis University Liver Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd., Saint Louis, MO, 63104, USA
| | - John E Tavis
- Department of Molecular Microbiology and Immunology, Saint Louis University Liver Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd., Saint Louis, MO, 63104, USA.
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Villain P, Gonzalez P, Almonte M, Franceschi S, Dillner J, Anttila A, Park JY, De Vuyst H, Herrero R. European Code against Cancer 4th Edition: Infections and Cancer. Cancer Epidemiol 2015; 39 Suppl 1:S120-38. [PMID: 26589774 DOI: 10.1016/j.canep.2015.10.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 10/01/2015] [Accepted: 10/06/2015] [Indexed: 12/15/2022]
Abstract
Of the 2,635,000 new cancer cases (excluding non-melanoma skin cancers) occurring in the European Union (EU) in 2012, it is estimated that approximately 185,000 are related to infection with human papillomaviruses (HPVs), hepatitis B and C viruses (HBV and HCV), and Helicobacter pylori (H. pylori). Chronic infection with these agents can lead to cancers of the cervix uteri, liver, and stomach, respectively. Chronic infection with HCV can also lead to B-cell non-Hodgkin lymphoma. Human immunodeficiency virus (HIV) infection continues to be of major public health importance in several EU countries and increases cancer risk via HIV-induced immunosuppression. The fourth edition of the European Code Against Cancer presents recommendations on effective and safe preventive interventions in order to reduce the risk of infection-related cancers in EU citizens. Based on current available evidence, the fourth edition recommends that parents ensure the participation of their children in vaccination programs against HBV (for newborns) and HPV (for girls). In the 'Questions and Answers' (Q&As) section about vaccination and infections in the website for the European Code Against Cancer, individuals who are at risk of chronic HBV or HCV are advised to seek medical advice about testing and obtaining treatment when appropriate. Individuals most at risk of HIV are advised to consult their doctor or healthcare provider to access counselling and, if needed, testing and treatment without delay. Information about H. pylori testing and treatment is also provided as testing might currently be offered in some high-risk areas in Europe. The rationale and supporting evidence for the recommendations on vaccination in the European Code Against Cancer, and for the main recommendations on vaccination and infection in the Q&As, are explained in the present review.
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Affiliation(s)
- Patricia Villain
- International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France
| | - Paula Gonzalez
- International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France
| | - Maribel Almonte
- International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France
| | - Silvia Franceschi
- International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France
| | - Joakim Dillner
- Department of Laboratory Medicine, Karolinska Institutet, Nobels väg 12A, 171 77 Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, 171 77 Stockholm, Sweden
| | - Ahti Anttila
- Finnish Cancer Registry, Unioninkatu 22, FI-00130 Helsinki, Finland
| | - Jin Young Park
- International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France
| | - Hugo De Vuyst
- International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France
| | - Rolando Herrero
- International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France.
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10
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Development of Self-Management Indicators for Chronic Hepatitis B Patients on Antiviral Therapy: Results of a Chinese Delphi Panel Survey. PLoS One 2015; 10:e0134125. [PMID: 26327606 PMCID: PMC4556706 DOI: 10.1371/journal.pone.0134125] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 07/06/2015] [Indexed: 12/27/2022] Open
Abstract
Objective This study aimed to develop a set of indicators that could be used to measure and monitor the self-management performance for chronic hepatitis B (CHB) patients on antiviral therapy in China. Methods A two-round Delphi study via e-mail correspondence was conducted, with a group of 30 Chinese experts. The Delphi questionnaire consisted of 53 indicators identified from a literature review. Experts rated and scored the importance of indicators on a five-point Likert scale. Consensus was considered to be reached if a median score in the top tertile (4-5) and ≥80% of panel ratings in the top tertile (4-5) after Round 2. The included indicators were validated with a group of 106 CHB patients. Results The response rates for the first and second rounds were 90.9% (n=30) and 86.7% (n=26), respectively. Three new indicators were suggested in the first round. 55 indicators were included in the second round after modified. 45 (81.8%) indicators achieved on the level of consensus, all of which had an inter-quartile range of 1 or below. The final set included 4 domains and 45 indicators which were well accepted and understandable by CHB patients. Conclusion This Delphi study produced a set of 45 self-management indicators for CHB patients on antiviral therapy in China. These indicators could be used to measure and monitor the patients’ self-management performance, with the goal of improving the quality of life in this population.
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Kim WR, Loomba R, Berg T, Aguilar Schall RE, Yee LJ, Dinh PV, Flaherty JF, Martins EB, Therneau TM, Jacobson I, Fung S, Gurel S, Buti M, Marcellin P. Impact of long-term tenofovir disoproxil fumarate on incidence of hepatocellular carcinoma in patients with chronic hepatitis B. Cancer 2015; 121:3631-8. [PMID: 26177866 DOI: 10.1002/cncr.29537] [Citation(s) in RCA: 161] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Revised: 04/20/2015] [Accepted: 04/21/2015] [Indexed: 12/18/2022]
Abstract
BACKGROUND Efficacy trials have shown that antiviral therapy improves the outcomes of patients with chronic hepatitis B virus (HBV) infection. However, prospective data regarding the effect of antiviral therapy on the incidence of hepatocellular carcinoma (HCC), especially among patients without cirrhosis, are limited. The authors examined the impact of tenofovir disoproxil fumarate (TDF) on the incidence of HCC using a validated prediction model. METHODS The incidence of HCC in patients treated with TDF was obtained in the pivotal TDF registration studies after 384 weeks of follow-up. The predicted risk of HCC in individual patients was calculated using the Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B (REACH-B) model, which estimates HCC incidence for up to 10 years based on age, sex, alanine aminotransferase level, hepatitis B e antigen status, and HBV-DNA. Standardized incidence ratios (SIRs) were calculated comparing the observed and predicted numbers of HCC cases in the study cohort. RESULTS Among 634 patients with evaluable baseline biopsies, 152 had cirrhosis (Ishak fibrosis score of 5 or 6) and 482 did not. During the 384 weeks of study, 14 cases of HCC were reported, with 4 occurring within the first year. The incidence of HCC was 0.37% per year in the study as a whole (0.28% among patients without cirrhosis and 0.65% among patients with cirrhosis). Among patients without cirrhosis, the observed incidence of HCC was significantly lower than predicted (SIR, 0.40; 95% confidence interval, 0.199-0.795). The last HCC case in a patient with cirrhosis occurred around week 192 with an SIR of 0.51 (95% confidence interval, 0.231-1.144) reported at week 384. CONCLUSIONS Based on the REACH-B risk calculator, long-term therapy with TDF was associated with a reduced incidence of HCC among patients without cirrhosis who met treatment criteria.
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Affiliation(s)
- W Ray Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California
| | - Rohit Loomba
- Divisions of Gastroenterology and Epidemiology, University of California at San Diego, La Jolla, California
| | - Thomas Berg
- Section of Hepatology, Division of Gastroenterology and Rheumatology, Department of Internal Medicine, University of Leipzig, Leipzig, Germany
| | | | | | | | | | | | | | - Ira Jacobson
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York
| | - Scott Fung
- Department of Gastroenterology, University of Toronto, Toronto, Ontario, Canada
| | - Selim Gurel
- Department of Gastroenterology, Uludag University Medical School, Bursa, Turkey
| | - Maria Buti
- Liver Unit, University Hospital Vall d'Hebron and Institute Ciberehd Carlos III, Barcelona, Spain
| | - Patrick Marcellin
- Hepatology Service, Beaujon Hospital, Paris-Diderot University and INSERM CRI/UMR 1149, Viral Hepatitis Research Centre, Clichy, France
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Abstract
Hepatitis outbreaks in hemodialysis (HD) patients and staff were reported in the late 1960s, and a number of hepatotropic viruses transmitted by blood and other body fluids have been identified. Hepatitis B virus (HBV) was the first significant hepatotropic virus to be identified in HD centers. HBV infection has been effectively controlled by active vaccination, screening of blood donors, the use of erythropoietin and segregation of HBV carriers. Hepatitis delta virus is a defective virus that can only infect HBV-positive individuals. Hepatitis C virus (HCV) is the most significant cause of non-A, non-B hepatitis and is mainly transmitted by blood transfusion. The introduction in 1990 of routine screening of blood donors for HCV contributed significantly to the control of HCV transmission. An effective HCV vaccine remains an unsolved challenge; however, pegylation of interferon-alfa has made it possible to treat HCV-positive dialysis patients. Unexplained sporadic outbreaks of hepatitis by the mid-1990s prompted the discovery of hepatitis G virus, hepatitis GB virus C and the TT virus. The vigilant observation of guidelines on universal precaution and regular virologic testing are the cornerstones of the effective control of chronic hepatitis in the setting of HD. Major recent advances in the viral diagnosis technology and the development of new oral, direct-acting antiviral agents allow early diagnosis and better therapeutic response. The current update will review the recent developments, controversies and new treatment of viral hepatitis in HD patients.
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Affiliation(s)
- Bassam Bernieh
- Consultant and Chief of Nephrology, Tawam Hospital in Affiliation with Johns Hopkins Medicine, Clinical Professor of Medicine, COMHS, UAE University, Al Ain, UAE
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13
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Perrillo RP, Gish R, Falck-Ytter YT. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 2015; 148:221-244.e3. [PMID: 25447852 DOI: 10.1053/j.gastro.2014.10.038] [Citation(s) in RCA: 389] [Impact Index Per Article: 38.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Robert P Perrillo
- Hepatology Division, Baylor University Medical Center, Department of Medicine, University of Texas Southwestern, Dallas, Texas
| | - Robert Gish
- Division of Gastroenterology and Hepatology, Department of Medicine,Stanford University, Palo Alto, California; Hepatitis B Foundation, Doylestown, Pennsylvania
| | - Yngve T Falck-Ytter
- Division of Gastroenterology and Hepatology, Department of Medicine, Case and VA Medical Center, Case Western Reserve University, Cleveland, Ohio
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14
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Kountouras DA. Viral Hepatitis B and C. Cure or Treatment? THALASSEMIA REPORTS 2014. [DOI: 10.4081/thal.2014.4870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
HBV and HCV infections are among the most important global health problems; both represent also the leading cause of cirrhosis and HCC worldwide. HBV treatment cannot be considered cure but effective viral suppression can be achieved and remains the current principal goal of therapy. Talking about HCV treatment today equals to talking about total cure of the patient, with treatments of very high SVR rates, shorter if not shortest duration, minimal risk for resistance, pangenotypic and practically with no serious adverse events, no fibrosis or previous treatment status limitations, but also with a very high cost.
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15
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Fernández-Rodríguez CM, Gutiérrez-García ML. Prevention of hepatocellular carcinoma in patients with chronic hepatitis B. World J Gastrointest Pharmacol Ther 2014; 5:175-182. [PMID: 25133046 PMCID: PMC4133443 DOI: 10.4292/wjgpt.v5.i3.175] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 04/01/2014] [Accepted: 07/12/2014] [Indexed: 02/06/2023] Open
Abstract
Patients with chronic hepatitis B are at significant risk for hepatocellular carcinoma (HCC). Globally, over half a million people each year are diagnosed with HCC, with marked geographical variations. Despite overwhelming evidence for a causal role of hepatitis B virus (HBV) infection in the development of HCC and a well-established relationship between high baseline hepatitis B viral load and cumulative risk of HCC, the molecular basis for this association has not been fully elucidated. In addition, a beneficial role for antiviral therapy in preventing the development of HCC has been difficult to establish. This review examines the biological and molecular mechanisms of HBV-related hepatocarcinogenesis, recent results on the effect of modern nucleos(t)ides on the rate of HCC development in high risk HBV cohorts and the potential mechanisms by which long-term antiviral therapy with potent inhibitors of HBV replication might reduce the risk of HCC in patients with chronic hepatitis B. Although evidence from randomized controlled trials shows the favourable effects of antiviral agents in achieving profound and durable suppression of HBV DNA levels while improving liver function and histology, robust evidence of other long-term clinical outcomes, such as prevention of HCC, are limited.
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Ke W, Liu L, Zhang C, Ye X, Gao Y, Zhou S, Yang Y. Comparison of efficacy and safety of tenofovir and entecavir in chronic hepatitis B virus infection: a systematic review and meta-analysis. PLoS One 2014; 9:e98865. [PMID: 24905092 PMCID: PMC4048232 DOI: 10.1371/journal.pone.0098865] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 05/07/2014] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE Tenofovir (TDF) and entecavir (ETV) are both potent antiviral agents for the treatment of chronic hepatitis B virus (HBV) infection. Multiple studies have compared efficacy and safety of these two agents, but yielded inconsistent results. Hence, we conducted a meta-analysis to discern comparative efficacy and safety. METHODS Published data relevant to a comparison of TDF and ETV used in HBV were included. HBV DNA suppression rate, ALT normalization rate, and HBeAg seroconversion rate at 24 weeks and 48 weeks were reviewed. Drug safety profiles and resistance were also discussed. RESULTS Seven articles met entry criteria. Four and six articles included data for 24 and 48-week HBV DNA suppression rates, respectively, and no significant differences for the rates between the two drugs were found in chronic HBV patients (TDF vs. ETV: relative risk [RR] = 1.10, 95% CI = 0.91-1.33 and RR = 1.07, 95% CI = 0.99-1.17 for 24 weeks and 48 weeks, respectively). For the ALT normalization rate (three studies for 24 weeks, four articles for 48 weeks) and HBeAg seroconversion rate (two and four studies for 24 weeks and 48 weeks, respectively), no difference was observed between TDF and ETV. Additionally, no significant distinction in short term safety was found for CHB patients. CONCLUSIONS TDF and ETV are similarly effective and safe in chronic HBV patients after 24 weeks and 48 weeks of anti-viral therapy. Nevertheless, the long-term efficacy and safety of TDF and ETV should be monitored in prolonged therapy.
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Affiliation(s)
- Weixia Ke
- Department of Epidemiology and Biostatistics and Guangdong Key Lab of Molecular Epidemiology, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Li Liu
- Department of Epidemiology and Biostatistics and Guangdong Key Lab of Molecular Epidemiology, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Chi Zhang
- Department of Epidemiology and Biostatistics and Guangdong Key Lab of Molecular Epidemiology, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Xiaohua Ye
- Department of Epidemiology and Biostatistics and Guangdong Key Lab of Molecular Epidemiology, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Yanhui Gao
- Department of Epidemiology and Biostatistics and Guangdong Key Lab of Molecular Epidemiology, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Shudong Zhou
- Department of Epidemiology and Biostatistics and Guangdong Key Lab of Molecular Epidemiology, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Yi Yang
- Department of Epidemiology and Biostatistics and Guangdong Key Lab of Molecular Epidemiology, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
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Hadziyannis SJ, Vassilopoulos D, Sevastianos V, Hadziyannis E. Can Nucleos(t)ide Analogue (NA) Therapy Ever be Stopped in HBeAg-Negative Chronic Hepatitis B? ACTA ACUST UNITED AC 2014. [DOI: 10.1007/s11901-014-0236-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Chokshi S, Cooksley H, Riva A, Phillips S, Williams R, Gaggar A, Naoumov NV. Identification of serum cytokine profiles associated with HBeAg seroconversion following antiviral treatment interruption. Viral Immunol 2014; 27:235-44. [PMID: 24797262 DOI: 10.1089/vim.2014.0022] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The major shortcoming of nucleos(t)ide analogue therapy for chronic hepatitis B (CHB) is the frequent requirement for indefinite therapy. Withdrawal of treatment can result in viral rebound with an alanine aminotransferase (ALT) flare leading to hepatic decompensation, while in others this can lead to hepatitis B e antigen (HBeAg) seroconversion. The aim of the study was to identify host immune profiles associated with these different outcomes. Eighteen HBeAg(+) patients, enrolled on a phase III trial with the nucleoside analogue adefovir dipivoxil, were followed for up to 128 weeks. For the first 48 weeks, all patients received continuous therapy. Subsequently, patients experienced cycles of treatment interruptions due to random drug/placebo misallocations. Host immune profiles were characterized by measuring a panel of serum cytokines before, during, and after each cycle of treatment withdrawal. Virus-specific T-cell responses were also determined at these time points in a subset of patients to elucidate the mechanisms utilized to control hepatitis B virus (HBV) replication post-treatment. Significantly, elevated levels of IFN-γ, IP-10, and IL-2 on-treatment were associated with HBeAg seroconversion after treatment withdrawal. In these patients, treatment interruption induced further increases in serum IFN-γ levels and marked increases in virus-specific T-cells producing IFN-γ, but minimal alterations in viremia and ALT. In HBeAg(+) patients with low on-treatment levels of serum IFN-γ, the interruption of therapy induced significant elevations in HBV-DNA, ALT, IP-10, and increases in virus-specific T-cells producing IL-10. Evaluating on-treatment serum cytokines in concert with virologic and clinical parameters may help to identify CHB patients who can successfully discontinue nucleos(t)ide analogue therapy.
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Affiliation(s)
- Shilpa Chokshi
- 1 Institute of Hepatology , Foundation for Liver Research, London, United Kingdom
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19
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Gerlich WH. Medical virology of hepatitis B: how it began and where we are now. Virol J 2013; 10:239. [PMID: 23870415 PMCID: PMC3729363 DOI: 10.1186/1743-422x-10-239] [Citation(s) in RCA: 219] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Accepted: 07/18/2013] [Indexed: 02/06/2023] Open
Abstract
Infection with hepatitis B virus (HBV) may lead to acute or chronic hepatitis. HBV infections were previously much more frequent but there are still 240 million chronic HBV carriers today and ca. 620,000 die per year from the late sequelae liver cirrhosis or hepatocellular carcinoma. Hepatitis B was recognized as a disease in ancient times, but its etiologic agent was only recently identified. The first clue in unraveling this mystery was the discovery of an enigmatic serum protein named Australia antigen 50 years ago by Baruch Blumberg. Some years later this was recognized to be the HBV surface antigen (HBsAg). Detection of HBsAg allowed for the first time screening of inapparently infected blood donors for a dangerous pathogen. The need to diagnose clinically silent HBV infections was a strong driving force in the development of modern virus diagnostics. HBsAg was the first infection marker to be assayed with a highly sensitive radio immune assay. HBV itself was among the first viruses to be detected by assay of its DNA genome and IgM antibodies against the HBV core antigen were the first to be selectively detected by the anti-μ capture assay. The cloning and sequencing of the HBV genome in 1978 paved the way to understand the viral life cycle, and allowed development of efficient vaccines and drugs. Today’s hepatitis B vaccine was the first vaccine produced by gene technology. Among the problems that still remain today are the inability to achieve a complete cure of chronic HBV infections, the recognition of occult HBV infections, their potential reactivation and the incomplete protection against escape mutants and heterologous HBV genotypes by HBV vaccines.
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Affiliation(s)
- Wolfram H Gerlich
- Institute for Medical Virology, National Reference Center for Hepatitis B and D, Justus Liebig University Giessen, Schubert Str, 81, 35392 Giessen, Germany.
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Affiliation(s)
- Daniel Shouval
- Liver Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel.
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