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1
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Tsutsumi Y, Ito S, Shiratori S, Teshima T. Hepatitis C Virus (HCV)-Ribonucleic Acid (RNA) As a Biomarker for Lymphoid Malignancy with HCV Infection. Cancers (Basel) 2023; 15:2852. [PMID: 37345190 DOI: 10.3390/cancers15102852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/15/2023] [Accepted: 05/15/2023] [Indexed: 06/23/2023] Open
Abstract
The hepatitis C virus (HCV) is potentially associated with liver cancer, and advances in various drugs have led to progress in the treatment of hepatitis C and attempts to prevent its transition to liver cancer. Furthermore, reactivation of HCV has been observed in the treatment of lymphoma, during which the immortalization and proliferation of lymphocytes occur, which leads to the possibility of further stimulating cytokines and the like and possibly to the development of lymphoid malignancy. There are also cases in which the disappearance of lymphoid malignancy has been observed by treating HCV and suppressing HCV-Ribonucleic acid (RNA), as well as cases of recurrence with an increase in HCV-RNA. While HCV-associated lymphoma has a poor prognosis, improving the prognosis with Direct Acting Antivirals (DAA) has recently been reported. The reduction and eradication of HCV-RNA by means of DAA is thus important for the treatment of lymphoid malignancy associated with HCV infection, and HCV-RNA can presumably play a role as a biomarker. This review provides an overview of what is currently known about HCV-associated lymphoma, its epidemiology, the mechanisms underlying the progression to lymphoma, its treatment, the potential and limits of HCV-RNA as a therapeutic biomarker, and biomarkers that are expected now that DAA therapy has been developed.
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Affiliation(s)
- Yutaka Tsutsumi
- Department of Hematology, Hakodate Municipal Hospital, Hakodate, 1-10-1, Minato-cho, Hakodate 041-8680, Japan
| | - Shinichi Ito
- Department of Hematology, Hakodate Municipal Hospital, Hakodate, 1-10-1, Minato-cho, Hakodate 041-8680, Japan
| | - Souichi Shiratori
- Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
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Goble SR, Nyembo P, Rodin H, Konstantinides G, Powell J, Noska AJ. Statin Utilization Among Individuals Infected With Hepatitis C Virus: A Retrospective Cohort Study. Cureus 2023; 15:e36049. [PMID: 37056557 PMCID: PMC10089619 DOI: 10.7759/cureus.36049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2023] [Indexed: 03/13/2023] Open
Abstract
Introduction and Objectives Statin use for primary prevention of coronary artery disease (CAD) has historically been limited in patients with chronic liver disease due to concerns for increased adverse events with statin use in this population. We aimed to quantify the underutilization of statins among individuals with a history of HCV infection in a community health system to understand the clinical implications of statin underutilization in a diverse, generalizable population of patients infected with HCV. Materials and Methods We performed a single-center retrospective study of individuals with a history of HCV infection aged 40-75 years from 2019-2021. Statin eligibility was determined using the 2019 American College of Cardiology/American Heart Association (ACC/AHA) guidelines with the 2013 Pooled Cohort Equation used to determine atherosclerotic cardiovascular disease (ASCVD) risk. Baseline characteristics and adverse events of statin and non-statin users were compared, and factors associated with statin use were determined using multivariable logistical regression. Results Based on 2019 ACC/AHA guidelines, 752/1,077 (69.8%) subjects had an indication for a statin, 280/752 (37.2%) of which were treated with a statin. Cirrhosis was independently associated with statin underutilization. Diabetes, anti-hypertensive use, and Black race were all independently associated with statin use in subjects with an indication for therapy. Statin use was not associated with adverse events. Conclusions Statins were underutilized and well tolerated in the cohort of individuals with a history of HCV infection. This high-risk population would benefit from increased CAD screening and utilization of statins for the primary prevention of CAD.
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Hasselbalch HC, Silver RT. New Perspectives of Interferon-alpha2 and Inflammation in Treating Philadelphia-negative Chronic Myeloproliferative Neoplasms. Hemasphere 2021; 5:e645. [PMID: 34805764 PMCID: PMC8601345 DOI: 10.1097/hs9.0000000000000645] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 09/03/2021] [Indexed: 12/11/2022] Open
Affiliation(s)
- Hans C Hasselbalch
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Richard T Silver
- Myeloproliferative Neoplasms Center, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York, USA
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Tenesaca S, Vasquez M, Alvarez M, Otano I, Fernandez-Sendin M, Di Trani CA, Ardaiz N, Gomar C, Bella A, Aranda F, Medina-Echeverz J, Melero I, Berraondo P. Statins act as transient type I interferon inhibitors to enable the antitumor activity of modified vaccinia Ankara viral vectors. J Immunother Cancer 2021; 9:jitc-2020-001587. [PMID: 34321273 PMCID: PMC8320251 DOI: 10.1136/jitc-2020-001587] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/27/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Modified vaccinia virus Ankara (MVA) are genetically engineered non-replicating viral vectors. Intratumoral administration of MVA induces a cyclic GMP-AMP synthase-mediated type I interferon (IFN) response and the production of high levels of the transgenes engineered into the viral genome such as tumor antigens to construct cancer vaccines. Although type I IFNs are essential for establishing CD8-mediated antitumor responses, this cytokine family may also give rise to immunosuppressive mechanisms. METHODS In vitro assays were performed to evaluate the activity of simvastatin and atorvastatin on type I IFN signaling and on antigen presentation. Surface levels of IFN α/β receptor 1, endocytosis of bovine serum albumin-fluorescein 5 (6)-isothiocyanate, signal transducer and activator of transcription (STAT) phosphorylation, and real-time PCR of IFN-stimulated genes were assessed in the murine fibroblast cell line L929. In vivo experiments were performed to characterize the effect of simvastatin on the MVA-induced innate immune response and on the antitumor effect of MVA-based antitumor vaccines in B16 melanoma expressing ovalbumin (OVA) and Lewis lung carcinoma (LLC)-OVA tumor models. RNAseq analysis, depleting monoclonal antibodies, and flow cytometry were used to evaluate the MVA-mediated immune response. RESULTS In this work, we identified commonly prescribed statins as potent IFNα pharmacological inhibitors due to their ability to reduce surface expression levels of IFN-α/β receptor 1 and to reduce clathrin-mediated endocytosis. Simvastatin and atorvastatin efficiently abrogated for 8 hours the transcriptomic response to IFNα and enhanced the number of dendritic cells presenting an OVA-derived peptide bound to major histocompatibility complex (MHC) class I. In vivo, intraperitoneal or intramuscular administration of simvastatin reduced the inflammatory response mediated by peritumoral administration of MVA and enhanced the antitumor activity of MVA encoding tumor-associated antigens. The synergistic antitumor effects critically depend on CD8+ cells, whereas they were markedly improved by depletion of CD4+ lymphocytes, T regulatory cells, or NK cells. Either MVA-OVA alone or combined with simvastatin augmented B cells, CD4+ lymphocytes, CD8+ lymphocytes, and tumor-specific CD8+ in the tumor-draining lymph nodes. However, only the treatment combination increased the numbers of these lymphocyte populations in the tumor microenvironment and in the spleen. CONCLUSION In conclusion, blockade of IFNα functions by simvastatin markedly enhances lymphocyte infiltration and the antitumor activity of MVA, prompting a feasible drug repurposing.
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Affiliation(s)
- Shirley Tenesaca
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Marcos Vasquez
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Maite Alvarez
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Itziar Otano
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Myriam Fernandez-Sendin
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Claudia Augusta Di Trani
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Nuria Ardaiz
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Celia Gomar
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Angela Bella
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Fernando Aranda
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | | | - Ignacio Melero
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.,Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Pedro Berraondo
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain .,Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
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Sharma S, Tiarks G, Haight J, Bassuk AG. Neuropathophysiological Mechanisms and Treatment Strategies for Post-traumatic Epilepsy. Front Mol Neurosci 2021; 14:612073. [PMID: 33708071 PMCID: PMC7940684 DOI: 10.3389/fnmol.2021.612073] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/26/2021] [Indexed: 12/11/2022] Open
Abstract
Traumatic brain injury (TBI) is a leading cause of death in young adults and a risk factor for acquired epilepsy. Severe TBI, after a period of time, causes numerous neuropsychiatric and neurodegenerative problems with varying comorbidities; and brain homeostasis may never be restored. As a consequence of disrupted equilibrium, neuropathological changes such as circuit remodeling, reorganization of neural networks, changes in structural and functional plasticity, predisposition to synchronized activity, and post-translational modification of synaptic proteins may begin to dominate the brain. These pathological changes, over the course of time, contribute to conditions like Alzheimer disease, dementia, anxiety disorders, and post-traumatic epilepsy (PTE). PTE is one of the most common, devastating complications of TBI; and of those affected by a severe TBI, more than 50% develop PTE. The etiopathology and mechanisms of PTE are either unknown or poorly understood, which makes treatment challenging. Although anti-epileptic drugs (AEDs) are used as preventive strategies to manage TBI, control acute seizures and prevent development of PTE, their efficacy in PTE remains controversial. In this review, we discuss novel mechanisms and risk factors underlying PTE. We also discuss dysfunctions of neurovascular unit, cell-specific neuroinflammatory mediators and immune response factors that are vital for epileptogenesis after TBI. Finally, we describe current and novel treatments and management strategies for preventing PTE.
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Affiliation(s)
- Shaunik Sharma
- Medical Laboratories, Department of Pediatrics, University of Iowa, Iowa City, IA, United States
| | - Grant Tiarks
- Medical Laboratories, Department of Pediatrics, University of Iowa, Iowa City, IA, United States
| | - Joseph Haight
- Medical Laboratories, Department of Pediatrics, University of Iowa, Iowa City, IA, United States
| | - Alexander G Bassuk
- Medical Laboratories, Department of Pediatrics, University of Iowa, Iowa City, IA, United States
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Kashour T, Halwani R, Arabi YM, Sohail MR, O'Horo JC, Badley AD, Tleyjeh IM. Statins as an adjunctive therapy for COVID-19: the biological and clinical plausibility. Immunopharmacol Immunotoxicol 2021; 43:37-50. [PMID: 33406943 DOI: 10.1080/08923973.2020.1863984] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the coronavirus disease 2019 (COVID-19) has infected millions of individuals and has claimed hundreds of thousands of human lives worldwide. Patients with underlying cardiovascular conditions are at high risk for SARS-CoV-2 infection, and COVID-19 patients have high incidence of cardiovascular complications such as acute cardiac injury, arrhythmias, heart failure, and thromboembolism. The disease has no approved proven effective therapy and hence repurposing of existing approved drugs has been considered as the fastest treatment approach. Statins have been shown to exhibit lipid lowering dependent and independent cardiovascular protective effects as well as favorable effects in various other pathophysiological states. These beneficial properties of statins are a result of their multiple pleotropic effects that include, anti-inflammatory, immunomodulatory, antithrombotic and antimicrobial properties. In this review, we provide a comprehensive description of the mechanisms of the pleotropic effects of statins, the relevant pre-clinical and clinical data pertinent to their role in infections and acute lung injury, the possible cardiovascular benefits of statins in COVID-19, and the implications of the therapeutic potential of statins in COVID-19 disease. We conclude with the rationale for conducting randomized controlled trials of statins in COVID-19 disease.
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Affiliation(s)
- Tarek Kashour
- Department of Cardiac Sciences, King Fahad Cardiac Center, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Rabih Halwani
- Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah, UAE
| | - Yaseen M Arabi
- Intensive Care Department, Ministry of National Guard Health Affairs, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.,King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - M Rizwan Sohail
- Section of Infectious Diseases, Baylor College of Medicine Houston, TX, USA.,Division of Infectious Diseases, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - John C O'Horo
- Division of Infectious Diseases, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.,Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Andrew D Badley
- Division of Infectious Diseases, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.,Department of Molecular Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Imad M Tleyjeh
- Division of Infectious Diseases, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.,Division of Epidemiology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.,Department of Medical Specialties, Infectious Diseases Section, King Fahad Medical City, Riyadh, Saudi Arabia.,College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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Iqbal Z, Ho JH, Adam S, France M, Syed A, Neely D, Rees A, Khatib R, Cegla J, Byrne C, Qureshi N, Capps N, Ferns G, Payne J, Schofield J, Nicholson K, Datta D, Pottle A, Halcox J, Krentz A, Durrington P, Soran H, Heart UK's Medical Scientific and Research Committee. Managing hyperlipidaemia in patients with COVID-19 and during its pandemic: An expert panel position statement from HEART UK. Atherosclerosis 2020; 313:126-136. [PMID: 33045618 PMCID: PMC7490256 DOI: 10.1016/j.atherosclerosis.2020.09.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 09/02/2020] [Accepted: 09/08/2020] [Indexed: 02/06/2023]
Abstract
The emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes Coronavirus Disease 2019 (COVID-19) has resulted in a pandemic. SARS-CoV-2 is highly contagious and its severity highly variable. The fatality rate is unpredictable but is amplified by several factors including advancing age, atherosclerotic cardiovascular disease, diabetes mellitus, hypertension and obesity. A large proportion of patients with these conditions are treated with lipid lowering medication and questions regarding the safety of continuing lipid-lowering medication in patients infected with COVID-19 have arisen. Some have suggested they may exacerbate their condition. It is important to consider known interactions with lipid-lowering agents and with specific therapies for COVID-19. This statement aims to collate current evidence surrounding the safety of lipid-lowering medications in patients who have COVID-19. We offer a consensus view based on current knowledge and we rated the strength and level of evidence for these recommendations. Pubmed, Google scholar and Web of Science were searched extensively for articles using search terms: SARS-CoV-2, COVID-19, coronavirus, Lipids, Statin, Fibrates, Ezetimibe, PCSK9 monoclonal antibodies, nicotinic acid, bile acid sequestrants, nutraceuticals, red yeast rice, Omega-3-Fatty acids, Lomitapide, hypercholesterolaemia, dyslipidaemia and Volanesorsen. There is no evidence currently that lipid lowering therapy is unsafe in patients with COVID-19 infection. Lipid-lowering therapy should not be interrupted because of the pandemic or in patients at increased risk of COVID-19 infection. In patients with confirmed COVID-19, care should be taken to avoid drug interactions, between lipid-lowering medications and drugs that may be used to treat COVID-19, especially in patients with abnormalities in liver function tests.
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Affiliation(s)
- Zohaib Iqbal
- Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom,Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Jan Hoong Ho
- Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom,Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Safwaan Adam
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom,The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Michael France
- Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Akheel Syed
- Department of Diabetes, Endocrinology and Obesity Medicine, Salford Royal NHS Foundation Trust, Salford, United Kingdom
| | - Dermot Neely
- Department of Blood Sciences and NIHR MedTech and IVD Centre, Newcastle Upon Tyne Hospitals, Newcastle Upon Tyne, United Kingdom
| | - Alan Rees
- HEART UK, Maidenhead, United Kingdom
| | - Rani Khatib
- Departments of Cardiology & Pharmacy, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom,Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
| | - Jaimini Cegla
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, 6th Floor Commonwealth Building, Hammersmith Hospital, Du Cane Road, W12 0NN, London, United Kingdom
| | - Christopher Byrne
- Department of Nutrition and Metabolism, Faculty of Medicine, University of Southampton, United Kingdom
| | - Nadeem Qureshi
- Division of Primary Care, University of Nottingham, Nottingham, United Kingdom
| | - Nigel Capps
- The Shrewsbury and Telford Hospital NHS Trust, United Kingdom
| | - Gordon Ferns
- Department of Medical Education, Brighton and Sussex Medical School, Brighton, United Kingdom
| | | | - Jonathan Schofield
- Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom,Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Kirsty Nicholson
- Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Dev Datta
- Department of Metabolic Medicine, University Hospital of Wales, Cardiff, United Kingdom
| | - Alison Pottle
- Department of Cardiology, Harefield Hospital, United Kingdom
| | - Julian Halcox
- Department of Medicine, Swansea University, Swansea, United Kingdom
| | - Andrew Krentz
- Institute of Cardiovascular & Metabolic Research, University of Reading, United Kingdom
| | - Paul Durrington
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Handrean Soran
- Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom; Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
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Affiliation(s)
- S. A. El‐Sebaey
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Girls) Al-Azhar University Youssef Abbas street, Nasr City Cairo Egypt
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Abstract
HMG-CoA reductase inhibitors (known as statins) are commonly prescribed worldwide for the management of coronary heart disease and the underlying dyslipidemia. This class of drugs has been shown to infer a significant decrease in the risk of cardiovascular morbidity and mortality. Only recently though have the beneficial effects of statins in other diseases such as non-alcoholic steatohepatitis been highlighted. Importantly, also, multiple studies have revealed that statin use was associated with lower cancer-associated mortality across multiple types of cancers. This work aims to review those studies with a particular focus on liver cancer. We also provide a review of the proposed mechanisms of action describing how statins can induce chemo-preventive and antitumor effects.
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Affiliation(s)
- Ghazal Alipour Talesh
- miRCaDe team, Univ. Bordeaux, INSERM, BMGIC, U1035, F-33000 Bordeaux, France.,Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Véronique Trézéguet
- miRCaDe team, Univ. Bordeaux, INSERM, BMGIC, U1035, F-33000 Bordeaux, France
| | - Aksam Merched
- miRCaDe team, Univ. Bordeaux, INSERM, BMGIC, U1035, F-33000 Bordeaux, France
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Clinical effects of simvastatin in chronic hepatitis C patients receiving sofosbuvir/daclatasvir combination. A randomized, placebo-controlled, double-blinded study. Clin Exp Hepatol 2020; 6:99-105. [PMID: 32728626 PMCID: PMC7380473 DOI: 10.5114/ceh.2020.95566] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 02/17/2020] [Indexed: 11/17/2022] Open
Abstract
Aim of the study Chronic hepatitis C (CHC) affects more than 71 million people worldwide. Many therapies containing different direct-acting antivirals (DAAs) are now used. However, lipid profile is considered an important outcome with DAAs. So, this study aimed to assess clinical effects of statins in CHC patients. Material and methods One hundred patients were recruited from Kobri El koba Armed Forces Hospital and randomly assigned to: the drug group (D;n = 50) receiving simvastatin 10 mg plus sofosbuvir 400 mg/daclatasvir 60 mg (SOF/DAC) daily for 12 weeks; and the placebo group (P; n = 50), receiving placebo plus the same (SOF/DAC) regimen. Sustained virological response at 12 weeks after treatment (SVR12), lipid profile, C-reactive protein (CRP) and fibrosis stage were assessed. Results One hundred treatment-naïve CHC patients completed 12 weeks of the protocol with no clinically significant side effects. There was an increase in SVR failure rate in P (10%) compared to D (only 2%) but not reaching statistical significant difference; SVR12 (p > 0.05). Logistic regression analysis showed that high baseline CRP, low baseline hemoglobin level and non-statin usage had an independent effect on increasing the probability of SVR failure in both groups; p = 0.03, p = 0.0028, p = 0.02, respectively. Conclusions Statins could have an irreplaceable role in successful treatment of CHC patients receiving sofosbuvir/daclatasvir.
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Todorovska B, Caloska-Ivanova V, Dimitrova-Genadieva M, Trajkovska M, Popova-Jovanovska R, Grivceva-Stardelova K, Licoska-Josifovic F, Andreevski V, Curakova-Ristovska E, Joksimovic N. Atorvastatin in Combination with Pegylated Interferon and Ribavirin Provided High Rate of Sustained Virological Response in Patients with Genotype 3 Hepatitis C Virus. Open Access Maced J Med Sci 2019; 7:1641-1648. [PMID: 31210815 PMCID: PMC6560281 DOI: 10.3889/oamjms.2019.459] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 05/19/2019] [Accepted: 05/20/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND: Chronic hepatitis C virus infection represents a more frequent cause of liver cirrhosis and hepatocellular carcinoma. Statins, inhibit HCV replication in vitro, enhance the antiviral effect of the already known antiviral drugs and reduce their resistance. AIM: To determine the impact of additional therapy (treatment with Atorvastatin 20 mg) to the standard antiviral therapy (pegylated interferon alpha-peg-IFN α and ribavirin) on achieving sustained virological response (SVR). MATERIAL AND METHODS: In the study which is comparative, open-label, prospective-retrospective, 70 patients diagnosed with chronic hepatitis C virus infection who met criteria for treatment with standard antiviral therapy combined with anti-lipemic therapy (Atorvastatin 20 mg) were included. Patients in the study were divided into two groups: one group of 35 patients receiving combination therapy (Atorvastatin + peg-IFN α + Ribavirin) and another group of 35 patients received only standard antiviral therapy. Those parameters were followed in all patients: genotyping, quantification of the virus, histological assessment of liver inflammation and fibrosis degree (before starting treatment), the presence of steatosis, laboratory analysis: hematology, liver, lipid and carbohydrate status, insulin blood level (the calculation of HOMA-IR) and body mass index (BMI) calculation. The overall treatment of the patients depends from the virus genotype, thus, patients with genotype 1 and 4 received 48 weeks standard antiviral therapy, but patients with genotypes 2 and 3 received 24 weeks of antiviral therapy. SVR was considered an undetectable level of HCV RNA levels 24 weeks after completion of antiviral therapy. The results were statistically analysed, and all results for p < 0.05 were considered statistically significant. RESULTS: Combination therapy leads to a slightly higher percentage of SVR (85.71%) in patients with chronic hepatitis C versus standard therapy (74.29%), but in a group of patients with genotype 3 this rate of SVR amounting to 95.83%. Combination therapy leads to significant improvement of lipid and glucose status after treatment, and in terms of side effects, there was no appearance of serious adverse events that would be a reason for discontinuation of the therapy. CONCLUSION: Combination therapy Atorvastatin + pegylated interferon alpha + Ribavirin leads to high rate of SVR of 95.83% in patients with chronic hepatitis C, genotype 3. Statins can be used safely in patients with chronic hepatitis C.
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Affiliation(s)
- Beti Todorovska
- University Clinic of Gastroenterohepatology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Viktorija Caloska-Ivanova
- University Clinic of Gastroenterohepatology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Magdalena Dimitrova-Genadieva
- University Clinic of Gastroenterohepatology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Meri Trajkovska
- University Clinic of Gastroenterohepatology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Rozalinda Popova-Jovanovska
- University Clinic of Gastroenterohepatology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Kalina Grivceva-Stardelova
- University Clinic of Gastroenterohepatology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Fana Licoska-Josifovic
- University Clinic of Gastroenterohepatology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Vladimir Andreevski
- University Clinic of Gastroenterohepatology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Elena Curakova-Ristovska
- University Clinic of Gastroenterohepatology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Nenad Joksimovic
- University Clinic of Gastroenterohepatology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
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Drazilova S, Gazda J, Janicko M, Jarcuska P. Chronic Hepatitis C Association with Diabetes Mellitus and Cardiovascular Risk in the Era of DAA Therapy. Can J Gastroenterol Hepatol 2018; 2018:6150861. [PMID: 30186821 PMCID: PMC6110000 DOI: 10.1155/2018/6150861] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 07/31/2018] [Indexed: 12/15/2022] Open
Abstract
Patients with chronic hepatitis C have both higher prevalence of diabetes mellitus type 2 (T2DM) and increased cardiovascular risk compared to never infected people. Sustained viral response (SVR) achievement led to decreasing incidence and prevalence of T2DM during the interferon era of HCV treatment. Currently, direct-acting antiviral drugs (DAA) are the gold standard for treating HCV infection, while yielding SVR in nearly all patients. In chronic HCV patients with T2DM (prediabetes most likely too), DAA therapy is associated with both better fasting glucose and glycated hemoglobin (HbA1C) controls; thus reducing pharmacotherapy in a certain part of patients is possible. Papers mentioned in the review confirmed DAA role in both total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) increase. This alteration was accompanied by an increase in high-density lipoprotein cholesterol (HDL-C) and a decrease in triglycerides (TG) verified by most of the studies. However, the clinical significance of lipoprotein alterations caused by DAA therapy has not been explained yet. Moreover, DAA treatment of chronic hepatitis C improves hypertension control and atherosclerotic plaques. It is very likely that DAA therapeutic regimens will decrease both T2DM prevalence and cardiovascular risk in chronic hepatitis C patients; further research, however, is needed.
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Affiliation(s)
- Sylvia Drazilova
- Department of Internal Medicine, Hospital Poprad, Poprad, Slovakia
| | - Jakub Gazda
- 1st Department of Internal Medicine, PJ Safarik University, Faculty of Medicine and L Pasteur University Hospital, Kosice, Slovakia
| | - Martin Janicko
- 1st Department of Internal Medicine, PJ Safarik University, Faculty of Medicine and L Pasteur University Hospital, Kosice, Slovakia
| | - Peter Jarcuska
- 1st Department of Internal Medicine, PJ Safarik University, Faculty of Medicine and L Pasteur University Hospital, Kosice, Slovakia
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13
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The benefit of statins in chronic hepatitis C patients: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2017; 29:759-766. [PMID: 28240613 DOI: 10.1097/meg.0000000000000867] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Besides regulating lipid metabolism, statins have garnered considerable interest because of their antiviral and antineoplastic properties. The potential benefit of statins using in chronic hepatitis C (CHC) patients is not well described. This meta-analysis was carried out to quantitatively assess the efficacy of statins in improving the therapeutic effect and prognosis of patients with CHC. PATIENTS AND METHODS We searched electronic databases for relevant studies comparing the course of benefit in CHC patients with statins versus without statins. Risk estimates were pooled to assess the association of statins use with sustained virological response and the prognosis of CHC patients. RESULTS Twenty-three studies fulfilled the inclusion criteria. Meta-analysis of 16 homogeneous studies showed that the sustained virological response rate increased by 31% [relative risk (RR)=1.31; 95% confidence interval (CI): 1.23-1.39] in 12 791 CHC patients with statins as an adjuvant under the general antiviral therapy compared with those without this adjuvant therapy. Moreover, meta-analysis of seven studies suggested that statins was beneficial on several specific poor outcomes of CHC patients (RR=0.49; 95% CI: 0.42-0.56). CHC patients with statin use were found to be inversely associated with a 55% reduced risk of hepatocellular carcinoma (RR=0.45; 95% CI: 0.36-0.57) and 53% reduced risk of cirrhosis (RR=0.47; 95% CI: 0.33-0.67) as well as 44% reduced risk of mortality (RR=0.56; 95% CI: 0.46-0.69). However, significant heterogeneity and publication bias were present in some of our analyses. CONCLUSION Beneficial effects of statins use were found in the therapy and the prognosis of CHC patients. Further prospective studies are still needed to confirm these benefits.
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Abstract
PURPOSE OF REVIEW Potent antivirals are successfully used for the treatment of infections with herpesviruses, hepatitis B and C viruses, HIV, and with some success for influenza viruses. However, no selective inhibitors are available for a multitude of medically important viruses, most of which are (re-)emerging RNA viruses. As it is impossible to develop drugs against each of these viruses, broad-spectrum antiviral agents (BSAA) are a prime strategy to cope with this challenge. RECENT FINDINGS We propose four categories of antiviral molecules that hold promise as BSAA. Several nucleoside analogues with broad antiviral activity have been described and given the relatively conserved nature of viral polymerases, it may be possible to develop more broad-spectrum nucleoside analogues. A number of viral proteins are relatively conserved between families and may also be interesting targets. Host-targeting antiviral drugs such as modulators of lipid metabolism and cyclophilin inhibitors can be explored as well. Finally, the potent and broad antiviral function of the immune system can be exploited by the development of immune-modulating BSAA. SUMMARY Despite the recent advances, the BSAA field is still in its infancy. Nevertheless, the discovery and development of such molecules will be a key aim of antiviral research in the coming decades.
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Janicko M, Drazilova S, Pella D, Fedacko J, Jarcuska P. Pleiotropic effects of statins in the diseases of the liver. World J Gastroenterol 2016; 22:6201-6213. [PMID: 27468210 PMCID: PMC4945979 DOI: 10.3748/wjg.v22.i27.6201] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 05/26/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Statins are a class of molecules that inhibit HMG CoA reductase. They are usually prescribed as a lipid lowering medication. However, there is accumulating evidence that statins have multiple secondary effects both related and unrelated to their lipid-lowering effect. This narrative review of the literature aims to provide the reader with information from clinical studies related to the effect of statin and statins' potential use in patients with liver diseases. In patients with advanced liver disease due to any etiology, statins exhibit an antifibrotic effect possibly through the prevention of hepatic sinusoidal microthrombosis. Two randomized controlled trials confirmed that statins decrease hepatic vein pressure gradient in patients with portal hypertension and improve the survival of patients after variceal bleeding. Lower rates of infections were observed in patients with cirrhosis who received statin treatment. Statins decrease the risk of hepatocellular carcinoma (HCC) in patients with advanced liver disease in general but particularly in patients with chronic hepatitis B and C. Statins in patients with chronic hepatitis C likely increase the virological response to the treatment with pegylated interferon and ribavirin and have the potential to decrease the rate of fibrosis. Finally, data from randomized controlled trials also confirmed that the addition of statin prolongs the survival of patients with advanced HCC even more than sorafenib. Statins are a very promising group of drugs especially in patients with liver disease, where therapeutic options can often be limited. Some indications, such as the prevention of re-bleeding from esophageal varices and the palliative treatment of HCC have been proven through randomized controlled trials, while additional indications still need to be confirmed through prospective studies.
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16
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Fukuhara T, Ono C, Puig-Basagoiti F, Matsuura Y. Roles of Lipoproteins and Apolipoproteins in Particle Formation of Hepatitis C Virus. Trends Microbiol 2016; 23:618-629. [PMID: 26433694 DOI: 10.1016/j.tim.2015.07.007] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 07/07/2015] [Accepted: 07/20/2015] [Indexed: 02/06/2023]
Abstract
More than 160 million people worldwide are infected with hepatitis C virus (HCV), and cirrhosis and hepatocellular carcinoma induced by HCV infection are life-threatening diseases. HCV takes advantage of many aspects of lipid metabolism for an efficient propagation in hepatocytes. Due to the morphological and physiological similarities of HCV particles to lipoproteins, lipid-associated HCV particles are named lipoviroparticles. Recent analyses have revealed that exchangeable apolipoproteins directly interact with the viral membrane to generate infectious HCV particles. In this review, we summarize the roles of lipid metabolism in the life cycle of HCV.
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Affiliation(s)
- Takasuke Fukuhara
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Chikako Ono
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Francesc Puig-Basagoiti
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Yoshiharu Matsuura
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
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17
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Abstract
Lipid lowering, particularly with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ("statins"), reduces the risk of cardiovascular disease. Patients with chronic liver disease present challenges to the use of lipid medications. In the case of most liver disorders, the concern has been one of safety. There is evidence that most lipid-lowering medications can be used safely in many situations, although large outcomes trials are lacking. This review examines lipid physiology and cardiovascular risk in specific liver diseases and reviews the evidence for lipid lowering and the use of statins in chronic liver disease.
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Affiliation(s)
- Cynthia Herrick
- Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, Campus Box 8127, 660 South Euclid, St Louis, MO 63110, USA.
| | - Samira Bahrainy
- VA Medical Center, Puget Sound, 1660 South Columbian Way, Seattle, WA 98104, USA
| | - Edward A Gill
- Harborview Medical Center, University of Washington School of Medicine, 325 Ninth Avenue, Box 359748, Seattle, WA 98104, USA
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19
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Yang X, Ouyang H, Chen F, Ma T, Dong M, Wang F, Pang D, Peng Z, Ren L. Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase increases the expression of interferon-responsive genes. Clin Exp Pharmacol Physiol 2015; 41:950-5. [PMID: 25115523 DOI: 10.1111/1440-1681.12299] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 08/01/2014] [Accepted: 08/04/2014] [Indexed: 02/06/2023]
Abstract
The 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) pathway is an important metabolic route that is present in almost every organism. However, whether HMGCR affects the expression of interferon (IFN)-responsive genes is unclear. In the present study, expression levels of IFN-responsive genes were monitored by real time polymerase chain reaction and enzyme-linked immunosorbent assay. The results showed that expression levels of IFN-responsive genes were significantly increased in HMGCR-downregulated cells and HMGCR inhibitor-treated cells, indicating that inhibition of HMGCR activates the expression of IFN-responsive genes. The result in this study will provide new insight into the role of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in antiviral research.
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Affiliation(s)
- Xin Yang
- Jilin Provincial Key Laboratory of Animal Embryo Engineering, College of Animal Sciences, Jilin University, Changchun, Jilin, China
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Yang X, Ma T, Ouyang H, Chen F, Peng Z, Li C, Ma Y, Chen X, Li B, Pang D, Ren L. Effect of atovastatin treatment on porcine circovirus 2 infection in BALB/c mice. Clin Exp Pharmacol Physiol 2015; 42:817-21. [DOI: 10.1111/1440-1681.12434] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Revised: 05/13/2015] [Accepted: 05/24/2015] [Indexed: 11/27/2022]
Affiliation(s)
- Xin Yang
- Jilin Provincial Key Laboratory of Animal Embryo Engineering; College of Animal Sciences; Changchun Jilin China
| | - Teng Ma
- Jilin Provincial Key Laboratory of Animal Embryo Engineering; College of Animal Sciences; Changchun Jilin China
| | - Hongsheng Ouyang
- Jilin Provincial Key Laboratory of Animal Embryo Engineering; College of Animal Sciences; Changchun Jilin China
| | - Fuwang Chen
- Jilin Provincial Key Laboratory of Animal Embryo Engineering; College of Animal Sciences; Changchun Jilin China
| | - Zhiyuan Peng
- Jilin Provincial Key Laboratory of Animal Embryo Engineering; College of Animal Sciences; Changchun Jilin China
| | - Chun Li
- The Chinese Peoples' Liberation Army 208 Hospital; Changchun China
| | - Yunzhi Ma
- Heping Campus; Jilin University; Changchun Jilin China
| | - Xinrong Chen
- Jilin Provincial Key Laboratory of Animal Embryo Engineering; College of Animal Sciences; Changchun Jilin China
| | - Boyu Li
- Jilin Provincial Key Laboratory of Animal Embryo Engineering; College of Animal Sciences; Changchun Jilin China
| | - Daxing Pang
- Jilin Provincial Key Laboratory of Animal Embryo Engineering; College of Animal Sciences; Changchun Jilin China
| | - Linzhu Ren
- Jilin Provincial Key Laboratory of Animal Embryo Engineering; College of Animal Sciences; Changchun Jilin China
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21
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Simon TG, Butt AA. Lipid dysregulation in hepatitis C virus, and impact of statin therapy upon clinical outcomes. World J Gastroenterol 2015; 21:8293-8303. [PMID: 26217081 PMCID: PMC4507099 DOI: 10.3748/wjg.v21.i27.8293] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 04/17/2015] [Accepted: 06/10/2015] [Indexed: 02/06/2023] Open
Abstract
The hepatitis C virus (HCV) is one of the most common causes of chronic liver disease and the leading indication for liver transplantation worldwide. Every aspect of the HCV life cycle is closely tied to human lipid metabolism. The virus circulates as a lipid-rich particle, utilizing lipoprotein cell receptors to gain entry into the hepatocyte. It has also been shown to upregulate lipid biosynthesis and impair lipid degradation, resulting in significant intracellular lipid accumulation and circulating hypocholesterolemia. Patients with chronic hepatitis C (CHC) are at increased risk of hepatic steatosis, fibrosis, and cardiovascular disease including accelerated atherosclerosis. HMG CoA Reductase inhibitors, or statins, have been shown to play an important role in the modulation of hepatic steatosis and fibrosis, and recent attention has focused upon their potential therapeutic role in CHC. This article reviews the hepatitis C viral life cycle as it impacts host lipoproteins and lipid metabolism. It then describes the pathogenesis of HCV-related hepatic steatosis, hypocholesterolemia and atherosclerosis, and finally describes the promising anti-viral and anti-fibrotic effects of statins, for the treatment of CHC.
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22
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Cavalcante LN, Lyra AC. Predictive factors associated with hepatitis C antiviral therapy response. World J Hepatol 2015; 7:1617-31. [PMID: 26140082 PMCID: PMC4483544 DOI: 10.4254/wjh.v7.i12.1617] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/16/2014] [Accepted: 05/05/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection may lead to significant liver injury, and viral, environmental, host, immunologic and genetic factors may contribute to the differences in the disease expression and treatment response. In the early 2000s, dual therapy using a combination of pegylated interferon plus ribavirin (PR) became the standard of care for HCV treatment. In this PR era, predictive factors of therapy response related to virus and host have been identified. In 2010/2011, therapeutic regimens for HCV genotype 1 patients were modified, and the addition of NS3/4a protease inhibitors (boceprevir or telaprevir) to dual therapy increased the effectiveness and chances of sustained virologic response (SVR). Nevertheless, the first-generation triple therapy is associated with many adverse events, some of which are serious and associated with death, particularly in cirrhotic patients. This led to the need to identify viral and host predictive factors that might influence the SVR rate to triple therapy and avoid unnecessary exposure to these drugs. Over the past four years, hepatitis C treatment has been rapidly changing with the development of new therapies and other developments. Currently, with the more recent generations of pangenotipic antiviral therapies, there have been higher sustained virologic rates, and prognostic factors may not have the same importance and strength as before. Nonetheless, some variables may still be consistent with the low rates of non-response with regimens that include sofosbuvir, daclatasvir and ledipasvir. In this manuscript, we review the predictive factors of therapy response across the different treatment regimens over the last decade including the new antiviral drugs.
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Affiliation(s)
- Lourianne Nascimento Cavalcante
- Lourianne Nascimento Cavalcante, André Castro Lyra, Hospital Sao Rafael - Gastro-Hepatology Service, Salvador, Bahia 41253-190, Brazil
| | - André Castro Lyra
- Lourianne Nascimento Cavalcante, André Castro Lyra, Hospital Sao Rafael - Gastro-Hepatology Service, Salvador, Bahia 41253-190, Brazil
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23
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Delang L, Scheers E, Grabner M, Verpaalen B, Helsen N, Vanstreels E, Daelemans D, Verfaillie C, Neyts J. Understanding the molecular mechanism of host-based statin resistance in hepatitis C virus replicon containing cells. Biochem Pharmacol 2015; 96:190-201. [PMID: 26070251 DOI: 10.1016/j.bcp.2015.06.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 06/02/2015] [Indexed: 12/16/2022]
Abstract
A number of statins, the cholesterol-lowering drugs, inhibit the in vitro replication of hepatitis C virus (HCV). In HCV-infected patients, addition of statins to the earlier standard of care therapy (pegIFN-α and ribavirin) resulted in increased sustained virological response rates. The mechanism by which statins inhibit HCV replication has not yet been elucidated. In an attempt to gain insight in the underlying mechanism, hepatoma cells carrying an HCV replicon were passaged in the presence of increasing concentrations of fluvastatin. Fluvastatin-resistant replicon containing cells could be generated and proved ∼8-fold less susceptible to fluvastatin than wild-type cultures. The growth efficiency of the resistant replicon containing cells was comparable to that of wild-type replicon cells. The fluvastatin-resistant phenotype was not conferred by mutations in the viral genome but is caused by cellular changes. The resistant cell line had a markedly increased HMG-CoA reductase expression upon statin treatment. Furthermore, the expression of the efflux transporter P-gp was increased in fluvastatin-resistant replicon cells (determined by qRT-PCR and flow cytometry). This increased expression resulted also in an increased functional transport activity as measured by the P-gp mediated efflux of calcein AM. In conclusion, we demonstrate that statin resistance in HCV replicon containing hepatoma cells is conferred by changes in the cellular environment.
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Affiliation(s)
- Leen Delang
- Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
| | - Els Scheers
- Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
| | - Mareike Grabner
- Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
| | - Ben Verpaalen
- Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
| | - Nicky Helsen
- Stem Cell Biology and Embryology, University of Leuven, O&N IV Herestraat 49 - bus 804, 3000 Leuven, Belgium.
| | - Els Vanstreels
- Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
| | - Dirk Daelemans
- Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
| | - Catherine Verfaillie
- Stem Cell Biology and Embryology, University of Leuven, O&N IV Herestraat 49 - bus 804, 3000 Leuven, Belgium.
| | - Johan Neyts
- Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
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Abstract
The benefits of statins go beyond decreasing cholesterol levels; in liver disease, statins reduce the risk of progressive liver fibrosis and provide protection during infections and ischaemia–reperfusion injury. New evidence shows that statins improve response to interferon-based anti-HCV therapy, decrease progression to cirrhosis and likelihood of developing hepatocellular carcinoma.
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26
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Ammer E, Nietzsche S, Rien C, Kühnl A, Mader T, Heller R, Sauerbrei A, Henke A. The anti-obesity drug orlistat reveals anti-viral activity. Med Microbiol Immunol 2015; 204:635-45. [DOI: 10.1007/s00430-015-0391-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Accepted: 02/06/2015] [Indexed: 12/28/2022]
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27
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Abstract
Although chronic infection of hepatitis C virus (HCV) induces disorders of lipid metabolism, HCV is known to utilize lipid metabolism for efficient propagation in the liver. Due to the morphological and physiological similarities of HCV particles to lipoproteins, lipid-associated HCV particles are named lipoviroparticles. Previous reports have shown that lipoprotein receptors or cholesterol transporter participate in the entry of lipoviroparticles. In addition, recent analyses revealed that exchangeable apolipoproteins directly interact with the viral membrane to generate infectious HCV particles. In this review, we would like to discuss about involvement of lipoprotein and apolipoprotein in HCV lifecycle.
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Affiliation(s)
- Takasuke Fukuhara
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University
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Robaldo L, Berzal-Herranz A, Montserrat JM, Iribarren AM. Activity of core-modified 10-23 DNAzymes against HCV. ChemMedChem 2014; 9:2172-2177. [PMID: 25079672 DOI: 10.1002/cmdc.201402222] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Indexed: 02/05/2023]
Abstract
The highly conserved untranslated regions of the hepatitis C virus (HCV) play a fundamental role in viral translation and replication and are therefore attractive targets for drug development. A set of modified DNAzymes carrying (2'R)-, (2'S)-2'-deoxy-2'-C-methyl- and -2'-O-methylnucleosides at various positions of the catalytic core were assayed against the 5'-internal ribosome entry site element (5'-IRES) region of HCV. Intracellular stability studies showed that the highest stabilization effects were obtained when the DNAzymes' cores were jointly modified with 2'-C-methyl- and 2'-O-methylnucleosides, yielding an increase by up to fivefold in the total DNAzyme accumulation within the cell milieu within 48 h of transfection. Different regions of the HCV IRES were explored with unmodified 10-23 DNAzymes for accessibility. A subset of these positions was tested for DNAzyme activity using an HCV IRES-firefly luciferase translation-dependent RNA (IRES-FLuc) transcript, in the rabbit reticulocyte lysate system and in the Huh-7 human hepatocarcinoma cell line. Inhibition of IRES-dependent translation by up to 65 % was observed for DNAzymes targeting its 285 position, and it was also shown that the modified DNAzymes are as active as the unmodified one.
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Affiliation(s)
- Laura Robaldo
- INGEBI (CONICET), Vuelta de Obligado 2490-(1428), Buenos Aires (Argentina)
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30
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Grammatikos G, Farnik H, Bon D, Böhlig A, Bader T, Berg T, Zeuzem S, Herrmann E. The impact of antihyperlipidemic drugs on the viral load of patients with chronic hepatitis C infection: a meta-analysis. J Viral Hepat 2014; 21:533-41. [PMID: 24943517 DOI: 10.1111/jvh.12274] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 05/25/2014] [Indexed: 12/16/2022]
Abstract
Several studies investigating the role of statins and fibrates in chronic hepatitis C virus (HCV) infection offered so far conflicting evidence regarding the antiviral potency of these medications, whereas combination of these drugs with pegylated interferon and ribavirin improved in some trials therapeutic outcome. We conducted a literature search to identify trials that included monoinfected HCV patients, treated with statins or fibrates as monotherapy with the primary end point of our meta-analysis being the quantitative change of HCV-RNA induced by these medications. Logarithmic changes of the viral load (ΔlogVL) and confidence intervals (CIs) were calculated according to the DerSimonian-Laird estimate. Statistical heterogeneity was assessed with the I² statistic. We identified eight observational studies that evaluated the potency of bezafibrate and different statins as monotherapy to induce a significant reduction of HCV-RNA in HCV-monoinfected patients (n = 281). Overall, a significant reduction of viral load with mean 0.19 [log10 IU/mL] (95%-confidence interval, (CI) 0.11-0.28) could be observed when antihyperlipidemic medications were administered. Bezafibrate featured the highest antiviral efficacy (0.45 log10 reduction, 95%-CI, 0.17-0.72) among all medications and fluvastatin (0.20 log10 reduction, 95%-CI, 0.09-0.31) among all statins tested. Based on meta-analysis, fibrates and statins induce a reduction of HCV viral load. We suggest that the addition of statins and fibrates to antiviral regimes, especially in HCV patients with concomitant dyslipidemia, could beside the established reduction of cardiovascular risk increase the potency of antiviral therapy.
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Affiliation(s)
- G Grammatikos
- University Hospital Frankfurt, Frankfurt am Main, Germany
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Kim G, Baik SK. Overview and recent trends of systematic reviews and meta-analyses in hepatology. Clin Mol Hepatol 2014; 20:137-50. [PMID: 25032179 PMCID: PMC4099328 DOI: 10.3350/cmh.2014.20.2.137] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 05/29/2014] [Indexed: 12/12/2022] Open
Abstract
A systematic review (SR) is a research methodology that involves a comprehensive search for and analysis of relevant studies on a specific topic. A strict and objective research process is conducted that comprises a systematic and comprehensive literature search in accordance with predetermined inclusion/exclusion criteria, and an assessment of the risk of bias of the selected literature. SRs require a multidisciplinary approach that necessitates cooperation with clinical experts, methodologists, other experts, and statisticians. A meta-analysis (MA) is a statistical method of quantitatively synthesizing data, where possible, from the primary literature selected for the SR. Review articles differ from SRs in that they lack a systematic methodology such as a literature search, selection of studies according to strict criteria, assessment of risk bias, and synthesis of the study results. The importance of evidence-based medicine (EBM) in the decision-making for public policy has recently been increasing thanks to the realization that it should be based on scientific research data. SRs and MAs are essential for EBM strategy and evidence-based clinical practice guidelines. This review addresses the current trends in SRs and MAs in the field of hepatology via a search of recently published articles in the Cochrane Library and Ovid-MEDLINE.
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Affiliation(s)
- Gaeun Kim
- Department of Nursing, Keimyung University College of Nursing, Daegu, Korea
| | - Soon Koo Baik
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
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Abstract
Lipid lowering, particularly with HMG CoA reductase inhibitors ("statins"), reduces the risk of cardiovascular disease. Patients with chronic liver and kidney disease present challenges to the use of lipid medications. In the case of most liver disorders, the concern has been one of safety. There is evidence that most lipid-lowering medications can be used safely in many situations, although large outcomes trials are not available. In contrast, in chronic kidney disease, dosing of lipid medications may require substantial modification depending on creatinine clearance. There are significant alterations in lipid metabolism in chronic kidney disease with concomitant increases in cardiovascular risk. Some data are available on cardiovascular outcomes with dyslipidemia treatment in renal patients. This review will examine lipid physiology and cardiovascular risk in specific liver and kidney diseases and review the evidence for lipid lowering and the use of statin and non-statin therapies in chronic liver and kidney disease.
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Affiliation(s)
- Cynthia Herrick
- Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, Campus Box 8127, 660 South Euclid, St. Louis, MO 63110, USA.
| | - Marina Litvin
- Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, Campus Box 8127, 660 South Euclid, St. Louis, MO 63110, USA; Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Campus Box 8127, 660 S. Euclid Ave, St. Louis, MO 63110, USA.
| | - Anne Carol Goldberg
- Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, Campus Box 8127, 660 South Euclid, St. Louis, MO 63110, USA; Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Campus Box 8127, 660 S. Euclid Ave, St. Louis, MO 63110, USA.
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Kawaguchi Y, Mizuta T. Interaction between hepatitis C virus and metabolic factors. World J Gastroenterol 2014; 20:2888-2901. [PMID: 24659880 PMCID: PMC3961972 DOI: 10.3748/wjg.v20.i11.2888] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 11/15/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection disrupts the normal metabolism processes, but is also influenced by several of the host’s metabolic factors. An obvious and significantly detrimental pathophysiological feature of HCV infection is insulin resistance in hepatic and peripheral tissues. Substantial research efforts have been put forth recently to elucidate the molecular mechanism of HCV-induced insulin resistance, and several cytokines, such as tumor necrosis factor-α, have been identified as important contributors to the development of insulin resistance in the distant peripheral tissues of HCV-infected patients and animal models. The demonstrated etiologies of HCV-induced whole-body insulin resistance include oxidative stress, lipid metabolism abnormalities, hepatic steatosis and iron overload. In addition, myriad effects of this condition have been characterized, including glucose intolerance, resistance to antiviral therapy, progression of hepatic fibrosis, development of hepatocellular carcinoma, and general decrease in quality of life. Metabolic-related conditions and disorders, such as visceral obesity and diabetes mellitus, have been shown to synergistically enhance HCV-induced metabolic disturbance, and are associated with worse prognosis. Yet, the molecular interactions between HCV-induced metabolic disturbance and host-associated metabolic factors remain largely unknown. The diet and lifestyle recommendations for chronic hepatitis C are basically the same as those for obesity, diabetes, and metabolic syndrome. Specifically, patients are suggested to restrict their dietary iron intake, abstain from alcohol and tobacco, and increase their intake of green tea and coffee (to attain the beneficial effects of caffeine and polyphenols). While successful clinical management of HCV-infected patients with metabolic disorders has also been achieved with some anti-diabetic (i.e., metformin) and anti-lipid (i.e., statins) medications, it is recommended that sulfonylurea and insulin be avoided.
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Toshikuni N, Arisawa T, Tsutsumi M. Hepatitis C-related liver cirrhosis - strategies for the prevention of hepatic decompensation, hepatocarcinogenesis, and mortality. World J Gastroenterol 2014; 20:2876-2887. [PMID: 24659879 PMCID: PMC3961980 DOI: 10.3748/wjg.v20.i11.2876] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Revised: 01/13/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis (LC) is a critical stage of chronic liver disease, including that caused by hepatitis C virus (HCV). In the absence of antiviral therapy, 67%-91% of patients with HCV-related LC patients die of liver-related causes, including hepatocellular carcinoma (HCC) and liver failure. Among the therapeutic strategies used to prevent liver-related complications in these patients is standard therapy with pegylated interferon and ribavirin, which induces a sustained virological response (SVR) in 25% of HCV genotype 1-infected patients and in 69% of patients infected with genotypes 2 and 3. SVR in patients with HCV-related LC has been associated with reduced rates of hepatic decompensation, HCC, and mortality. More recently developed direct-acting antiviral agents have shown excellent antiviral efficacy, with preliminary data demonstrating that an interferon-free regimen that includes these direct-acting antiviral agents achieved SVR in more than 50% of patients with HCV genotype 1 LC. Branched-chain amino acid supplementation, improvement of insulin resistance, and the use of β-blockers for portal hypertension may also reduce liver-related complications. Here, we review advances in antiviral and adjunctive therapies for improved outcomes in patients with HCV-associated LC.
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Verpaalen B, Neyts J, Delang L. Are statins a viable option for the treatment of infections with the hepatitis C virus? Antiviral Res 2014; 105:92-9. [PMID: 24613180 DOI: 10.1016/j.antiviral.2014.02.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 02/20/2014] [Accepted: 02/24/2014] [Indexed: 12/11/2022]
Abstract
Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that are widely used for the treatment of hypercholesterolemia. Besides their cholesterol-lowering effect, statins have been reported to have antiviral activity against a variety of viruses, including hepatitis C virus (HCV). Several statins inhibit the in vitro replication of subgenomic HCV replicons and also suppress in vitro RNA replication of infectious HCV. The precise mechanism of the anti-HCV activity of statins has not yet been defined. Recent studies suggest that the antiviral effect may result from the inhibition of geranylgeranylation of cellular proteins, rather than the inhibition of cholesterol synthesis. Despite the antiviral effect observed in vitro, statin monotherapy seems to be insufficient for the treatment of chronic HCV infection. However, several prospective and retrospective studies have demonstrated that the addition of statins to IFN-α and ribavirin therapy increases SVR, RVR, and EVR rates without the occurrence of additional adverse events. These clinical data, together with the excellent safety profile and low cost, suggest that statins may play a role in HCV therapy until more potent and safe direct-acting antivirals become available. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication."
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Affiliation(s)
- Ben Verpaalen
- Rega Institute for Medical Research, KU Leuven, Belgium
| | - Johan Neyts
- Rega Institute for Medical Research, KU Leuven, Belgium.
| | - Leen Delang
- Rega Institute for Medical Research, KU Leuven, Belgium
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Pawlotsky JM, Novruzov N, Baskiran A, Yetisir F, Unal B, Aydın C, Bayramov N, Kayaalp C, Yilmaz S. What are the pros and cons of the use of host-targeted agents against hepatitis C? Antiviral Res 2014; 105:22-5. [PMID: 24583032 PMCID: PMC7173253 DOI: 10.1016/j.antiviral.2014.02.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Revised: 02/13/2014] [Accepted: 02/14/2014] [Indexed: 12/12/2022]
Abstract
Host-targeted agents block hepatitis C virus production by interacting with host cell components. Blocking the interaction of a cell component involved in the HCV lifecycle results in blockade of viral production. Cyclophilin A inhibitors and antagonists of microRNA-122 have reached clinical development. Host-targeted agents represent ideal “backbones” for pangenotypic drug combinations. Research on host-targeted approaches to combat viral infections other than HCV should be encouraged. Hepatitis C virus (HCV) therapy is living a revolution. Host-targeted agents (HTAs) block HCV production by interacting with host cell components. Because they target conserved host proteins, not variable viral proteins, HTAs have the potential for pangenotypic antiviral activity and a high barrier to resistance. Only two HTAs have reached clinical development, including specific inhibitors of cyclophilin A peptidyl-prolyl cis/trans isomerase activity and antagonists of microRNA-122. Cyclophilin inhibitors have proven to be relatively well tolerated and can be confidently used as backbones of all-oral, interferon-free regimens. In addition, HTAs such as cyclophilin inhibitors offer opportunities for “panviral” approaches when they target mechanisms common to viruses of the same or different families. This article forms part of a symposium in Antiviral Research on “Hepatitis C: next steps toward global eradication.”
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Affiliation(s)
- Jean-Michel Pawlotsky
- National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France; INSERM U955, Créteil, France.
| | - Namig Novruzov
- Inonu University, Liver Transplantation Institute, Malatya, Turkey; Central Customs Hospital, Baku, Azerbaijan
| | - Adil Baskiran
- Inonu University, Liver Transplantation Institute, Malatya, Turkey
| | - Fahri Yetisir
- Department of General Surgery, Atatürk Research and Training Hospital, Ankara, Turkey; Inonu University, Liver Transplantation Institute, Malatya, Turkey.
| | - Bulent Unal
- Inonu University, Liver Transplantation Institute, Malatya, Turkey
| | - Cemalettın Aydın
- Inonu University, Liver Transplantation Institute, Malatya, Turkey
| | | | - Cuneyt Kayaalp
- Inonu University, Liver Transplantation Institute, Malatya, Turkey
| | - Sezai Yilmaz
- Inonu University, Liver Transplantation Institute, Malatya, Turkey
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Cheng FKF, Torres DM, Harrison SA. Hepatitis C and lipid metabolism, hepatic steatosis, and NAFLD: still important in the era of direct acting antiviral therapy? J Viral Hepat 2014; 21:1-8. [PMID: 24329852 DOI: 10.1111/jvh.12172] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) have an individual prevalence of 1.8-3% and at least 30%, respectively, in the United States. It is therefore not surprising that there is overlap between these two common chronic liver diseases, although the relationship appears to go beyond isolated co-existence. Hepatic steatosis is a common feature of CHC infection and can be related to both metabolic and viral specific factors. Steatosis in the setting of nongenotype 3 CHC has been predictive of response to therapy prior to the advent of the direct acting antiviral medications (DAAs). Similarly, lipid metabolism appears important in response to CHC treatment. The pathways for both lipid homeostasis and NAFLD as it pertains to CHC infection as well as the utilization of statin therapy in CHC infection will be reviewed with a focus on the relevance of these topics in the era of DAA therapy.
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Affiliation(s)
- F-K F Cheng
- Division of Gastroenterology, Department of Medicine, Walter Reed National Military Medical Center, Washington, DC, USA
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Zhu Q, Han Q, Liu Z. Potential Role for Statins in the Treatment of Chronic HCV Infection. Future Virol 2013; 8:727-729. [DOI: 10.2217/fvl.13.70] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Qianqian Zhu
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi‘an Jiaotong University, No. 277 Yanta West Road, Xi‘an, 710061, Shaanxi Province, China
| | - Qunying Han
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi‘an Jiaotong University, No. 277 Yanta West Road, Xi‘an, 710061, Shaanxi Province, China
| | - Zhengwen Liu
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi‘an Jiaotong University, No. 277 Yanta West Road, Xi‘an, 710061, Shaanxi Province, China
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