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1
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Warner BM, Safronetz D, Stein DR. Current perspectives on vaccines and therapeutics for Lassa Fever. Virol J 2024; 21:320. [PMID: 39702419 PMCID: PMC11657583 DOI: 10.1186/s12985-024-02585-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 11/21/2024] [Indexed: 12/21/2024] Open
Abstract
Lassa virus, the cause of deadly Lassa fever, is endemic in West Africa, where thousands of cases occur on an annual basis. Nigeria continues to report increasingly severe outbreaks of Lassa Fever each year and there are currently no approved vaccines or therapeutics for the prevention or treatment of Lassa Fever. Given the high burden of disease coupled with the potential for further escalation due to climate change the WHO has listed Lassa virus as a priority pathogen with the potential to cause widespread outbreaks. Several candidate vaccines have received support and have entered clinical trials with promising early results. This review focuses on the current state of vaccine and therapeutic development for LASV disease and the potential of these interventions to advance through clinical trials. The growing burden of LASV disease in Africa highlights the importance of advancing preclinical and clinical testing of vaccines and therapeutics to respond to the growing threat of LASV disease.
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Affiliation(s)
- Bryce M Warner
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Canada.
- Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, Canada.
| | - David Safronetz
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
| | - Derek R Stein
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada
- Cadham Provincial Laboratory, Winnipeg, Canada
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2
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Sinclair S, Shearen S, Ghobrial Y, Trad G, Abdul Basit S, Shih D, Ryan JK. Review of the Effects of Antiviral Therapy on Hepatitis B/C-Related Mortality and the Regression of Fibrosis. Viruses 2024; 16:1531. [PMID: 39459866 PMCID: PMC11512229 DOI: 10.3390/v16101531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 09/19/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
Hepatitis B and Hepatitis C are viral causes of Hepatitis that lead to significant worldwide mortality and morbidity through the sequelae of fibrosis and hepatocellular carcinoma. In this review, we have summarized recent studies that have examined the effects of antiviral therapy on the regression of fibrosis and the reduction in mortalities associated with the viruses. Antiviral therapy significantly decreases mortality and induces the regression of fibrosis.
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Affiliation(s)
| | | | | | | | | | | | - John K. Ryan
- Comprehensive Digestive Institute of Nevada, Las Vegas, NV 89148, USA (S.A.B.); (D.S.)
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3
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Tok D. Analysis of articles on hepatitis C by scientific mapping: 1989-2022. World J Clin Cases 2024; 12:4301-4316. [PMID: 39015889 PMCID: PMC11235547 DOI: 10.12998/wjcc.v12.i20.4301] [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] [Received: 02/22/2024] [Revised: 05/01/2024] [Accepted: 05/24/2024] [Indexed: 06/30/2024] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) poses a significant quandary about public health. It is challenging to study the literature in a particular discipline comprehensively today. One solution is bibliometric analysis, which is often used to track the attributes and evolutionary trajectories of scientific outputs. AIM To examine the 35-year scientific evolution of articles focused on HCV. METHODS This study examined the 35-year scientific evolution of articles focused on HCV. Our study utilized the Web of Science database. The study encompassed a total of 11930 articles. RESULTS Regarding the cumulative count of articles, the leading countries are the United States, Japan, and Italy. Rice CM is the author with the highest recorded H-index and G-index values. The journal with the highest recorded H-index and G-index values is the Journal of Virology. The Journal of Viral Hepatitis contributed 10.94% of the articles, whereas the Journal of Virology published 9.68%. According to the strategic diagram, the keywords most frequently used in 2020-2022 are HCV, epidemiology, and sofosbuvir. CONCLUSION This study provides valuable information about 40 years of academic knowledge on HCV.
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Affiliation(s)
- Duran Tok
- Department of Infectious Diseases, Liv Hospital, Ankara 06100, Türkiye
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Bernal LA, Soti V. Hepatitis C Virus: Insights Into Its History, Treatment, Challenges, and Future Directions. Cureus 2023; 15:e43924. [PMID: 37614826 PMCID: PMC10443603 DOI: 10.7759/cureus.43924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/22/2023] [Indexed: 08/25/2023] Open
Abstract
Hepatitis C virus (HCV) is a global public health concern with significant impacts. It primarily spreads through blood-to-blood contact, such as sharing needles among drug users. Given the wide prevalence of risk factors, HCV continues to pose a major threat. Hence, it is crucial to understand its characteristics, structure, and genotypes to prevent, treat, and potentially eradicate it. This narrative review aims to explore the history of HCV treatment, highlight the breakthroughs achieved with direct-acting antiviral (DAA) therapy, address potential barriers to HCV eradication, and discuss future treatment possibilities. For this article, relevant studies were identified using various databases, including PubMed, ClinicalTrials.gov, and Journal Storage. The literature search revealed that after identifying HCV and studying its characteristics, interferon alfa and ribavirin became primary treatment options. However, due to their limited coverage against different HCV genotypes, ethnic variations, and suboptimal sustained virological response, the development of DAAs became essential. Combining various DAAs, such as sofosbuvir and velpatasvir, for a duration of 12 weeks has become the standard HCV treatment, with effectiveness against most genotypes. Additionally, ongoing clinical trials have shown promising results for other drugs such as CDI31244/sofosbuvir/velpatasvir, sofosbuvir/coblopasvir, and daclatasvir/asunaprevir. Despite the success of DAAs and ongoing efforts to discover more effective treatments, the high costs of DAAs pose a significant challenge to eradicating HCV, as not all patients can afford these expensive therapies. Furthermore, the ability of HCV to mutate limits the potential for vaccine development. Therefore, it is crucial to focus on developing more cost-effective strategies to control the spread of HCV and create novel, highly effective, and affordable DAAs.
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Affiliation(s)
- Luis A Bernal
- Internal Medicine, Lake Erie College of Osteopathic Medicine, Elmira, USA
| | - Varun Soti
- Pharmacology and Therapeutics, Lake Erie College of Osteopathic Medicine, Elmira, USA
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5
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Flower B, Nguyen Thi Ngoc P, McCabe L, Le Ngoc C, Vo Thi T, Thi Kim HV, Dang Trong T, Rahman M, Thwaites G, Walker AS, Hung LM, Vinh Chau NV, Cooke GS, Day JN. Rise in alanine aminotransferase after HCV treatment is a highly sensitive screen for treatment failure. Clin Liver Dis (Hoboken) 2023; 21:138-142. [PMID: 37274950 PMCID: PMC10237684 DOI: 10.1097/cld.0000000000000055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 04/10/2023] [Indexed: 06/07/2023] Open
Abstract
Nucleic acid testing to confirm sustained virological response (SVR) after HCV therapy is technical, often expensive, and frequently unavailable where disease prevalence is highest. Alternative surrogate biomarkers merit evaluation. In a short-treatment trial in Vietnam (SEARCH-1; n = 52) we analysed how changes in alanine transaminase (ΔALT) and aspartate transaminase (ΔAST), from end of treatment (EOT) to EOT + 12 weeks, related to SVR, defined as HCV RNA < lower limit of quantification 12 weeks after EOT. In a separate UK trial (STOPHCV1; n = 202), we then tested the hypothesis that any elevation in ALT or AST between EOT and EOT12 is a sensitive screen for treatment failure. In SEARCH-1, among 48 individuals with data, 13 failed to achieve SVR. Median ΔALT and ΔAST were negative in cured patients but elevated when treatment failed [median ΔALT (IQR): -2 IU/L (-6, +2)] versus +17 IU/L (+7.5, +38) (p< 0.001). Amongst treatment failures, 12/13 had increase in ALT and 13/13 had increase in AST after EOT, compared with 12/35 in those cured. In STOPHCV1, 196/202 patients had evaluable data, of which 57 did not achieve SVR. A rise in ALT after EOT was 100% sensitive (95% C.I. [93.7 - 100%]) and 51% specific (42.4 - 59.7%) for detecting treatment failure. ΔAST >0 IU/L was 98.1% (89.9 - 99.9%) sensitive and 35.8% (27.3 - 45.1%) specific. A rise in ALT or AST after HCV therapy is a highly sensitive screen for treatment failure in mild liver disease. This finding could reduce costs and complexity of managing HCV.
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Affiliation(s)
- Barnaby Flower
- Department of CNS Infection, HIV and Viral Hepatitis, Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam
- Department of Infectious Disease, Imperial College London, London, UK
| | - Phuong Nguyen Thi Ngoc
- Department of CNS Infection, HIV and Viral Hepatitis, Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam
| | - Leanne McCabe
- MRC Clinical Trials Unit at UCL, University College London, London, UK
| | - Chau Le Ngoc
- Department of CNS Infection, HIV and Viral Hepatitis, Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam
| | - Thu Vo Thi
- Department of CNS Infection, HIV and Viral Hepatitis, Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam
| | - Hang Vu Thi Kim
- Department of CNS Infection, HIV and Viral Hepatitis, Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam
| | - Thuan Dang Trong
- Department of CNS Infection, HIV and Viral Hepatitis, Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam
| | - Motiur Rahman
- Department of CNS Infection, HIV and Viral Hepatitis, Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam
- Nuffield Department of Medicine, Centre for Tropical Medicine and Global Health, Oxford University, Oxford, UK
| | - Guy Thwaites
- Department of CNS Infection, HIV and Viral Hepatitis, Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam
- Nuffield Department of Medicine, Centre for Tropical Medicine and Global Health, Oxford University, Oxford, UK
| | - Ann Sarah Walker
- MRC Clinical Trials Unit at UCL, University College London, London, UK
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
- The National Institute for Health Research, Oxford Biomedical Research Centre, University of Oxford, Oxford, UK
| | - Le Manh Hung
- Department of Hepatology, Hospital for Tropical Diseases, Ho Chi Minh City
| | | | - Graham S. Cooke
- Department of Infectious Disease, Imperial College London, London, UK
| | - Jeremy N. Day
- Department of CNS Infection, HIV and Viral Hepatitis, Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam
- Nuffield Department of Medicine, Centre for Tropical Medicine and Global Health, Oxford University, Oxford, UK
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6
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Abstract
Hepatitis C virus (HCV) infection contributes significantly to liver cirrhosis and hepatocellular carcinoma (HCC), often requiring liver transplantation. Introducing direct-acting antiviral agents (DAAs) has radically changed HCV treatment. DAAs achieve high rates of sustained virological response (>98%). Even then, resistant-associated substitution and HCC during or after treatment have become prominent clinical concerns. Further, several clinically significant issues remain unresolved after successful HCV eradication by DAAs, including treating patients with chronic kidney disease or decompensated liver cirrhosis. Extensive and large-scale screening and treatment implementation programs are needed to make DAA therapies effective at the population level.
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Abstract
In the 1970s, an unknown virus was suspected for documented cases of transfusion-associated hepatitis, a phenomenon called non-A, non-B hepatitis. In 1989, the infectious transmissible agent was identified and named hepatitis C virus (HCV) and, soon enough, the first diagnostic HCV antibody test was developed, which led to a dramatic decrease in new infections. Today, HCV infection remains a global health burden and a major cause of liver cirrhosis, hepatocellular carcinoma and liver transplantation. However, tremendous advances have been made over the decades, and HCV became the first curable, chronic viral infection. The introduction of direct antiviral agents revolutionized antiviral treatment, leading to viral eradication in more than 98% of all patients infected with HCV. This Perspective discusses the history of HCV research, which reads like a role model for successful translational research: starting from a clinical observation, specific therapeutic agents were developed, which finally were implemented in national and global elimination programmes.
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Affiliation(s)
- Michael P. Manns
- grid.10423.340000 0000 9529 9877Hannover Medical School, Hannover, Germany
| | - Benjamin Maasoumy
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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8
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Agnew-Francis KA, Williams CM. Squaramides as Bioisosteres in Contemporary Drug Design. Chem Rev 2020; 120:11616-11650. [DOI: 10.1021/acs.chemrev.0c00416] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Kylie A. Agnew-Francis
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia
| | - Craig M. Williams
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia
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9
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Alhaddad O, Wahb A, Sabry A, Khalil F, Elsabaawy D, Elshazly H, Shebl N, Rady M, Elsabaawy M. Role of Ribavirin in the Era of Direct-Acting Antiviral Therapies of Chronic Hepatitis C. Expert Rev Anti Infect Ther 2020; 18:817-822. [PMID: 32397842 DOI: 10.1080/14787210.2020.1758557] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 04/17/2020] [Indexed: 01/05/2023]
Abstract
BACKGROUND The efficacy of adding ribavirin (RBV) to direct antivirals (DAAs) in HCV treatment is still debatable, with allegations of insecure profiles. OBJECTIVES To evaluate safety and efficacy of RBV in the era of DAAs in chronic HCV Egyptian patients. METHODS In this cohort retrospective study, data of 847 HCV patients treated with different regimens of DAAs with or without RBV were recruited between June 2017 and September 2018. Cases were categorized into five groups: non-cirrhotic (318), compensated (196), decompensated liver cirrhosis (53), post liver transplantation (30), and 250 treatment experienced patients. All patients' demographics and laboratory characteristics were evaluated at baseline, week4, 12, 24 of treatment. Ribavirin was prescribed or banned outside international guideline recommendations of HCV treatment in cases assembled from the private sector.Results: No statistically significant difference between RBV and non-RBV treated patients was documented regarding SVR12 (97.2%, 97.8%) respectively in the whole cohort (p 0.509). On grouping, adding RBV was only significant in the treatment experienced patients (96.8%, 85% in RBV and non-RBV regimens respectively) (p 0.001). Adding RBV to DAA regimens was generally associated with modest adverse events particularly anemia (8.5%), and hepatic decompensation (jaundice and ascites) (0.3%). Bilirubin, INR, and platelet counts all were found to be the most independent predictors of SVR achievement by multivariate analysis (p ≤ 0.05).Conclusion: RBV may still have an augmenting role in treatment experienced patients; permitting effectual shortening of therapy particularly in patients with cirrhosis, with modest side and adverse consequences.
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Affiliation(s)
- Omkolsoum Alhaddad
- Department of Hepatology, National Liver Institute, Menoufia University , Shebin El-kom, Egypt
| | - Ahmed Wahb
- Department of Hepatology, National Liver Institute, Menoufia University , Shebin El-kom, Egypt
| | - Alyaa Sabry
- Department of Hepatology, National Liver Institute, Menoufia University , Shebin El-kom, Egypt
| | - Fatma Khalil
- Department of Microbiology and Immunology, National Liver Institute, Menoufia University , Shebin El-kom, Egypt
| | - Dalia Elsabaawy
- Department of Clinical Pharmacy, Pharmacy College, Menoufia University , Shebin El-kom, Egypt
| | - Helmy Elshazly
- Department of Hepatology, National Liver Institute, Menoufia University , Shebin El-kom, Egypt
| | | | - Mohamed Rady
- Department of Hepatology, National Liver Institute, Menoufia University , Shebin El-kom, Egypt
| | - Maha Elsabaawy
- Department of Hepatology, National Liver Institute, Menoufia University , Shebin El-kom, Egypt
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10
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Oancea CN, Butaru AE, Streba CT, Pirici D, Rogoveanu I, Diculescu MM, Gheonea DI. Global hepatitis C elimination: history, evolution, revolutionary changes and barriers to overcome. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY = REVUE ROUMAINE DE MORPHOLOGIE ET EMBRYOLOGIE 2020; 61:643-653. [PMID: 33817705 PMCID: PMC8112794 DOI: 10.47162/rjme.61.3.02] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 03/25/2021] [Indexed: 02/05/2023]
Abstract
The fundamental discovery of the hepatitis C virus (HCV) in 1989 has led to winning this year's Nobel Prize in Medicine. This achievement guided all the steps in identifying the elements of the virus, in order to develop the treatment and to increase the screening solutions, which have slowed the exposure to the virus. The management of infection started with interferon-alpha (IFN-α), which has later enhanced by adding Ribavirin. Nowadays, HCV treatment is based on direct-acting antiviral agents (DAAs). Currently, HCV infection benefits of curative treatment, with which most patients can be cured. When speaking about hepatitis C future, we can say it is looking bright, considering all the progress that has been made in recent years and all the options that we have for curing all genotypes of HCV infection. The aim of this review is to sum up the historical characteristics of HCV discovery, the evolution of treatment and screening actions, gaps, and stages for achieving the international elimination target of the World Health Organization.
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Affiliation(s)
- Carmen Nicoleta Oancea
- Department of Scientific Research Methodology and Department of Pulmonology, University of Medicine and Pharmacy of Craiova, Romania;
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Mejer N, Galli A, Ramirez S, Fahnøe U, Benfield T, Bukh J. Ribavirin inhibition of cell-culture infectious hepatitis C genotype 1-3 viruses is strain-dependent. Virology 2019; 540:132-140. [PMID: 31778898 DOI: 10.1016/j.virol.2019.09.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 09/27/2019] [Accepted: 09/27/2019] [Indexed: 12/20/2022]
Abstract
Ribavirin remains relevant for successful treatment of chronic hepatitis C virus (HCV) infections in low-income settings, as well as for therapy of difficult-to-treat HCV patients. We studied the effect of ribavirin against cell-culture adapted HCV of genotypes 1, 2 and 3, representing ~80% of global infections. TNcc(1a) was the most sensitive to ribavirin, while J6/JFH1(2a) was the most resistant. EC50s ranged from 21 μM (95%CI: 20-22 μM) to 189 μM (95%CI: 173-207 μM). Substitutions at position 415 of NS5B resulted in little or no change to ribavirin sensitivity (0.7-0.9 fold) but conferred moderate drug resistance during extended treatment of genotype 1 (1.8-fold). NS5A and NS5B sequences could alter ribavirin sensitivity 2-4-fold, although their contribution was not simply additive. Finally, we detected limited accumulation of mutations associated with ribavirin treatment. Our findings show that the antiviral effect of ribavirin on HCV is strain-dependent and is influenced by the specific sequence of multiple HCV nonstructural proteins.
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Affiliation(s)
- Niels Mejer
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Hvidovre Hospital, Hvidovre, Denmark
| | - Andrea Galli
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Hvidovre Hospital, Hvidovre, Denmark
| | - Santseharay Ramirez
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Hvidovre Hospital, Hvidovre, Denmark
| | - Ulrik Fahnøe
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Hvidovre Hospital, Hvidovre, Denmark
| | - Thomas Benfield
- Department of Infectious Diseases, Hvidovre Hospital, Hvidovre, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Jens Bukh
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Hvidovre Hospital, Hvidovre, Denmark.
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12
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Nyström K, Waldenström J, Tang KW, Lagging M. Ribavirin: pharmacology, multiple modes of action and possible future perspectives. Future Virol 2019. [DOI: 10.2217/fvl-2018-0166] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ribavirin is a unique guanosine analog with broad-spectrum activity against many RNA and DNA viruses. In addition to its mutational properties, ribavirin exerts extensive perturbation of cellular and viral gene expression. Furthermore, recent advances indicate that the impact of ribavirin on divergent cellular and viral pathways may be concentration dependent. This review aims at providing an overview of the pharmacology and multiple modes of action of ribavirin as well as pointing to possible novel future uses.
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Affiliation(s)
- Kristina Nyström
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Västra Götaland Region, Sweden
| | - Jesper Waldenström
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Västra Götaland Region, Sweden
| | - Ka-Wei Tang
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Västra Götaland Region, Sweden
| | - Martin Lagging
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Västra Götaland Region, Sweden
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13
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14
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Ahmed KT, Almashhrawi AA, Ibdah JA, Tahan V. Is the 25-year hepatitis C marathon coming to an end to declare victory? World J Hepatol 2017; 9:921-929. [PMID: 28824743 PMCID: PMC5545137 DOI: 10.4254/wjh.v9.i21.921] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2017] [Revised: 06/04/2017] [Accepted: 07/07/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) which was originally recognized as posttransfusion non-A, non-B hepatitis has been a major global health problem affecting 3% of the world population. Interferon/peginterferon and ribavirin combination therapy was the backbone of chronic HCV therapy for two decades of the journey. However, the interferon based treatment success rate was around 50% with many side effects. Many chronic HCV patients with psychiatric diseases, or even cytopenias, were ineligible for HCV treatment. Now, we no longer need any injectable medicine. New direct-acting antiviral agents against HCV allowed the advance of interferon-free and ribavirin-free oral regimens with high rates of response and tolerability. The cost of the medications should not be a barrier to their access in certain parts of the world. While we are getting closer, we should still focus on preventing the spread of the disease, screening and delivering the cure globally to those in need. In the near future, development of an effective vaccine against HCV would make it possible to eradicate HCV infection worldwide completely.
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Affiliation(s)
- Khulood T Ahmed
- Khulood T Ahmed, Ashraf A Almashhrawi, Jamal A Ibdah, Veysel Tahan, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, United States
| | - Ashraf A Almashhrawi
- Khulood T Ahmed, Ashraf A Almashhrawi, Jamal A Ibdah, Veysel Tahan, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, United States
| | - Jamal A Ibdah
- Khulood T Ahmed, Ashraf A Almashhrawi, Jamal A Ibdah, Veysel Tahan, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, United States
| | - Veysel Tahan
- Khulood T Ahmed, Ashraf A Almashhrawi, Jamal A Ibdah, Veysel Tahan, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, United States
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15
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Ni Y. Hepatitis C: a successful story of cure. Sci Bull (Beijing) 2016. [DOI: 10.1007/s11434-016-1211-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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16
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Snell NJC. The Activity of Ribavirin against the Human Immunodeficiency Virus: A Review of Laboratory and Clinical Experience. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/095632029100200501] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- N. J. C. Snell
- European Medical Affairs Department, ICN Pharmaceuticals, Eagle House, Peregrine Business Park, High Wycombe, HP13 7DL, UK
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17
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Sharma SA, Feld JJ. Management of HCV in cirrhosis-a rapidly evolving landscape. Curr Gastroenterol Rep 2015; 17:443. [PMID: 25896437 DOI: 10.1007/s11894-015-0443-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Despite the rapid progress in treatment, chronic hepatitis C virus (HCV) infection remains a growing cause of liver-related mortality globally. Patients who have been infected for decades are now presenting with advanced liver disease with the complications of cirrhosis and liver cancer. Early attempts at treatment with peginterferon and ribavirin were limited by toxicity, long treatment duration, and limited efficacy. This was especially relevant for patients with cirrhosis, where exposure to peginterferon-based therapy was relatively ineffective and led to high rates of toxicity. However, the recent development of multiple novel direct-acting antivirals (DAAs) has revolutionized the treatment of HCV. The majority of patients can now be cured with short courses of extremely well-tolerated all-oral regimens. However, the real test of these regimens comes in patients with more advanced liver disease, both in terms of safety and efficacy. Patients with cirrhosis have the greatest need for therapy and have traditionally been the most difficult to cure. The new therapies are rapidly changing this paradigm. Accumulating data suggest that high cure rates are achievable in patients with compensated cirrhosis and may even be possible in patients with signs of liver failure. This review will focus on the treatment of HCV in patients with cirrhosis, with an emphasis on the challenges that remain and strategies to deal with this important population.
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Affiliation(s)
- Suraj A Sharma
- Toronto Center for Liver Disease, Sandra Rotman Centre for Global Health, University Health Network, University of Toronto, 6B-Fell Pavilion, Room 158, 399 Bathurst Street, Toronto, Ontario, M5T 2S8, Canada
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Kushner T, Khungar V. Direct-Acting Antiviral Agents: Regimens for the Interferon Failure Patient. Clin Liver Dis 2015; 19:629-39, v-vi. [PMID: 26466652 DOI: 10.1016/j.cld.2015.06.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Over the past few years, tremendous advances have been made in the treatment of hepatitis C with direct-acting antiviral agents (DAAs), allowing treatment options for patients who have failed prior treatment with interferon. In addition to interferon's severe adverse effect profile, and the inability of many patients to tolerate it, prior interferon-containing regimens were not as effective in achieving sustained virologic response as emerging therapies. New DAAs have demonstrated higher rates of sustained virologic response, shorter duration of treatment, and improved adverse effect profile.
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Affiliation(s)
- Tatyana Kushner
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA
| | - Vandana Khungar
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA.
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Bryan-Marrugo O, Ramos-Jiménez J, Barrera-Saldaña H, Rojas-Martínez A, Vidaltamayo R, Rivas-Estilla A. History and progress of antiviral drugs: From acyclovir to direct-acting antiviral agents (DAAs) for Hepatitis C. MEDICINA UNIVERSITARIA 2015. [DOI: 10.1016/j.rmu.2015.05.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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Abstract
The hepatitis C virus (HCV) was discovered in the late 1980s. Interferon (IFN)-α was proposed as an antiviral treatment for chronic hepatitis C at about the same time. Successive improvements in IFN-α-based therapy (dose finding, pegylation, addition of ribavirin) increased the rates of sustained virologic response, i.e. the rates of curing HCV infection. These rates were further improved by adding the first available direct-acting antiviral (DAA) drugs to the combination of pegylated IFN-α and ribavirin. An IFN-free era finally started in 2014, yielding rates of sustained virologic response over 90% in patients treated for 8 to 24 weeks with all-oral regimens. Major challenges however remain in implementation of these new treatment strategies, not only in low- to middle-income countries, but also in high-income countries where the price of these therapies is still prohibitive. Elimination of HCV infection through treatment in certain areas is possible but raises major public health issues.
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Ribavirin at the Era of Novel Direct Antiviral Agents for the Treatment of Hepatitis C Virus Infection: Relevance of Pharmacological Monitoring. ACTA ACUST UNITED AC 2014. [DOI: 10.1155/2014/493087] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Ribavirin is often used for the treatment of hepatitis C virus (HCV) infection. Although its mechanisms of action remain to be clearly elucidated, ribavirin plays a beneficial role for achieving virological response and decreasing the rate of virological relapse after treatment cessation. However, ribavirin may induce side effects leading to early treatment discontinuation. Among them, hemolytic anemia is the most frequent and results from intraerythrocyte accumulation. Pharmacological studies have shown that early ribavirin exposure assessed by the area under the curve (AUC) at day 0 and ribavirin trough concentration during the first three months of therapy were correlated with sustained virological response (SVR). These studies highlighted the relevance of ribavirin pharmacologic monitoring and early dose adaptation during therapy. Although the role of ribavirin within new direct acting antiviral (DAA) combinations will probably decrease in the future, its potential benefit in difficult-to-treat patients such as patients with severe hepatopathy or patients who failed triple therapy including patients with multiresistance will need to be further investigated.
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Quiles-Pérez R, Muñoz-de-Rueda P, Maldonado AML, Martín-Álvarez A, Quer J, Salmerón J. Effects of ribavirin monotherapy on the viral population in patients with chronic hepatitis C genotype 1: direct sequencing and pyrosequencing of the HCV regions. J Med Virol 2014; 86:1886-97. [PMID: 25091333 DOI: 10.1002/jmv.24035] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/04/2014] [Indexed: 11/11/2022]
Abstract
Ribavirin remains essential to chronic hepatitis C treatment. This paper investigates the influence of ribavirin priming to steady state before combined pegylated-interferon/ribavirin treatment on viral kinetics, ribavirin trough concentrations, genetic variability within HCV-core, -NS5B and -NS5A, and response to antiviral therapy. A prospective cohort study was made of 27 chronic hepatitis C genotype 1 naïve patients who received four weeks of ribavirin followed by pegIFN-α-2a/ribavirin for 48 weeks (Group A). The results obtained were compared with those for a control/historical group (Group B). In addition, direct sequencing and pyrosequencing were applied to determine ribavirin monotherapy-induced sequence changes. The rapid, early, and sustained virological response values obtained were 48%, 89%, and 52%, respectively, in Group A, and 52%, 90%, and 52% in Group B (P > 0.05). In the four-week combined treatment, the Group A patients showed a greater decrease in HCV-RNA (2.3 log10 IU/ml vs. 1.2 log10 IU/ml; P = 0.04), lower alanine aminotransferase levels (23.5 ± 1.33 U/L vs. 60.11 ± 18 U/L; P < 0.001) and higher mean ribavirin trough concentrations (3.28 ± 1.26 mg/L vs. 1.74 ± 0.7 mg/L; P = 0.001). No general increase in rates of nucleotide substitutions in the ribavirin monotherapy-treated patients was observed in NS5B, ISDR, or PKRbd, but there was a decrease in silent mutations in the HCV core (P = 0.04). This result was confirmed by pyrosequencing in the NS5A region. It is concluded that the ribavirin priming combined treatment with pegIFN-α-2a does not improve sustained virological response rates in HCV genotype 1 naïve infected patients. However, the greater reductions in viral load and alanine aminotransferase levels, together with the higher ribavirin trough concentration values obtained, could reflect the greater effectiveness of the treatment. Ribavirin does not have a mutagenic effect on the virus in patients with chronic hepatitis C.
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Affiliation(s)
- R Quiles-Pérez
- Research Support Unit, UNAI, San Cecilio University Hospital, Granada, Spain; CIBEREHD, Spain
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Lamers MH, Broekman M, Drenth JPH, Gluud C, Cochrane Hepato‐Biliary Group. Aminoadamantanes versus other antiviral drugs for chronic hepatitis C. Cochrane Database Syst Rev 2014; 2014:CD011132. [PMID: 24937404 PMCID: PMC10542095 DOI: 10.1002/14651858.cd011132.pub2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Hepatitis C virus infection affects around 3% of the world population or approximately 160 million people. A variable proportion (5% to 40%) of the infected people develop clinical symptoms. Hence, hepatitis C virus is a leading cause of liver-related morbidity and mortality with hepatic fibrosis, end-stage liver cirrhosis, and hepatocellular carcinoma as the dominant clinical sequelae. Combination therapy with pegylated (peg) interferon-alpha and ribavirin achieves sustained virological response (that is, undetectable hepatitis C virus RNA in serum by sensitivity testing six months after the end of treatment) in approximately 40% to 80% of treated patients, depending on viral genotype. Recently, a new class of drugs have emerged for hepatitis C infection, the direct acting antivirals, which in combination with standard therapy or alone can lead to sustained virological response in 80% or more of treated patients. Aminoadamantanes, mostly amantadine, are antiviral drugs used for the treatment of patients with chronic hepatitis C. We have previously systematically reviewed amantadine versus placebo or no intervention and found no significant effects of the amantadine on all-cause mortality or liver-related morbidity and on adverse events in patients with hepatitis C. Overall, we did not observe a significant effect of amantadine on sustained virological response. In this review, we systematically review aminoadamantanes versus other antiviral drugs. OBJECTIVES To assess the beneficial and harmful effects of aminoadamantanes versus other antiviral drugs for patients with chronic hepatitis C virus infection by conducting a systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. SEARCH METHODS The Cochrane Hepato-Biliary Group Controlled Trials Register (1996 to December 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11 of 12, 2013), MEDLINE (1946 to December 2013), EMBASE (1974 to December 2013), Science Citation Index EXPANDED (1900 to December 2013), the WHO International Clinical Trials Registry Platform (www.who.int/ictrp), Google Scholar, and Eudrapharm up to December 2013. Furthermore, full text searches were conducted until December 2013. SELECTION CRITERIA Randomised clinical trials assessing aminoadamantanes in participants with chronic hepatitis C virus infection. DATA COLLECTION AND ANALYSIS Two authors independently extracted data. RevMan Analysis was used for statistical analysis of dichotomous data using risk ratio (RR) with 95% confidence intervals (CI). Methodological domains were used to assess the risk of systematic errors ('bias'). We used trial sequential analysis to assess risk of random errors ('play of chance'). MAIN RESULTS Six randomised clinical trials with 581 participants with chronic hepatitis C were included. All trials had high risk of bias. The included trials compared amantadine versus other antiviral drugs: ribavirin, mycophenolate mofetil, interferon-alpha, or interferon-gamma. Standard antiviral therapy (interferon-alpha, interferon-alpha plus ribavirin, or peg interferon alpha) was administered equally to the intervention and the control groups in five trials, depending on when the trial was conducted. Four trials compared amantadine versus ribavirin. There were no deaths or liver-related morbidity in the two intervention groups (0/216 (0%) versus 0/211 (0%); 4 trials; very low quality of the evidence). The lower estimated risk for (serious) adverse events leading to treatment discontinuation with amantadine was imprecise (RR 0.56, 95% CI 0.27 to 1.16; based on 10/216 (5%) versus 18/211 (9%) participants in 4 trials; very low quality of the evidence). There were more participants with failure of sustained virological response in the amantadine group than in the ribavirin group (206/216 (96%) versus 176/211 (84%); RR 1.14, 95% CI 1.07 to 1.22, 4 trials; low quality of the evidence). Amantadine versus ribavirin more often failed to achieve end-of follow-up biochemical response (41/46 (89%) versus 31/46 (67%); RR 1.31, 95% CI 1.05 to 1.63; 2 trials; very low quality of the evidence). One trial compared amantadine versus mycophenolate mofetil. There were no significant differences between the two treatment groups, except that amantadine was inferior to mycophenolate mofetil regarding the outcome failure to achieve end-of treatment virological response (low quality of evidence). One trial each compared amantadine versus interferon-alpha or interferon-gamma. Both comparisons showed no significant differences in the treatment outcomes (very low quality of the evidence). The observed effects could be due to real effects, systematic errors (bias), or random errors (play of chance). This possible influence on the observed effect by play of chance is due to the fact that trial sequential analyses could not confirm our findings. We were not able to perform meta-analyses on failure of histological improvement and quality of life due to lack of valid data in all trial comparisons. AUTHORS' CONCLUSIONS This systematic review has identified evidence of very low quality for the key outcomes of all-cause mortality or liver-related morbidity and adverse events in people with chronic hepatitis C when treated with amantadine compared with ribavirin, mycophenolate, interferon-alpha, or interferon-gamma. The timeframe for measuring the composite outcome was insufficient in the included trials. There was low quality evidence that amantadine led to more participants who failed to achieve sustained virological response compared with ribavirin. This observation may be real or caused by systematic errors (bias), but it does not seem to be caused by random error (play of chance). Due to the low quality of the evidence, we are unable to determine definitively whether amantadine is less effective than other antivirals in patients with chronic hepatitis C. As it appears less likely that future trials assessing amantadine or potentially other aminoadamantanes for patients with chronic hepatitis C would show strong benefits, it is probably better to focus on the assessments of other direct acting antiviral drugs. We found no evidence assessing other aminoadamantanes in randomised clinical trials in order to recommend or refute their use.
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Affiliation(s)
- Mieke H Lamers
- Radboud University Medical Center NijmegenDepartment of Gastroenterology and HepatologyGeert Grooteplein Zuid 10NijmegenNetherlands6525 GA
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Mark Broekman
- Radboud University Medical Center NijmegenDepartment of Gastroenterology and HepatologyGeert Grooteplein Zuid 10NijmegenNetherlands6525 GA
| | - Joost PH Drenth
- Radboud University Medical Center NijmegenDepartment of Gastroenterology and HepatologyGeert Grooteplein Zuid 10NijmegenNetherlands6525 GA
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
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Lamers MH, Broekman M, Drenth JPH, Gluud C. Aminoadamantanes versus other antiviral drugs for chronic hepatitis C. Cochrane Database Syst Rev 2014. [DOI: 10.1002/14651858.cd011132] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Lamers MH, Broekman M, Drenth JPH, Gluud C, Cochrane Hepato‐Biliary Group. Aminoadamantanes for chronic hepatitis C. Cochrane Database Syst Rev 2014; 2014:CD010125. [PMID: 24793264 PMCID: PMC10542096 DOI: 10.1002/14651858.cd010125.pub2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Around 3% of the world's population (approximately 160 million people) are chronically infected with hepatitis C virus. The proportion of infected people who develop clinical symptoms varies between 5% and 40%. Combination therapy with pegylated interferon-alpha plus ribavirin eradicates the virus from the blood six months after treatment (sustained virological response) in approximately 40% to 80% of infected patients, depending on the viral genotype. New antiviral agents, such as boceprevir and telaprevir, in combination with standard therapy, can increase sustained virological response in genotype 1 infected patients to at least 70%. There is therefore an unmet need for drugs that can achieve a higher proportion of sustained virological response. Aminoadamantanes are antiviral drugs used for treatment of patients with chronic hepatitis C. OBJECTIVES To assess the beneficial and harmful effects of aminoadamantanes for patients with chronic hepatitis C infection by conducting a systematic review with meta-analyses of randomised clinical trials, as well as trial sequential analyses. SEARCH METHODS We conducted electronic searches of the Cochrane Hepato-Biliary Group Controlled Trials Register (1996 to December 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 11 of 12 (1995 to December 2013), MEDLINE (1946 to December 2013), EMBASE (1974 to December 2013), Science Citation Index EXPANDED (1900 to December 2013), the WHO International Clinical Trials Registry Platform (www.who.int/ictrp), Google Scholar, and Eudrapharm up to December 2013 and checked the reference lists of identified publications. SELECTION CRITERIA Randomised clinical trials assessing aminoadamantanes in patients with chronic hepatitis C infection. DATA COLLECTION AND ANALYSIS Two authors independently extracted data. We assessed for risks of systematic errors ('bias') using the 'Risk of bias' tool. We analysed dichotomous data with risk ratio (RR) and continuous data with mean difference (MD) or standardised mean difference (SMD), both with 95% confidence intervals (CI). We used trial sequential analysis to assess the risk of random errors ('play of chance'). We assessed quality using the GRADE system. MAIN RESULTS We included 41 randomised clinical trials with 6193 patients with chronic hepatitis C. All trials had high risk of bias. All included trials compared amantadine versus placebo or no intervention. Standard antiviral therapy was administered equally to the intervention and the control groups in 40 trials. The standard antiviral therapy, which was administered to both intervention groups, was interferon-alpha, interferon-alpha plus ribavirin, and peg interferon-alpha plus ribavirin, depending on the time when the trial was conducted.When we meta-analysed all trials together, the overall results demonstrated no significant effects of amantadine, when compared with placebo or no intervention, on our all-cause mortality or liver-related morbidity composite outcome (5/2353 (0.2%) versus 6/2264 (0.3%); RR 0.90, 95% CI 0.38 to 2.17; I² = 0%; 32 trials; very low quality). There was also no significant effect on adverse events (288/2869 (10%) versus 293/2777 (11%); RR 0.98, 95% CI 0.84 to 1.14; I² = 0%; 35 trials; moderate quality). We used both fixed-effect and random-effects meta-analyses. Amantadine, when compared with placebo or no intervention, did not significantly influence the number of patients who failed to achieve a sustained virological response (1821/2861 (64%) versus 1737/2721 (64%); RR 0.98, 95% CI 0.95 to 1.02; I² = 35%; 35 trials; moderate quality). However, in the subgroup using interferon plus ribavirin, amantadine decreased the number of patients who failed to achieve a sustained virological response (422/666 (63%) versus 447/628 (71%); RR 0.89, 95% CI 0.83 to 0.96; I² = 41%; 11 trials; low quality). Similar results were found for failure to achieve an end of treatment virological response. Amantadine, when compared with placebo or no intervention, significantly decreased the number of patients without normalisation of alanine aminotransferase (ALT) serum levels at the end of treatment (671/1141 (59%) versus 732/1100 (67%); RR 0.88, 95% CI 0.83 to 0.94; I² = 47%; 19 trials; low quality). Amantadine, when compared with placebo or no intervention, did not significantly influence the end of follow-up biochemical response (1133/1896 (60%) versus 1151/1848 (62%); RR 0.95, 95% CI 0.91 to 1.00; I² = 49%; 21 trials; low quality).The observed beneficial effects could be true effects but could also be due to both systematic errors (bias) and random errors (play of chance). The latter is due to the fact that trial sequential analyses could not confirm or refute our findings. We were not able to perform meta-analyses for failure of histological improvement or quality of life due to a lack of valid data. AUTHORS' CONCLUSIONS This systematic review does not demonstrate any significant effects of amantadine on all-cause mortality or liver-related morbidity composite outcome and on adverse events in patients with hepatitis C; however, the median trial duration was 12 months, with a median follow-up of six months, which is not long enough to assess the composite outcome sufficiently. Overall, we did not see an effect of amantadine on failure to achieve a sustained virological response. Subgroup analyses demonstrated that the combination of amantadine plus interferon-alpha and ribavirin seems to increase the number of patients achieving a sustained virological response. This finding may be caused by both systematic errors (bias) and risks of random errors (play of chance), but it could also be real. Based on the results of the overall evidence, it appears less likely that future trials assessing amantadine for patients with chronic hepatitis C will show strong benefits. Therefore, it is probably advisable to wait for the results of trials assessing other direct-acting antiviral drugs. In the absence of convincing evidence of benefit, the use of amantadine is justified in the context of randomised clinical trials assessing the effects of combination therapy. We found a lack of evidence on other aminoadamantanes than amantadine.
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Affiliation(s)
- Mieke H Lamers
- Radboud University Medical Center NijmegenDepartment of Gastroenterology and HepatologyGeert Grooteplein Zuid 10NijmegenNetherlands6525 GA
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Mark Broekman
- Radboud University Medical Center NijmegenDepartment of Gastroenterology and HepatologyGeert Grooteplein Zuid 10NijmegenNetherlands6525 GA
| | - Joost PH Drenth
- Radboud University Medical Center NijmegenDepartment of Gastroenterology and HepatologyGeert Grooteplein Zuid 10NijmegenNetherlands6525 GA
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
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Abstract
Hepatitis has been a major plague of mankind. The history of the discovery of causative viruses is one of the most fascinating scientific adventures of this half century. Individualization of several types of hepatitis only emerged after world war two. Their identification has been associated with milestones which revolutionized medicine and public health. The discovery of HBV brought the first ever vaccine not prepared by tissue culture but initially directly from plasma and soon the first vaccine produced by genetic engineering. HBV vaccine proved to be the first "anti-cancer" vaccine by preventing hepatocellular carcinoma and practically eradicating it from childhood in Taiwan. Successful vaccines became also available for HAV and more recently HEV. The discovery of HCV in 1989 opened a new era since it was the first virus was identified by a direct molecular approach. Two billion people are infected with HBV and 350 million are chronic carriers of the virus. The extraordinary effectiveness of HBV vaccination was best illustrated in Taiwan and Singapore where in less than 2 decades HBs Ag carriers dropped from 9,1% to 2,7% and HCC from 27% to 17%. Successful development of nucleos(t)ides analogs make it now possible to fully control disease progression with a daily pill long term therapy. The progress in HCV therapy has been even more spectacular and successful treatment jumped from 6 % with interferon alone in 1986 to more than 80% in 2013 with triple combination therapies. Remarkably chronic hepatitis C is the only chronic disease which is curable. It will be soon possible to eradicate HCV infection with, an all oral, daily single pill (containing several molecules) for 3 to 6 months which will cure over 90% of patients. This unprecedented therapeutic victory benefiting hundred millions of people matches the triumphs over small pox, polio and tuberculosis. The next 10 years should undoubtedly witness cure or full control over all forms of acute and chronic hepatitis.
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Affiliation(s)
- Christian Trepo
- Hepatology Unit, CROIX ROUSSE Hospital and INSERM U1052, Lyon, France
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Koh C, Liang TJ. What is the future of ribavirin therapy for hepatitis C? Antiviral Res 2014; 104:34-9. [PMID: 24468277 DOI: 10.1016/j.antiviral.2014.01.005] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2013] [Revised: 01/08/2014] [Accepted: 01/12/2014] [Indexed: 02/06/2023]
Abstract
With the introduction of direct-acting antiviral (DAA) therapy against hepatitis C virus (HCV) infection, the field is rapidly evolving towards interferon-free regimens with high sustained virologic response (SVR) rates. The ultimate goal of therapy in chronic HCV infection should include an easily dosed all-oral regimen that is highly effective, inexpensive, pan-genotypic, safe and tolerable, with minimal to no resistance. Various investigational DAA regimens are currently under evaluation with and without ribavirin (Rbv). With the projected arrival of improved therapies over the next 5years, the future role of Rbv comes into question. Despite being plagued by the lack of understanding of its mechanism of action and significant side effects such as anemia, Rbv has been a part of the standard-of-care therapies in chronic HCV infection for more than 10years. As we look towards the future HCV therapy, Rbv may still have utility in the care of patients infected with HCV because of its low cost and potentially added value in combination with other DAAs. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication."
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Affiliation(s)
- Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, United States.
| | - T Jake Liang
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, United States.
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Vogel W. Peginterferon-α2a(40 kDa)/ribavirin combination for the treatment of chronic hepatitis C infection. Expert Rev Anti Infect Ther 2014; 1:423-31. [PMID: 15482139 DOI: 10.1586/14787210.1.3.423] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Chronic hepatitis C is the leading cause of liver disease and liver-related mortality in the western world. Treatment of this chronic viral infection has considerably improved with the introduction of ribavirin-interferon combination therapy. Ribavirin (Copegus, Rebetol) is a synthetic nucleoside analogue with broad antiviral effects. It is absorbed readily upon oral administration with meals. Daily doses of up to 1200 mg are usually well-tolerated, causing dose-dependent haemolysis, reversible with dose reduction in most patients, in particular in those with renal insufficiency. In the circulation it is bound to erythrocytes, and eliminated by phosphorylation and deribolysation. The drug accumulates in blood with renal insufficiency. Impairment of hepatic function does not influence drug levels in the circulation. In animal studies, teratogenic and reproductive toxicity was shown. In chronic hepatitis C virus infection, monotherapy with ribavirin has no effect on concentrations of viral RNA or liver histology. Combination therapy with pegylated interferon-alpha2a (40 kDa) (Pegasys) produces significantly higher sustained virological response rates in infections with all viral genotypes, even in advanced stages of liver disease compared pegylated interferon-alpha2a monotherapy, adverse effects and quality of life are not significantly different.
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Affiliation(s)
- Wolfgang Vogel
- Department of Gastroenterology and Hepatology, Innsbruck University, Austria.
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Carreño V. Review article: management of chronic hepatitis C in patients with contraindications to anti-viral therapy. Aliment Pharmacol Ther 2014; 39:148-62. [PMID: 24279580 DOI: 10.1111/apt.12562] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Revised: 08/13/2013] [Accepted: 11/05/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND There are patients with chronic hepatitis C who are not eligible for the current interferon-based therapies or refuse to be treated due to secondary effects. AIM To provide information on alternative treatments for the management of these patients. METHODS A PubMed search was performed to identify relevant literature. Search terms included hepatitis C virus, anti-inflammatory treatment, antioxidant, natural products and alternative treatment, alone or in combination. Additional publications were identified using the references cited by primary and review articles. RESULTS Several approaches, such as iron depletion (phlebotomy), treatment with ursodeoxycholic acid or glycyrrhizin, have anti-inflammatory and/or anti-fibrotic effects. Life interventions like weight loss, exercise and coffee consumption are associated with a biochemical improvement. Other alternatives (ribavirin monotherapy, amantadine, silibinin, vitamin supplementation, etc.) do not have any beneficial effect or need to be tested in larger clinical studies. CONCLUSION There are therapeutic strategies and lifestyle interventions that can be used to improve liver damage in patients with chronic hepatitis C who cannot receive or refuse interferon-based treatments.
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Affiliation(s)
- V Carreño
- Fundación Estudio Hepatitis Virales, Madrid, Spain
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Coats SJ, Garnier-Amblard EC, Amblard F, Ehteshami M, Amiralaei S, Zhang H, Zhou L, Boucle SRL, Lu X, Bondada L, Shelton JR, Li H, Liu P, Li C, Cho JH, Chavre SN, Zhou S, Mathew J, Schinazi RF. Chutes and ladders in hepatitis C nucleoside drug development. Antiviral Res 2013; 102:119-47. [PMID: 24275341 DOI: 10.1016/j.antiviral.2013.11.008] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 11/08/2013] [Accepted: 11/12/2013] [Indexed: 02/07/2023]
Abstract
Chutes and Ladders is an exciting up-and-down-again game in which players race to be the first to the top of the board. Along the way, they will find ladders to help them advance, and chutes that will cause them to move backwards. The development of nucleoside analogs for clinical treatment of hepatitis C presents a similar scenario in which taking shortcuts may help quickly advance a program, but there is always a tremendous risk of being sent backwards as one competes for the finish line. In recent years the treatment options for chronic hepatitis C virus (HCV) infection have expand due to the development of a replicon based in vitro evaluation system, allowing for the identification of multiple drugable viral targets along with a concerted and substantial drug discovery effort. Three major drug targets have reached clinical study for chronic HCV infection: the NS3/4A serine protease, the large phosphoprotein NS5A, and the NS5B RNA-dependent RNA polymerase. Recently, two oral HCV protease inhibitors were approved by the FDA and were the first direct acting anti-HCV agents to result from the substantial research in this area. There are currently many new chemical entities from several different target classes that are being evaluated worldwide in clinical trials for their effectiveness at achieving a sustained virologic response (SVR) (Pham et al., 2004; Radkowski et al., 2005). Clearly the goal is to develop therapies leading to a cure that are safe, widely accessible and available, and effective against all HCV genotypes (GT), and all stages of the disease. Nucleoside analogs that target the HCV NS5B polymerase that have reached human clinical trials is the focus of this review as they have demonstrated significant advantages in the clinic with broader activity against the various HCV GT and a higher barrier to the development of resistant viruses when compared to all other classes of HCV inhibitors.
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Affiliation(s)
- Steven J Coats
- RFS Pharma, LLC, 1860 Montreal Road, Tucker, GA 30084, USA
| | | | - Franck Amblard
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA 30033, USA
| | - Maryam Ehteshami
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA 30033, USA
| | - Sheida Amiralaei
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA 30033, USA
| | - Hongwang Zhang
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA 30033, USA
| | - Longhu Zhou
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA 30033, USA
| | - Sebastien R L Boucle
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA 30033, USA
| | - Xiao Lu
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA 30033, USA
| | - Lavanya Bondada
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA 30033, USA
| | - Jadd R Shelton
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA 30033, USA
| | - Hao Li
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA 30033, USA
| | - Peng Liu
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA 30033, USA
| | - Chengwei Li
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA 30033, USA
| | - Jong Hyun Cho
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA 30033, USA
| | - Satish N Chavre
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA 30033, USA
| | - Shaoman Zhou
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA 30033, USA
| | - Judy Mathew
- RFS Pharma, LLC, 1860 Montreal Road, Tucker, GA 30084, USA
| | - Raymond F Schinazi
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA 30033, USA.
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Heim MH. 25 years of interferon-based treatment of chronic hepatitis C: an epoch coming to an end. Nat Rev Immunol 2013; 13:535-42. [PMID: 23743475 DOI: 10.1038/nri3463] [Citation(s) in RCA: 113] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis caused by infection with hepatitis C virus C (HCV) (therefore known as chronic hepatitis C (CHC)) is a leading cause of liver disease worldwide. For the past 25 years, recombinant interferon-α (IFNα) has been the main component of treatments for HCV infection. Treatment efficacy has shown a stepwise improvement following the pegylation of IFNα and its use in combination with other antiviral drugs. However, viral escape mechanisms, refractory IFNα signalling in the liver and substantial drug toxicity still limit the efficacy of this treatment. A new generation of HCV-specific antiviral drugs will probably improve response rates and might replace IFNs in CHC treatment in the next few years. This Timeline article summarizes the history of CHC treatment using recombinant IFNα with an emphasis on the mechanisms of action and the causes of non-response.
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Affiliation(s)
- Markus H Heim
- Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
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the Ochanomizu-Liver Conference Study Group, Nakagawa M, Sakamoto N, Watanabe T, Nishimura-Sakurai Y, Onozuka I, Azuma S, Kakinuma S, Nitta S, Kiyohashi K, Kusano-Kitazume A, Murakawa M, Yoshino K, Itsui Y, Tanaka Y, Mizokami M, Watanabe M. Association of ITPA gene variation and serum ribavirin concentration with a decline in blood cell concentrations during pegylated interferon-alpha plus ribavirin therapy for chronic hepatitis C. Hepatol Int 2013; 7:153-161. [DOI: 10.1007/s12072-012-9363-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Guidelines for the Management of Hepatitis C Virus Infection: First edition, May 2012, The Japan Society of Hepatology. Hepatol Res 2013; 43:1-34. [PMID: 23332085 DOI: 10.1111/hepr.12020] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
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- Department of Gastroenterology and Hepatology, Faculty of Medicine, Tokyo Medical and Dental University
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Warren RP, Sidwell RW. The Potential Role of Cytokines in the Treatment of Viral Infections. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/bf03258488] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Habersetzer F, Leboeuf C, Doffoël M, Baumert TF. Boceprevir and personalized medicine in hepatitis C virus infection. Pharmgenomics Pers Med 2012; 5:125-37. [PMID: 23226068 PMCID: PMC3513234 DOI: 10.2147/pgpm.s24259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Indexed: 12/22/2022] Open
Abstract
Boceprevir was the first agent, along with telaprevir, of a novel class of direct-acting antivirals that entered clinical practice for the treatment of chronic hepatitis C. Boceprevir is an antiprotease that directly blocks hepatitis C virus (HCV) replication. Two studies in patients with HCV genotype 1 infection have shown that addition of boceprevir to the standard of care, ie, pegylated interferon-alfa (PEG-IFN-α) and ribavirin, markedly increased the rate of sustained virological response. A sustained virological response was obtained in about 70% of patients who had never been treated, as well as in 69%-75% and 40% of previous relapsers and nonresponders to PEG-IFN-α-ribavirin, respectively. Side effects were observed in almost all treated patients. Anemia, the most frequent adverse event related to administration of boceprevir, occurred in about 50% of patients. The decision to add boceprevir to the standard of care is made on an individual basis, and takes into account the prognosis of the liver disease, the efficacy of therapy, as it could be at best predicted, and the side effects that may arise, taking into account the comorbidities of the patient. Ultimately, the treatment must be accepted by the patient, who should fully understand the benefits and risks. Boceprevir trials were designed with the concept of individualized and response-guided therapy which establishes treatment decisions on how rapidly patients respond to treatment. Individualized therapy for chronic hepatitis C is based on patient and viral characteristics to make the best choice about whether a person will benefit from therapy and to evaluate on-treatment predictors of response to shorten therapy in patients with a rapid response as well as in patients who did not respond sufficiently to expect HCV eradication. This review focuses on the main results obtained so far, their impact on the treatment of patients with chronic hepatitis C, and potential therapeutic perspectives.
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Affiliation(s)
| | | | - Michel Doffoël
- Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg
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Thomas E, Ghany MG, Liang TJ. The application and mechanism of action of ribavirin in therapy of hepatitis C. Antivir Chem Chemother 2012; 23:1-12. [PMID: 22592135 PMCID: PMC6271563 DOI: 10.3851/imp2125] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2012] [Indexed: 12/11/2022] Open
Abstract
Ribavirin has been used as an antiviral agent for several decades. Although it has activity against numerous viruses, its major use clinically has been in the treatment of respiratory syncytial virus in paediatric patients and chronic HCV infection in both children and adults. This review highlights the clinical application and mechanism of action of ribavirin and discusses the future role of ribavirin in treatment of HCV where there are intense research efforts to improve therapy.
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Affiliation(s)
- Emmanuel Thomas
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.
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Tanwar S, Trembling PM, Dusheiko GM. Hepatitis C Therapy: Lessons of the Last Two Decades. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/s11901-012-0141-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Stevenson NJ, Murphy AG, Bourke NM, Keogh CA, Hegarty JE, O'Farrelly C. Ribavirin enhances IFN-α signalling and MxA expression: a novel immune modulation mechanism during treatment of HCV. PLoS One 2011; 6:e27866. [PMID: 22114715 PMCID: PMC3218071 DOI: 10.1371/journal.pone.0027866] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2011] [Accepted: 10/26/2011] [Indexed: 12/26/2022] Open
Abstract
The nucleoside analogue Ribavirin significantly increases patient response to IFN-α treatment of HCV, by directly inhibiting viral replication. Recent studies indicate that Ribavirin also regulates immunity and we propose that Ribavirin enhances specific interferon sensitive gene (ISG) expression by amplifying the IFN-α-JAK/STAT pathway. We found that IFN-α-induced STAT1 and STAT3 phosphorylation was increased in hepatocytes co-treated with Ribavirin and IFN-α, compared to IFN-α alone. Ribavirin specifically enhanced IFN-α induced mRNA and protein of the anti-viral mediator MxA, which co-localised with HCV core protein. These novel findings indicate for the first time that Ribavirin, in addition to its viral incorporation, also enhances IFN-α-JAK/STAT signalling, leading to a novel MxA-mediated immuno-modulatory mechanism that may enhance IFN-α anti-viral activity against HCV.
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Affiliation(s)
- Nigel J Stevenson
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
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Fechner H, Pinkert S, Geisler A, Poller W, Kurreck J. Pharmacological and biological antiviral therapeutics for cardiac coxsackievirus infections. Molecules 2011; 16:8475-503. [PMID: 21989310 PMCID: PMC6264230 DOI: 10.3390/molecules16108475] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2011] [Revised: 09/29/2011] [Accepted: 09/30/2011] [Indexed: 01/16/2023] Open
Abstract
Subtype B coxsackieviruses (CVB) represent the most commonly identified infectious agents associated with acute and chronic myocarditis, with CVB3 being the most common variant. Damage to the heart is induced both directly by virally mediated cell destruction and indirectly due to the immune and autoimmune processes reacting to virus infection. This review addresses antiviral therapeutics for cardiac coxsackievirus infections discovered over the last 25 years. One group represents pharmacologically active low molecular weight substances that inhibit virus uptake by binding to the virus capsid (e.g., pleconaril) or inactivate viral proteins (e.g., NO-metoprolol and ribavirin) or inhibit cellular proteins which are essential for viral replication (e.g., ubiquitination inhibitors). A second important group of substances are interferons. They have antiviral but also immunomodulating activities. The third and most recently discovered group includes biological and cellular therapeutics. Soluble receptor analogues (e.g., sCAR-Fc) bind to the virus capsid and block virus uptake. Small interfering RNAs, short hairpin RNAs and antisense oligonucleotides bind to and led to degradation of the viral RNA genome or cellular RNAs, thereby preventing their translation and viral replication. Most recently mesenchymal stem cell transplantation has been shown to possess antiviral activity in CVB3 infections. Taken together, a number of antiviral therapeutics has been developed for the treatment of myocardial CVB infection in recent years. In addition to low molecular weight inhibitors, biological therapeutics have become promising anti-viral agents.
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Affiliation(s)
- Henry Fechner
- Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Gustav-Meyer-Allee 25, 13355 Berlin, Germany; (S.P.); (J.K.)
- Author to whom correspondence should be addressed; ; Tel.: +49-30-31472181; Fax: +49-30-31427502
| | - Sandra Pinkert
- Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Gustav-Meyer-Allee 25, 13355 Berlin, Germany; (S.P.); (J.K.)
| | - Anja Geisler
- Department of Cardiology & Pneumology, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany; (A.G.); wolfgang.poller@charite (W.P.)
| | - Wolfgang Poller
- Department of Cardiology & Pneumology, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany; (A.G.); wolfgang.poller@charite (W.P.)
| | - Jens Kurreck
- Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Gustav-Meyer-Allee 25, 13355 Berlin, Germany; (S.P.); (J.K.)
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Cariani E, Villa E, Rota C, Critelli R, Trenti T. Translating pharmacogenetics into clinical practice: interleukin (IL)28B and inosine triphosphatase (ITPA) polymophisms in hepatitis C virus (HCV) infection. Clin Chem Lab Med 2011; 49:1247-1256. [PMID: 21612542 DOI: 10.1515/cclm.2011.618] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hepatitis C virus (HCV) infection is frequently characterized by evolution to chronicity and by a variable clinical course of the disease. The clinical heterogeneities of HCV infection and the imperfect predictability of the response to interferon (IFN) have suggested the need to search for a genetic basis of clinical features. This led to the discovery of genetic polymorphisms playing a major role in the evolution of infection, as well as on treatment response and adverse effects. This review will cover recent reports on the subject, focusing on the potential use of the new genetic markers in the diagnostic algorithm for the stratification of patients for personalized antiviral regimens.
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Affiliation(s)
- Elisabetta Cariani
- Clinical Pathology-Toxicology, Ospedale Civile S. Agostino-Estense, Modena, Italy
| | - Erica Villa
- Department of Gastroenterology, Azienda Ospedaliera-Universitaria, University of Modena and Reggio Emilia, Modena, Italy
| | - Cristina Rota
- Clinical Pathology-Toxicology, Ospedale Civile S. Agostino-Estense, Modena, Italy
| | - Rosina Critelli
- Department of Gastroenterology, Azienda Ospedaliera-Universitaria, University of Modena and Reggio Emilia, Modena, Italy
| | - Tommaso Trenti
- Clinical Pathology-Toxicology, Ospedale Civile S. Agostino-Estense, Modena, Italy
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Abstract
UNLABELLED Viral hepatitis and its sequelae are important health problems worldwide, including Taiwan. For the last 40 years, Taiwan's scientists and health care providers have worked hard to control these sequelae, and the results have been excellent. The author, Ding-Shinn Chen, had a key role in planning and establishing the control program in Taiwan, and participated in the endeavors from the very beginning. In this perspective, he describes how he became interested in research as a medical student, his encounters with hepatitis B and C, how he and his colleagues started early detection of hepatocellular carcinoma (HCC), how he helped Taiwan's government create and implement the Viral Hepatitis Control Program, and how the effectiveness of the program in the decrease of hepatitis B carriage and HCC was monitored. He also discusses how he pioneered the use of interferon-α plus ribavirin to treat chronic hepatitis C. Hepatitis B viral load as a risk factor for HCC and cirrhosis in hepatitis B surface antigen carriers is reviewed briefly, as is the prevention of sequelae by antiviral therapies. Finally, Dr. Chen discusses unresolved issues that must be addressed and predicts the changes of the patterns of liver disease in Taiwan beyond the mid-21st century, which is in part affected by the fight against viral hepatitis that was initiated in the early 1980s. CONCLUSION Dr. Chen's perspective illustrates Taiwan's fight against viral hepatitis over the last 40 years. This experience can be shared by other countries in which the disease is equally prevalent.
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Affiliation(s)
- Ding-Shinn Chen
- Department of Internal Medicine, National Taiwan University College of Medicine, Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
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Abstract
Twenty-five years have passed since interferon-α was first used in the treatment of chronic hepatitis C infection, and even now it remains an essential part of the standard of care for this condition. At present, the recommended treatment is a combination of pegylated interferon and ribavirin A. There have been enormous advances in our understanding of the mechanisms through which interferon works and in identifying factors related to the response to this treatment. Even with the development of new protease inhibitors, it is likely that interferon will remain an essential component of hepatitis C treatment.
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Affiliation(s)
- Maria Buti
- Liver Unit, Hospital General, Universitario Valle Hebron, Paseo Valle Hebron 119, Barcelona 08035, Spain.
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Brillanti S, Mazzella G, Roda E. Ribavirin for chronic hepatitis C: and the mystery goes on. Dig Liver Dis 2011; 43:425-30. [PMID: 21093391 DOI: 10.1016/j.dld.2010.10.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2010] [Accepted: 10/12/2010] [Indexed: 12/11/2022]
Abstract
Twenty years ago, ribavirin was first used in the treatment for chronic hepatitis C. After few years, ribavirin, in combination with interferon-alpha, showed a dramatic synergistic efficacy against hepatitis C virus infection, leading to viral clearance in about 50% of patients. Recent discovery of potent inhibitors of hepatitis C virus proteases did not replace ribavirin as the mainstay of combination therapy for chronic hepatitis C. Despite this fundamental role of ribavirin, many aspects of the mechanism of action and of the optimal dose and duration of therapy remain to be discovered or settled. In the present review, the authors recall the milestones in the history of ribavirin and try to shed light on the more relevant features of ribavirin action and utilization, and on the clinical problems encountered in managing and optimizing treatment for chronic hepatitis C. Finally, some potential off-label use of this drug in most difficult-to-treat subjects is pointed out. In conclusion, even if a sort of mystery surrounds ribavirin, its efficacy against hepatitis C virus infection fortunately remains lasting and stable.
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Affiliation(s)
- Stefano Brillanti
- Divisione di Gastroenterologia, Policlinico S. Orsola - Malpighi, Bologna, Italy.
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45
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Oligomeric nucleic acids as antivirals. Molecules 2011; 16:1271-96. [PMID: 21278679 PMCID: PMC6259927 DOI: 10.3390/molecules16021271] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2010] [Revised: 01/12/2011] [Accepted: 01/25/2011] [Indexed: 02/07/2023] Open
Abstract
Based on the natural functions and chemical characteristics of nucleic acids, a variety of novel synthetic drugs and tools to explore biological systems have become available in recent years. To date, a great number of antisense oligonucleotides, RNA interference-based tools, CpG-containing oligonucleotides, catalytic oligonucleotides, decoys and aptamers has been produced synthetically and applied successfully for understanding and manipulating biological processes and in clinical trials to treat a variety of diseases. Their versatility and potency make them equally suited candidates for fighting viral infections. Here, we describe the different types of nucleic acid-based antivirals, their mechanism of action, their advantages and limitations, and their future prospects.
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Sakamoto N, Tanaka Y, Nakagawa M, Yatsuhashi H, Nishiguchi S, Enomoto N, Azuma S, Nishimura-Sakurai Y, Kakinuma S, Nishida N, Tokunaga K, Honda M, Ito K, Mizokami M, Watanabe M. ITPA gene variant protects against anemia induced by pegylated interferon-α and ribavirin therapy for Japanese patients with chronic hepatitis C. Hepatol Res 2010; 40:1063-1071. [PMID: 20977565 DOI: 10.1111/j.1872-034x.2010.00741.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Host genetic variants leading to inosine triphosphatase (ITPA) deficiency, a condition not thought to be clinically important, protect against hemolytic anemia in chronic hepatitis C patients receiving ribavirin. In this study, we evaluated the clinical significance of ITPA variants in Japanese hepatitis C patients who were treated with pegylated interferon plus ribavirin. METHODS In this multicenter retrospective cross-sectional study, 474 hepatitis C patients were enrolled who were treated with pegylated interferon plus ribavirin in four geographically different hospitals in Japan. Patients were grouped according to hemoglobin decline of more than 3 g/dL at week 4. Two single nucleotide polymorphisms (SNP) within or adjacent to the ITPA gene (rs6051702, rs1127354) were genotyped. RESULTS A functional SNP, rs1127354, within the ITPA exon was strongly associated with protection against anemia with only one (0.8%) in 129 patients with the ITPA minor variant A developing severe anemia (P=5.9×10(-20) ). For rs6051702, which had significant association in European-Americans, significant but weak association with severe hemoglobin reduction was found in Japanese (P= 0.009). In patients excluding genotype 1b and high viral load, those with the ITPA minor variant A achieved significantly higher sustained viral response rate than those with the major variant (CC) (96% vs 70%, respectively, P= 0.0066). CONCLUSION ITPA SNP, rs1127354, is confirmed to be a useful predictor of ribavirin-induced anemia in Japanese patients. Patients with the ITPA minor variant A (~ 27%) have an advantage in pegylated interferon plus ribavirin-based therapies, due to expected adherence of ribavirin doses, resulting in a higher viral clearance rate.
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Affiliation(s)
- Naoya Sakamoto
- Department of Gastroenterology and Hepatology Department for Hepatitis Control, Tokyo Medical and Dental University, Tokyo, Japan
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Nakagawa M, Sakamoto N, Ueyama M, Mogushi K, Nagaie S, Itsui Y, Azuma S, Kakinuma S, Tanaka H, Enomoto N, Watanabe M. Mutations in the interferon sensitivity determining region and virological response to combination therapy with pegylated-interferon alpha 2b plus ribavirin in patients with chronic hepatitis C-1b infection. J Gastroenterol 2010; 45:656-65. [PMID: 20112032 DOI: 10.1007/s00535-009-0195-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2009] [Accepted: 12/11/2009] [Indexed: 02/04/2023]
Abstract
BACKGROUND Pegylated-interferon-alpha 2b (PEG-IFN) plus ribavirin (RBV) therapy is currently the de-facto standard treatment for hepatitis C virus (HCV) infection. The aims of this study were to analyze the clinical and virological factors associated with a higher rate of response in patients with HCV genotype 1b infection treated with combination therapy. METHODS We analyzed, retrospectively, 239 patients with chronic hepatitis C-1b infection who received 48 weeks of combination therapy. We assessed clinical and laboratory parameters, including age, gender, pretreatment hemoglobin, platelet counts, HCV RNA titer, liver histology, the number of interferon sensitivity determining region (ISDR) mutations and substitutions of the core amino acids 70 and 91. Drug adherence was monitored in each patient. We carried out univariate and multivariate statistical analyses of these parameters and clinical responses. RESULTS On an intention-to-treat (ITT) analysis, 98 of the 239 patients (41%) had sustained virological responses (SVRs). Patients with more than two mutations in the ISDR had significantly higher SVR rates (P<0.01). Univariate analyses showed that stage of fibrosis, hemoglobin, platelet counts, ISDR mutations, serum HCV RNA level, and adherence to PEG-IFN plus RBV were significantly correlated with SVR rates. Multivariate analysis in subjects with good drug adherence extracted the number of ISDR mutations (two or more: odds ratio [OR] 5.181). CONCLUSIONS The number of mutations in the ISDR sequence of HCV-1b (>or=2) is the most effective parameter predicting a favorable clinical outcome of 48-week PEG-IFN plus RBV therapy in patients with HCV genotype 1b infection.
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Affiliation(s)
- Mina Nakagawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
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Weiland O, Zhang YY, Widell A. Serum HCV RNA Levels in Patients with Chronic Hepatitis C Given a Second Course of Interferon alpha-2b Treatment after Relapse following Initial Treatment. ACTA ACUST UNITED AC 2010. [DOI: 10.1080/00365549309169665] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Abstract
BACKGROUND Hepatitis C is a major cause of liver-related morbidity and mortality. Standard therapy is ribavirin plus pegylated interferon to achieve undetectable level of virus in the blood, but the effect on clinical outcomes is controversial. OBJECTIVES To assess the beneficial and harmful effects of ribavirin and interferon combination therapy versus interferon monotherapy for chronic hepatitis C. SEARCH STRATEGY We identified trials through electronic databases, manual searches of bibliographies and journals, approaching authors of trials, and pharmaceutical companies until March 2009. SELECTION CRITERIA We included randomised trials, irrespective of blinding, language, or publication status, comparing ribavirin plus interferon versus interferon for treatment of chronic hepatitis C. DATA COLLECTION AND ANALYSIS The primary outcome measures were serum sustained loss of hepatitis C virus, liver-related morbidity plus all-cause mortality, and adverse events. We performed subgroup analyses of patients who were naive, relapsers, or non-responders to previous antiviral treatment. All outcomes were analysed with the random-effects model. We used Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of morbidity plus mortality. The remaining outcomes were presented as relative risks (RR). We used trial sequential analyses to examine the robustness of our findings. MAIN RESULTS We included 83 randomised trials with 12,707 patients. Most trials had unclear or high risk of bias. We did not find any significant influence of bias on our results but cannot exclude outcome measure reporting bias as many trials did not report on the primary outcomes of this review. Compared with interferon, ribavirin plus interferon had a significant beneficial effect on sustained virological response in subgroups of naive patients (RR 0.72, 95% confidence interval (CI) 0.68 to 0.75), relapsers (RR 0.62, 95% CI 0.54 to 0.70), non-responders (RR 0.89, 95% CI 0.84 to 0.93), and in all patients (RR 0.75, 95% CI 0.71 to 0.79). Combination therapy significantly reduced morbidity plus mortality in all patients (Peto OR, 0.43, 95% CI 0.23 to 0.79), but not in naive, relapsers, or non-responders individually. Combination therapy significantly increased the risk of haematological, dermatological, gastrointestinal, infectious, and miscellaneous (cough, dyspnoea, fatigue) adverse reactions. Accordingly, combination therapy significantly increased the risk of treatment discontinuation and dose reductions. Trial sequential analyses confirmed our findings regarding virological effects, but not regarding liver-related morbidity and all-cause mortality. AUTHORS' CONCLUSIONS Compared with interferon alone, ribavirin plus interferon is more effective in clearing hepatitis C virus from the blood. Combination therapy may reduce liver-related morbidity and all-cause mortality, but we need more evidence. The number needed to treat to obtain a beneficial effect is considerable considering the increased risk of several severe adverse reactions and costs.
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Affiliation(s)
- Jesper Brok
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, Denmark, DK-2100
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Susser S, Dragan A, Zeuzem S, Sarrazin C, Lefkowitch JH, Dancygier H. Viral Infections by Hepatotropic Viruses. CLINICAL HEPATOLOGY 2010:671-821. [DOI: 10.1007/978-3-642-04519-6_9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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