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Salinas Parra N, Hoteit MA, Rattan P, Abt P, Mahmud N. Trends in candidate hepatitis C virus nucleic acid amplification test (NAT)+ listing and associated impacts on liver transplantation waitlist outcomes. Am J Transplant 2025; 25:793-803. [PMID: 39461480 PMCID: PMC11972885 DOI: 10.1016/j.ajt.2024.10.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 10/21/2024] [Accepted: 10/22/2024] [Indexed: 10/29/2024]
Abstract
Direct-acting antiviral agents have facilitated the utilization of hepatitis C virus (HCV)+ organs in HCV nucleic acid amplification test (NAT)- recipients. We evaluated trends in HCV NAT+ listing and its impact on transplant probability, waitlist mortality, and likelihood of receiving HCV NAT+ organs using the United Network for Organ Sharing data set of adult patients waitlisted for liver transplantation from January 2016 to September 2023. Multivariable regression models accounting for competing risks were fit to study waitlist outcomes. Initially, 21 776 patients were listed for HCV NAT+ organs whereas 45 378 were not. The percentage of waitlisted patients listed for these organs increased significantly from 2016 to 2023 (8.8% to 60.8%, P < .001). Initial HCV NAT+ listing was associated with a waitlist mortality benefit in 2021-2023 (subhazard ratio 0.73, 95% CI 0.68-0.79, P < .001) and 17% reduced hazard of overall mortality (hazard ratio 0.83, 95% CI 0.78-0.89, P < .001). Sixteen percent of the total protective effect associated with HCV NAT+ listing on overall survival was mediated through actual receipt of HCV NAT+ organs (total excess relative risk of -0.160 and a pure indirect effect of -0.026; P < .001). Patients not listed for HCV NAT+ organs in the modern era are relatively disadvantaged in terms of waitlist outcomes. Although listings have risen over time, there remains center-level and geographic variation.
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Affiliation(s)
- Natalia Salinas Parra
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Maarouf A Hoteit
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Puru Rattan
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Peter Abt
- Division of Transplant Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Nadim Mahmud
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Medicine, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA; Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology & Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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2
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Di Natale C, Coppola S, Vespini V, Tkachenko V, Luciani G, Vitiello G, Ferranti F, Mari S, Maffettone PL, Grilli S. Characterization of bovine serum albumin immobilization on surface modified glass slides in case of pyro-electrohydrodynamic spots. Anal Chim Acta 2024; 1329:343178. [PMID: 39396275 DOI: 10.1016/j.aca.2024.343178] [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: 05/14/2024] [Revised: 07/26/2024] [Accepted: 08/27/2024] [Indexed: 10/15/2024]
Abstract
BACKGROUND Pyro-electrohydrodynamic jetting (p-jet) has emerged recently as a promising technique for biosensing applications, through the concentration of highly diluted biomolecules in fluorescent spots at microscale. However, a great challenge still remains in optimizing the binding strategy for the sensing interface, enabling the detection of low abundance proteins through immunofluorescence protocols. Indeed, the surface of reaction can be functionalized with different chemical groups able to bind the target molecule with a strong interaction, prior to the p-jet spots decreasing the possibility to lose sensitivity after the common rinsing steps. RESULTS Here, we characterize the immobilization of a model protein, specifically the bovine serum albumin (BSA), in the concentrated p-jet spots to demonstrate the reliability of the technique for highly sensitive immunodetection assays. We first performed spectroscopic measurements on BSA deposited through pipette spots at relatively high concentrations and we achieved a higher efficiency in case of the covalent bond by using the carbonate buffer and the epoxy-based slides. We then tested the covalent setting in case of the p-jet spots with highly diluted samples of pre-labelled BSA. A significant concentration-dependent behavior of the signal was obtained down to picogram levels. Finally, an immunofluorescent protocol was settled with the p-jet spots and a Limit of the Detection (LOD) of 0. 27 pg/mL was reached. SIGNIFICANCE The demonstration here that the p-jet spots are compatible with immunodetection procedures and provide a LOD down to 0.27 pg/mL, launches the p-jet technique towards the development in future of a point-of-care (POC) diagnostic tool. This would become a major force in analytical chemical laboratories. The identification of highly diluted biomarkers from peripheral body fluids would help clinicians performing early diagnosis, overcoming the limitations of the traditional immunochemistry tests, such as the enzyme-linked immunosorbent assay (ELISA).
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Affiliation(s)
- Concetta Di Natale
- University of Naples Federico II, Dipartimento di Ingegneria Chimica, dei Materiali e della Produzione Industriale, P.le Tecchio 80, I-80125, Napoli, Italy; Institute of Applied Sciences and Intelligent Systems (ISASI), National Research Council of Italy (CNR), Pozzuoli, NA 80078, Italy.
| | - Sara Coppola
- University of Naples Federico II, Dipartimento di Ingegneria Chimica, dei Materiali e della Produzione Industriale, P.le Tecchio 80, I-80125, Napoli, Italy; Institute of Applied Sciences and Intelligent Systems (ISASI), National Research Council of Italy (CNR), Pozzuoli, NA 80078, Italy
| | - Veronica Vespini
- Institute of Applied Sciences and Intelligent Systems (ISASI), National Research Council of Italy (CNR), Pozzuoli, NA 80078, Italy
| | - Volodymyr Tkachenko
- Institute of Applied Sciences and Intelligent Systems (ISASI), National Research Council of Italy (CNR), Pozzuoli, NA 80078, Italy
| | - Giuseppina Luciani
- University of Naples Federico II, Dipartimento di Ingegneria Chimica, dei Materiali e della Produzione Industriale, P.le Tecchio 80, I-80125, Napoli, Italy
| | - Giuseppe Vitiello
- University of Naples Federico II, Dipartimento di Ingegneria Chimica, dei Materiali e della Produzione Industriale, P.le Tecchio 80, I-80125, Napoli, Italy; Center for Colloid and Surface Science (CSGI), via della Lastruccia, Sesto Fiorentino, FI 80078, Italy
| | | | - Silvia Mari
- Italian Space Agency, Via del Politecnico snc, 00133, Rome, Italy
| | - Pier Luca Maffettone
- University of Naples Federico II, Dipartimento di Ingegneria Chimica, dei Materiali e della Produzione Industriale, P.le Tecchio 80, I-80125, Napoli, Italy; Institute of Applied Sciences and Intelligent Systems (ISASI), National Research Council of Italy (CNR), Pozzuoli, NA 80078, Italy
| | - Simonetta Grilli
- University of Naples Federico II, Dipartimento di Ingegneria Chimica, dei Materiali e della Produzione Industriale, P.le Tecchio 80, I-80125, Napoli, Italy; Institute of Applied Sciences and Intelligent Systems (ISASI), National Research Council of Italy (CNR), Pozzuoli, NA 80078, Italy.
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3
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Di Natale C, Coppola S, Vespini V, Tkachenko V, Russo S, Luciani G, Vitiello G, Ferranti F, Mari S, Ferraro P, Maffettone PL, Grilli S. Highly sensitive detection of the neurodegenerative biomarker Tau by using the concentration effect of the pyro-electrohydrodynamic jetting. Biosens Bioelectron 2024; 254:116234. [PMID: 38522234 DOI: 10.1016/j.bios.2024.116234] [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: 12/05/2023] [Revised: 02/29/2024] [Accepted: 03/20/2024] [Indexed: 03/26/2024]
Abstract
It is largely documented that neurodegenerative diseases can be effectively treated only if early diagnosed. In this context, the structural changes of some biomolecules such as Tau, seem to play a key role in neurodegeneration mechanism becoming eligible targets for an early diagnosis. Post-translational modifications are responsible to drive the Tau protein towards a transition phase from a native disorder conformation into a preaggregation state, which then straight recruits the final fibrillization process. Here, we show for the first time the detection of pre-aggregated Tau in artificial urine at femto-molar level, through the concentration effect of the pyro-electrohydrodynamic jet (p-jet) technique. An excellent linear calibration curve is demonstrated at the femto-molar level with a limit of detection (LOD) of 130 fM. Moreover, for the first time we show here the structure stability of the protein after p-jet application through a deep spectroscopic investigation. Thanks to the small volumes required and the relatively compact and cost-effective characteristics, this technique represents an innovative breakthrough in monitoring the early stage associated to neurodegeneration syndromes in different scenarios of point of care (POC) and such as for example in long-term human space exploration missions.
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Affiliation(s)
- Concetta Di Natale
- Dipartimento di Ingegneria Chimica, Dei Materiali e Della Produzione Industriale (DICMaPI), Università Degli Studi di Napoli Federico II, Piazzale Tecchio 80, 80125, Naples, Italy; Institute of Applied Sciences and Intelligent Systems (ISASI), National Research Council of Italy (CNR), Pozzuoli, NA, 80078, Italy.
| | - Sara Coppola
- Dipartimento di Ingegneria Chimica, Dei Materiali e Della Produzione Industriale (DICMaPI), Università Degli Studi di Napoli Federico II, Piazzale Tecchio 80, 80125, Naples, Italy; Institute of Applied Sciences and Intelligent Systems (ISASI), National Research Council of Italy (CNR), Pozzuoli, NA, 80078, Italy
| | - Veronica Vespini
- Institute of Applied Sciences and Intelligent Systems (ISASI), National Research Council of Italy (CNR), Pozzuoli, NA, 80078, Italy
| | - Volodymyr Tkachenko
- Institute of Applied Sciences and Intelligent Systems (ISASI), National Research Council of Italy (CNR), Pozzuoli, NA, 80078, Italy
| | - Simone Russo
- Dipartimento di Ingegneria Chimica, Dei Materiali e Della Produzione Industriale (DICMaPI), Università Degli Studi di Napoli Federico II, Piazzale Tecchio 80, 80125, Naples, Italy
| | - Giuseppina Luciani
- Dipartimento di Ingegneria Chimica, Dei Materiali e Della Produzione Industriale (DICMaPI), Università Degli Studi di Napoli Federico II, Piazzale Tecchio 80, 80125, Naples, Italy
| | - Giuseppe Vitiello
- Dipartimento di Ingegneria Chimica, Dei Materiali e Della Produzione Industriale (DICMaPI), Università Degli Studi di Napoli Federico II, Piazzale Tecchio 80, 80125, Naples, Italy; Center for Colloid and Surface Science (CSGI), Via Della Lastruccia, Sesto Fiorentino, FI, 80078, Italy
| | | | - Silvia Mari
- Agenzia Spaziale Italiana, Via Del Politecnico snc, 00133, Rome, Italy
| | - Pietro Ferraro
- Institute of Applied Sciences and Intelligent Systems (ISASI), National Research Council of Italy (CNR), Pozzuoli, NA, 80078, Italy
| | - Pier Luca Maffettone
- Dipartimento di Ingegneria Chimica, Dei Materiali e Della Produzione Industriale (DICMaPI), Università Degli Studi di Napoli Federico II, Piazzale Tecchio 80, 80125, Naples, Italy; Institute of Applied Sciences and Intelligent Systems (ISASI), National Research Council of Italy (CNR), Pozzuoli, NA, 80078, Italy
| | - Simonetta Grilli
- Dipartimento di Ingegneria Chimica, Dei Materiali e Della Produzione Industriale (DICMaPI), Università Degli Studi di Napoli Federico II, Piazzale Tecchio 80, 80125, Naples, Italy; Institute of Applied Sciences and Intelligent Systems (ISASI), National Research Council of Italy (CNR), Pozzuoli, NA, 80078, Italy.
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4
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ZABARA M, TROFIN AM, CADAR R, NASTASE A, BLAJ M, CIUNTU BM, GARLEANU I, LUPASCU-URSULESCU C, LUPASCU C. Prognostic factors for outcome of liver transplantion hepatitis C cirrhosis. Chirurgia (Bucur) 2023. [DOI: 10.23736/s0394-9508.22.05393-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/12/2023]
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5
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Liver Transplantation from a Human Leukocyte Antigen-Matched Sibling Donor: Effectiveness of Direct-Acting Antiviral Therapy against Hepatitis C Virus Infection. REPORTS 2022. [DOI: 10.3390/reports5040049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
Abstract
Through living-donor liver transplantation (LDLT) from a human leukocyte antigen (HLA)-matched sibling donor, it may be possible to stop the use of immunosuppressants. It is possible that acute antibody-mediated rejection and chronic active antibody-mediated rejection through the positivity of donor-specific anti-HLA antibodies and/or T cell-mediated rejection may affect the prognosis of liver transplantation. The etiologies of liver diseases of the recipient may also affect the post-transplantation course. Herein, we report on the successful re-treatment with direct-acting antiviral (DAA) therapy against hepatitis C virus (HCV) infection in a patient who underwent a LDLT from HLA-matched sibling donor. After liver transplantation for HCV-related liver diseases, it is easy for HCV to re-infect the graft liver under a lack of immunosuppressants. DAA therapy against HCV re-infection immediately after transplantation should be commenced, and it is important to eradicate HCV for better prognosis of the recipients in LDLT for HCV-related liver diseases.
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6
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Hanif FM, Majid Z, Luck NH, Tasneem AA, Laeeq SM, Mubarak M. Revolution in the diagnosis and management of hepatitis C virus infection in current era. World J Hepatol 2022; 14:647-669. [PMID: 35646260 PMCID: PMC9099099 DOI: 10.4254/wjh.v14.i4.647] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 02/05/2022] [Accepted: 04/02/2022] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a major global public health problem, particularly in developing part of the world. Significant advances have been made in the early diagnosis and treatment of the disease. Its management has been particularly revolutionized during the past two decades. In this review, we summarize the major advances in the diagnostic and management armamentarium for chronic HCV infection. The focus of the present review is on the newer directly acting anti-viral agents, which have revolutionized the management of chronic HCV infection. Management of uncomplicated chronic HCV infection and of specific complications and special at-risk populations of patients will be covered in detail. Despite the advent and approval of highly effective and well tolerable oral agents, still many challenges remain, particularly the affordability, the equitable distribution and access to later drugs. The World Health Organization aims to eliminate viral hepatitis including HCV by 2030 since its poses a major public health threat. There is an urgent need to ensure uniform and early access to diagnostic and therapeutic facilities throughout the world if the later goal has to be realized.
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Affiliation(s)
- Farina M Hanif
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan
| | - Zain Majid
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan
| | - Nasir Hassan Luck
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan
| | - Abbas Ali Tasneem
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan
| | - Syed Muddasir Laeeq
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan
| | - Muhammed Mubarak
- Department of Histopathology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan.
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7
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Song X, Gao X, Wang Y, Raja R, Zhang Y, Yang S, Li M, Yao Z, Wei L. HCV Core Protein Induces Chemokine CCL2 and CXCL10 Expression Through NF-κB Signaling Pathway in Macrophages. Front Immunol 2021; 12:654998. [PMID: 34531848 PMCID: PMC8438213 DOI: 10.3389/fimmu.2021.654998] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 08/16/2021] [Indexed: 12/15/2022] Open
Abstract
HCV core protein is the first structural protein synthesized during hepatitis C virus (HCV) infection and replication. It is released from virus infected liver cells and mediates multiple functions to affect host cell response. The innate immune response is the first line of defense against viral infection. After HCV infection, Kupffer cells (KCs) which are liver macrophages play an important role in host innate immune response. Kupffer cells act as phagocytes and release different cytokines and chemokines to counter viral infection and regulate inflammation and fibrosis in liver. Earlier, we have demonstrated that HCV core protein interacts with gC1qR and activates MAPK, NF-κB and PI3K/AKT pathways in macrophages. In this study, we explored the effect of HCV core protein on CCL2 and CXCL10 expression in macrophages and the signaling pathways involved. Upon silencing of gC1qR, we observed a significant decrease expression of CCL2 and CXCL10 in macrophages in the presence of HCV core protein. Inhibiting NF-κB pathway, but not P38, JNK, ERK and AKT pathways greatly reduced the expression of CCL2 and CXCL10. Therefore, our results indicate that interaction of HCV core protein with gC1qR could induce CCL2 and CXCL10 secretion in macrophages via NF-κB signaling pathway. These findings may shed light on the understanding of how leukocytes migrate into the liver and exaggerate host-derived immune responses and may provide novel therapeutic targets in HCV chronic inflammation.
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Affiliation(s)
- Xiaotian Song
- Department of Immunology, Hebei Medical University, Shijiazhuang, China.,Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China
| | - Xue Gao
- Department of Immunology, Hebei Medical University, Shijiazhuang, China.,Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China
| | - Yadong Wang
- Department of Infectious Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Rameez Raja
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Yaoyu Zhang
- Department of Immunology, Hebei Medical University, Shijiazhuang, China.,Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China
| | - Shulin Yang
- Department of Immunology, Hebei Medical University, Shijiazhuang, China.,Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China
| | - Miao Li
- Department of Immunology, Hebei Medical University, Shijiazhuang, China.,Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China
| | - Zhiyan Yao
- Department of Immunology, Hebei Medical University, Shijiazhuang, China.,Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China
| | - Lin Wei
- Department of Immunology, Hebei Medical University, Shijiazhuang, China.,Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China
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8
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Tsien C, Selzner N. PSC recurrence post liver transplantation: retransplantation justified or not? Transpl Int 2021; 34:1754-1755. [PMID: 34411372 DOI: 10.1111/tri.14014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 08/05/2021] [Indexed: 11/29/2022]
Affiliation(s)
- Cynthia Tsien
- Ajmera Transplant Program, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Nazia Selzner
- Ajmera Transplant Program, Department of Medicine, University of Toronto, Toronto, ON, Canada
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Aregay A, Engel B, Port K, Vondran FWR, Bremer B, Niehaus C, Khera T, Richter N, Jaeckel E, Cornberg M, Taubert R, Wedemeyer H. Distinct Immune Imprints of Post-Liver Transplantation Hepatitis C Persist Despite Viral Clearance. Liver Transpl 2021; 27:887-899. [PMID: 33641215 DOI: 10.1002/lt.26031] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 01/21/2021] [Accepted: 01/27/2021] [Indexed: 01/13/2023]
Abstract
Recurrence or de novo infection of hepatitis C virus (HCV) after liver transplantation (LT) has been associated with progressive graft hepatitis that can be improved by treatment with novel direct-acting antivirals. Cases of rejection episodes have been described during and after HCV treatment. The evolution of innate and adaptive immune response during and after cure of HCV LT is unknown. We studied 74 protein biomarkers in the plasma of LT patients receiving antiviral therapy. In addition, deep immune phenotyping of both the myeloid and lymphoid immune cell subsets in peripheral blood mononuclear cells was performed. We found that LT patients with active HCV infection displayed distinct alterations of inflammatory protein biomarkers, such as C-X-Cmotif chemokine 10 (CXCL10), caspase 8, C-C motif chemokine 20 (CCL20), CCL19, interferon γ, CUB domain-containing protein 1 (CDCP1), interleukin (IL)-18R1, CXCL11, CCL3, IL8, IL12B, tumor necrosis factor-beta, CXCL6, osteoprotegerin, IL10, fms-related tyrosine kinase 3 ligand, hepatocyte growth factor, urokinase-type plasminogen activator, neurotrophin-3, CCL4, IL6, tumornecrosis factor receptor superfamily member 9, programmed death ligand 1, IL18, and monocyte chemotactic protein 1, and enrichment of peripheral immune cell subsets unlike patients without HCV infection who received transplants. Interestingly, patients who cleared HCV after LT did not normalize the altered inflammatory milieu nor did the peripheral immune cell subsets normalize to what would be seen in the absence of HCV recurrence. Overall, these data indicate that HCV-specific imprints on inflammatory analytes and immune cell subsets after LT are not completely normalized by therapy-induced HCV elimination. This is in line with the clinical observation that cure of HCV after LT did not trigger rejection episodes in many patients.
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Affiliation(s)
- Amare Aregay
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Bastian Engel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Kerstin Port
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Florian W R Vondran
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Christian Niehaus
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Tanvi Khera
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Nicolas Richter
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Centre Transplantation, Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Centre for Infection Research, DZIF, partner-site Hannover-Braunschweig, Hannover, Germany.,Centre for individualized infection medicine (CIIM), Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Centre Transplantation, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.,Integrated Research and Treatment Centre Transplantation, Hannover Medical School, Hannover, Germany.,German Centre for Infection Research, DZIF, partner-site Hannover-Braunschweig, Hannover, Germany
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10
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Impact of Behavioral Health Consultation on Hepatitis C Treatment Outcomes at a Federally Qualified Health Center; Philadelphia, PA. J Prim Prev 2021; 42:203-215. [PMID: 33733379 DOI: 10.1007/s10935-021-00627-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2021] [Indexed: 10/21/2022]
Abstract
Hepatitis C virus (HCV) infection is a public health issue that claims the lives of 350,000 individuals globally every year. Primary care providers are increasingly prescribing HCV medications with more modern, simplified administrations. Individuals with HCV are disproportionately affected by behavioral health challenges and substance use disorders. Integrated behavioral health providers can work in concert with their patients' primary care teams to provide innovative treatment programs to help support the needs of HCV care. We used simple and multivariable logistic regression to determine the association between receipt of behavioral health consultation and two outcomes on the care continuum: insurance approval for treatment and initiated HCV treatment regimen. These models were fitted using theoretically hypothesized variables and multivariable regression models included age, sex, and race/ethnicity as potential confounders. From January 2015 to May 2017, 189 patients at health centers were referred for onsite HCV primary care treatment. Of these, 142 were approved for participation, and 132 started treatment. Simple regression revealed a significant association between behavioral health consultation and treatment approval; however, behavioral health consultation was non-significant in the multivariable model for treatment approval. For initiating HCV treatment, onsite behavioral health consultation was significantly associated in both the unadjusted and adjusted regression models. Integrating behavioral health services for patients seeking HCV treatment may improve movement across the care continuum, optimizing patient's HCV health outcomes. Behavioral health consultation in primary care settings should be studied further to improve HCV treatment outcomes for patients with behavioral health and substance use disorders.
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11
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Tatar M, Keeshin SW, Mailliard M, Wilson FA. Cost-effectiveness of Universal and Targeted Hepatitis C Virus Screening in the United States. JAMA Netw Open 2020; 3:e2015756. [PMID: 32880650 PMCID: PMC7489814 DOI: 10.1001/jamanetworkopen.2020.15756] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 06/24/2020] [Indexed: 12/11/2022] Open
Abstract
Importance Between 2 and 3.5 million people live with chronic hepatitis C virus (HCV) infection in the US, most of whom (approximately 75%) are not aware of their disease. Despite the availability of effective HCV treatment in the early stages of infection, HCV will result in thousands of deaths in the next decade in the US. Objective To investigate the cost-effectiveness of universal screening for all US adults aged 18 years or older for HCV in the US and of targeted screening of people who inject drugs. Design, Setting, and Participants This simulated economic evaluation used cohort analyses in a Markov model to perform a 10 000-participant Monte Carlo microsimulation trail to evaluate the cost-effectiveness of HCV screening programs, and compared screening programs targeting people who inject drugs with universal screening of US adults age 18 years or older. Data were analyzed in December 2019. Exposures Cost per quality-adjusted life-year (QALY). Main Outcomes and Measures Cost per QALY gained. Results In a 10 000 Monte Carlo microsimulation trail that compared a baseline of individuals aged 40 years (men and women) and people who inject drugs in the US, screening and treatment for HCV were estimated to increase total costs by $10 457 per person and increase QALYs by 0.23 (approximately 3 months), providing an incremental cost-effectiveness ratio of $45 465 per QALY. Also, universal screening and treatment for HCV are estimated to increase total costs by $2845 per person and increase QALYs by 0.01, providing an incremental cost-effectiveness ratio of $291 277 per QALY. Conclusions and Relevance The findings of this study suggest that HCV screening for people who inject drugs may be a cost-effective intervention to combat HCV infection in the US, which could potentially decrease the risk of untreated HCV infection and liver-related mortality.
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Affiliation(s)
- Moosa Tatar
- Matheson Center for Health Care Studies, the University of Utah, Salt Lake City
| | - Susana W. Keeshin
- Division of Infectious Disease, the University of Utah School of Medicine, Salt Lake City
| | - Mark Mailliard
- University of Nebraska Medical Center College of Medicine, Omaha
| | - Fernando A. Wilson
- Matheson Center for Health Care Studies, the University of Utah, Salt Lake City
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12
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Chevallier E, Büchler M, Caillard S, Bouvier N, Colosio C, Rivalan J, Sayegh J, Bertrand D, Le Meur Y, Thierry A, Garrouste C, Rerolle JP, Rostaing L, Gatault P. Chronic Hepatitis C Virus Infection After Kidney Transplantation With or Without Direct-Acting Antivirals in a Real-Life Setting: A French Multicenter Experience. Transplant Proc 2020; 52:3179-3185. [PMID: 32636068 DOI: 10.1016/j.transproceed.2020.06.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 06/04/2020] [Indexed: 02/08/2023]
Abstract
PURPOSE Kidney transplant recipients (KTRs) are frequently infected with chronic hepatitis C virus (HCV), which can increase the risk of graft loss. Active HCV infections among KTRs are associated with shorter survival times. The emergence of very efficient interferon-free treatments (direct-acting antivirals [DAAs]) has revolutionized prognoses for chronic viral hepatitis. We performed a multicenter study where HCV (+)/RNA (+) KTRs were followed up and either received DAAs (group A) or not (group B) according to the transplant center. The aim was to assess, in a real-life setting, the impact of DAA therapy and to compare these results with those from HCV RNA (+) KTRs where HCV infection was not treated during the same period. METHODS This study included 66 patients from 11 centers: 44 patients (66.7%; group A) received DAAs, whereas 22 patients did not (group B); the 2 groups were comparable according to baseline data. Most patients (88.6%) received sofosbuvir, 50% received ledipasvir, and 34.7% received daclatasvir. The duration of treatments ranged from 8 to 24 weeks. RESULTS HCV RNA clearance (ie, a sustained virologic response) was observed in 95.4% of treated patients. Eradication of HCV led to a significant decrease in liver enzymes (50% reduction for alanine aminotransferase [P ≤ .001] and 41% for gamma glutamyl transpeptidase [P < .001]). Conversely, liver enzymes did not decrease in group B. Death occurred significantly more frequently in nontreated than treated patients (3 in group B vs none in group A, P = .003). Of the 10 treated patients with severe renal impairment before DAA therapy, 6 experienced graft loss. CONCLUSION DAAs are very effective at treating chronic HCV and have an excellent tolerance profile.
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Affiliation(s)
- Eloi Chevallier
- Department of Nephrology, Hemodialysis, Apheresis and Kidney Transplantation, CHU Grenoble-Alpes, Grenoble, France; Grenoble-Alpes University, Grenoble, France
| | - Matthias Büchler
- Department of Nephrology and Clinical Immunology, CHU Tours, Tours, France
| | - Sophie Caillard
- Department of Nephrology, Strasbourg University Hospital, Strasbourg, France
| | - Nicolas Bouvier
- Department of Nephrology, Caen University Hospital, Caen, France
| | | | - Joseph Rivalan
- Department of Nephrology, Rennes University Hospital, Rennes, France
| | - Johnny Sayegh
- Department of Nephrology, Angers University Hospital, Angers, France
| | | | - Yannick Le Meur
- Department of Nephrology, Brest University Hospital, Brest, France
| | - Antoine Thierry
- Department of Nephrology, Poitiers University Hospital, Poitiers, France
| | - Cyril Garrouste
- Department of Nephrology, Clermont Ferrand University Hospital, Clermont Ferrand, France
| | | | - Lionel Rostaing
- Department of Nephrology, Hemodialysis, Apheresis and Kidney Transplantation, CHU Grenoble-Alpes, Grenoble, France; Grenoble-Alpes University, Grenoble, France.
| | - Philippe Gatault
- Department of Nephrology and Clinical Immunology, CHU Tours, Tours, France
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13
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Melo RCN, Raas MWD, Palazzi C, Neves VH, Malta KK, Silva TP. Whole Slide Imaging and Its Applications to Histopathological Studies of Liver Disorders. Front Med (Lausanne) 2020; 6:310. [PMID: 31970160 PMCID: PMC6960181 DOI: 10.3389/fmed.2019.00310] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Accepted: 12/09/2019] [Indexed: 12/11/2022] Open
Abstract
Histological analysis of hepatic tissue specimens is essential for evaluating the pathology of several liver disorders such as chronic liver diseases, hepatocellular carcinomas, liver steatosis, and infectious liver diseases. Manual examination of histological slides on the microscope is a classically used method to study these disorders. However, it is considered time-consuming, limited, and associated with intra- and inter-observer variability. Emerging technologies such as whole slide imaging (WSI), also termed virtual microscopy, have increasingly been used to improve the assessment of histological features with applications in both clinical and research laboratories. WSI enables the acquisition of the tissue morphology/pathology from glass slides and translates it into a digital form comparable to a conventional microscope, but with several advantages such as easy image accessibility and storage, portability, sharing, annotation, qualitative and quantitative image analysis, and use for educational purposes. WSI-generated images simultaneously provide high resolution and a wide field of observation that can cover the entire section, extending any single field of view. In this review, we summarize current knowledge on the application of WSI to histopathological analyses of liver disorders as well as to understand liver biology. We address how WSI may improve the assessment and quantification of multiple histological parameters in the liver, and help diagnose several hepatic conditions with important clinical implications. The WSI technical limitations are also discussed.
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Affiliation(s)
- Rossana C N Melo
- Laboratory of Cellular Biology, Department of Biology, Federal University of Juiz de Fora, Juiz de Fora, Brazil
| | - Maximilian W D Raas
- Laboratory of Cellular Biology, Department of Biology, Federal University of Juiz de Fora, Juiz de Fora, Brazil.,Faculty of Medical Sciences, Radboud University, Nijmegen, Netherlands
| | - Cinthia Palazzi
- Laboratory of Cellular Biology, Department of Biology, Federal University of Juiz de Fora, Juiz de Fora, Brazil
| | - Vitor H Neves
- Laboratory of Cellular Biology, Department of Biology, Federal University of Juiz de Fora, Juiz de Fora, Brazil
| | - Kássia K Malta
- Laboratory of Cellular Biology, Department of Biology, Federal University of Juiz de Fora, Juiz de Fora, Brazil
| | - Thiago P Silva
- Laboratory of Cellular Biology, Department of Biology, Federal University of Juiz de Fora, Juiz de Fora, Brazil
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14
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Naz Z, Wahid B, Usman S, Saleem K, Rafique S, Ali A, Idrees M. Expression of SOCS1 and SOCS3 Genes in Interferon-Treated and Direct-Acting Antiviral Drugs-Treated Hepatitis C Patients. J Interferon Cytokine Res 2019; 38:255-260. [PMID: 29920131 DOI: 10.1089/jir.2017.0138] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Genetics of host plays a significant role in susceptibility and pathogenesis of disease. During hepatitis C virus (HCV) infection, HCV proteins interfere with interferon (IFN) signaling pathways and upregulate transcription of suppressor of cytokine signaling 1 and 3 genes (SOCS1 and SOCS3), which results in impaired immune response. In this study, we evaluated relative expression of SOCS1 and SOCS3 in untreated HCV patients and patients treated with 2 different treatment strategies that are, (IFN therapy and direct-acting antiviral (DAA) drug regimen. To study gene expression, peripheral blood mononuclear cells (PBMCs) were isolated by using Histopaque. Total RNA was extracted from PBMCs by using BIOzol. Nine microgram of total RNA from each sample was used and reverse transcribed into single-stranded complementary DNA (cDNA) by using M-MLV reverse transcriptase (Invitrogen). The synthesized cDNA was diluted to a final concentration of 500 ng/μL. This diluted cDNA was further used for expression analysis of SOCS1and SOCS3 genes using Rotor Gene Q Real-Time PCR Detection System (QIAGEN). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was amplified as a housekeeping gene. We found that the SOCS1 expression in IFN and DAA-treated patient groups was 5.4 fold and 1.2 fold, respectively, high compared with the healthy controls (IFN versus healthy, P = 0.019 and DAA versus healthy, P = 0.91), whereas the SOCS3 expression in IFN and DAA-treated patient groups was 3.7 fold and 2 fold, respectively, high in comparison with the expression in healthy controls (IFN versus healthy, P = 0.025 and DAA versus healthy, P = 0.03). We also found a significant difference in the relative expression of SOCS1 and SOCS3 in DAAs-treated and IFN/ribavirin (RBV)-treated and untreated individual. We concluded that by targeting HCV proteins with DAAs, SOCS1, and SOCS3 transcription can be more effectively normalized compared to the treatment with IFN/RBV therapy.
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Affiliation(s)
- Zara Naz
- 1 Molecular Virology Laboratory Centre for Applied Molecular Biology (CAMB), University of the Punjab , Lahore, Pakistan
| | - Braira Wahid
- 1 Molecular Virology Laboratory Centre for Applied Molecular Biology (CAMB), University of the Punjab , Lahore, Pakistan
| | - Sana Usman
- 1 Molecular Virology Laboratory Centre for Applied Molecular Biology (CAMB), University of the Punjab , Lahore, Pakistan
| | - Komal Saleem
- 1 Molecular Virology Laboratory Centre for Applied Molecular Biology (CAMB), University of the Punjab , Lahore, Pakistan
| | - Shazia Rafique
- 2 Divison of Molecular Virology, Center of Excellence in Molecular Biology (CEMB), University of the Punjab , Lahore, Pakistan
| | - Amjad Ali
- 1 Molecular Virology Laboratory Centre for Applied Molecular Biology (CAMB), University of the Punjab , Lahore, Pakistan
| | - Muhammad Idrees
- 1 Molecular Virology Laboratory Centre for Applied Molecular Biology (CAMB), University of the Punjab , Lahore, Pakistan .,3 Molecular Biology Department, Hazara University , Mansehra, Pakistan
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15
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Maghrabi HME, Elmowafy AY, Refaie AF, Elbasiony MA, Shiha GE, Rostaing L, Bakr MA. Efficacy and safety of the new antiviral agents for the treatment of hepatitis C virus infection in Egyptian renal transplant recipients. Int Urol Nephrol 2019; 51:2295-2304. [PMID: 31531807 DOI: 10.1007/s11255-019-02272-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 08/28/2019] [Indexed: 02/06/2023]
Abstract
PURPOSE Hepatitis C virus (HCV) infection in kidney transplant recipients (KTRs) is common and can impact on patient and graft survival rates. The efficacy and safety of direct-acting antivirals (DAAs) to treat genotype-4 HCV-infected KTRs have not been fully established. METHODS A prospective, single-arm, single-center study was conducted at Mansoura Urology/Nephrology Center (Mansoura University, Egypt). 114 HCV RNA(+) genotype 4 KTRs were enrolled in this study after a hepatology consultation and consented to start treatment with interferon-free DAAs. A sofosbuvir-based regimen was given to 109 recipients that had creatinine clearance (Crcl) of > 30 mL/min/1.73 m2. Ritonavir-boosted paritaprevir/ombitasvir was prescribed to five recipients with Crcl < 30 mL/min/1.73 m2. RESULTS The mean age of the cohort was 45.2 ± 11.2 years; most were male. The mean duration with a transplant was 14.2 ± 3.5 years, with different immunosuppressive regimens, mostly based on calcineurin inhibitors. A rapid virological response (RVR), i.e., clearance of viral load, was achieved in 100% at 4 weeks after starting treatment. All patients had a sustained virological response (SVR) at 12 and 24 weeks posttreatment, with one exception. During DAA therapy serum creatinine increased in 12 patients. In three, this was concomitant with elevated calcineurin inhibitor and sirolimus trough levels. Graft biopsies were performed in 8 of these 12 patients: these revealed an acute rejection in 4 cases (acute cellular rejection grade-1A: n = 2, and grade-1B: n = 2). The rejection episodes occurred at 4-6 weeks after starting treatment. CONCLUSION DAAs were highly efficacious and safely treated genotype-4 HCV-infected KTRs and had no significant adverse effects on graft function/survival.
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Affiliation(s)
- Hanzada Mohamed El Maghrabi
- Urology and Nephrology Center, Mansoura University, Mansoura, Egypt.,Nephrology Department, Port-Said University, Port Said, Egypt
| | | | | | - Mohammed Adel Elbasiony
- Egyptian Liver research Institute and Hospital, Mansoura, Egypt.,Internal Medicine Department, Mansoura University, Mansoura, Egypt
| | | | - Lionel Rostaing
- Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, CS 10217, 38043, Grenoble Cedex 09, France.
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16
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Izumi T, Sakata K, Okuzaki D, Inokuchi S, Tamura T, Motooka D, Nakamura S, Ono C, Shimokawa M, Matsuura Y, Mori M, Fukuhara T, Yoshizumi T. Characterization of human pegivirus infection in liver transplantation recipients. J Med Virol 2019; 91:2093-2100. [PMID: 31350911 DOI: 10.1002/jmv.25555] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 07/24/2019] [Indexed: 12/23/2022]
Abstract
Approximately 2% of healthy persons are infected with human pegivirus (HPgV). HPgV is transmitted via vertical, sexual, and blood-borne routes. Recently, the association of HPgV infection with the risk of lymphoma was reported. Here, we examined the prevalence of chronic HPgV infection in liver transplantation (LT) recipients and patients with hepatectomy and the influence of HPgV infection after LT on clinical and perioperative factors. We enrolled 313 LT recipients and 187 patients with hepatectomy who received care at the Kyusyu University Hospital between May 1997 and September 2017. Of the 313 recipients and 187 patients enrolled in this study, 44 recipients (14.1%) and 2 patients (1.1%) had HPgV viremia, respectively. There was no significant association between HPgV infection and LT outcomes. Interestingly, one recipient was infected with HPgV during the peritransplant period, which was likely transmitted via blood transfusion because HPgV RNA was detected from the blood bag transfused to the recipient during LT. We reviewed the available literature on the prevalence HPgV infections in other organ-transplanted patients and whether they impacted clinical outcomes. They also had the higher prevalence of HPgV infection, while it appears to be of low or no consequences. In addition, HPgV infection induced the upregulation of interferon-stimulated gene (ISG) expression in peripheral blood mononuclear cells. LT recipients had higher HPgV viremia compared to patients with hepatectomy. Although HPgV infection was not associated with LT-related outcomes, it induced ISG expression in recipients.
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Affiliation(s)
- Takuma Izumi
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.,Department of Surgery and Science, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan
| | - Kazuhito Sakata
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan
| | - Daisuke Okuzaki
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Shoichi Inokuchi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan
| | - Tomokazu Tamura
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Daisuke Motooka
- Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Shota Nakamura
- Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Chikako Ono
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Masahiro Shimokawa
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan
| | - Yoshiharu Matsuura
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Masaki Mori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan
| | - Takasuke Fukuhara
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan
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17
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O'Brien TR, Jackson SS. What Have We Learned from Studies of IFN-λ Variants and Hepatitis C Virus Infection? J Interferon Cytokine Res 2019; 39:618-626. [PMID: 31161939 DOI: 10.1089/jir.2019.0048] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Chronic infection with the hepatitis C virus (HCV) is a major cause of cirrhosis and hepatocellular carcinoma. In 2009, genome-wide association studies (GWAS) strongly linked genetic variants in the interferon lambda (IFN-λ) chromosomal region to HCV clearance. In 2013, discovery of the IFNL4 gene provided a functional explanation for those GWAS findings. The IFNL4-ΔG/TT (rs368234815) variant controls generation of the IFN-λ4 protein. Paradoxically, the IFNL4-TT allele, which abrogates IFN-λ4, associates with higher rates of spontaneous HCV clearance and better response to treatments for HCV infection. The finding that a "knock-out" allele for IFN-λ4 enhances HCV clearance challenges the paradigm of IFNs as antiviral cytokines. Genetic variants in the IFN-λ region have also been associated with hepatic inflammation and fibrosis from various etiologies, however, alleles that are linked with improved HCV clearance associates with worse inflammation and fibrosis. These studies demonstrate that GWAS of infectious diseases may yield important and unexpected biological insights.
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Affiliation(s)
- Thomas R O'Brien
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Sarah S Jackson
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
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18
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5-Oxo-1-[(2,3,6,7-tetramethoxy-9-phenanthrenyl)methyl]-L-proline Inhibits Hepatitis C Virus Entry. Sci Rep 2019; 9:7288. [PMID: 31086268 PMCID: PMC6514212 DOI: 10.1038/s41598-019-43783-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 04/30/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatitis C virus (HCV) is the major causative agent of chronic liver diseases, including liver cirrhosis and hepatocellular carcinoma. The recent development of highly effective direct-acting antivirals (DAAs) has revolutionized the treatment of HCV patients. However, these DAAs are exorbitantly expensive for the majority of HCV patients worldwide. Moreover, these drugs still show genotypic difference in cure rate and have some resistant-associated variants. Tylophorine, a natural compound derived from Tylophora indica plants, is known to have anti-inflammatory and anti-cancerous growth activities. In the present study, we showed that two tylophorine intermediates, 5-Oxo-1-[(2,3,6,7-tetramethoxy-9-phenanthrenyl) methyl]-L-proline (O859585) and 2,3,6,7-tetramethoxy-9-phenanthrenecarboxylic acid (T298875), displayed anti-HCV activity with an EC50 of 38.25 µM for T298875 and 29.11~35.3 µM for O859585 in various HCV genotypes. We demonstrated that O859585 efficiently blocked HCV attachment by neutralizing free viral particles without affecting other stages of the HCV life cycle and interferon stimulation. O859585 interrupted binding between HCV E2 and CD81. Of note, co-treatment of O859585 with either interferon alpha (IFNα) or sofosbuvir exerted either an additive or synergistic antiviral activity in HCV-infected cells with no measurable effect on cell viability. Most importantly, O859585 in combination with IFNα and sofosbuvir exhibited synergistic effects on anti-HCV activity in primary human hepatocytes. Collectively, these data suggest that O859585 may be a novel antiviral agent for HCV therapy.
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19
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Lee WP, Lan KL, Liao SX, Huang YH, Hou MC, Lan KH. Antiviral effect of saikosaponin B2 in combination with daclatasvir on NS5A resistance-associated substitutions of hepatitis C virus. J Chin Med Assoc 2019; 82:368-374. [PMID: 30920421 DOI: 10.1097/jcma.0000000000000095] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) is a major causative agent of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The rapid progress in the development of direct-acting antivirals has greatly elevated the cure rate to ≥95% in recent years. However, the high cost of treatment is not affordable to patients in some countries, necessitating the development of less expensive treatment. METHODS We adopted a cell culture-derived HCV system to screen a library of the pure compounds extracted from herbs deposited in the chemical bank of the National Research Institute of Chinese Medicine, Taiwan. RESULTS We found that saikosaponin B2 inhibited viral entry, replication, and translation. Saikosaponin B2 is a plant glycoside and a component of xiao-chai-hu-tang, a traditional Chinese herbal medicine extracted from the roots of Bupleurum falcatum. It also inhibited daclatasvir-resistant mutant strains of HCV, especially in combination with daclatasvir. CONCLUSION Our results may aid the development of a new combination therapy useful for patients with HCV who are intolerant or refractory to the currently available medications, including pegylated interferon and direct-acting antiviral agents.
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Affiliation(s)
- Wei-Ping Lee
- Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Keng-Li Lan
- Division of Radiation Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Shi-Xian Liao
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Keng-Hsin Lan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
- Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
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20
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Liu J, Ma B, Cao W, Li M, Bramer WM, Peppelenbosch MP, Pan Q. Direct-acting antiviral agents for liver transplant recipients with recurrent genotype 1 hepatitis C virus infection: Systematic review and meta-analysis. Transpl Infect Dis 2019; 21:e13047. [PMID: 30615227 PMCID: PMC6850617 DOI: 10.1111/tid.13047] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 12/18/2018] [Accepted: 12/23/2018] [Indexed: 12/15/2022]
Abstract
Background Comprehensive evaluation of safety and efficacy of different combinations of direct‐acting antivirals (DAAs) in liver transplant recipients with genotype 1 (GT1) hepatitis C virus (HCV) recurrence remains limited. Therefore, we performed this systematic review and meta‐analysis in order to evaluate the clinical outcome of DAA treatment in liver transplant patients with HCV GT1 recurrence. Methods Studies were included if they contained information of 12 weeks sustained virologic response (SVR12) after DAA treatment completion as well as treatment related complications for liver transplant recipients with GT1 HCV recurrence. Results We identified 16 studies comprising 885 patients. The overall pooled estimate proportion of SVR12 was 93% (95% confidence interval (CI): 0.89, 0.96), with moderate heterogeneity observed (τ2 = 0.01, P < 0.01, I2=75%). High tolerability was observed in liver transplant recipients reflected by serious adverse events (sAEs) with pooled estimate proportion of 4% (95% CI: 0.01, 0.07; τ2 = 0.02, P < 0.01, I2 = 81%). For subgroup analysis, a total of five different DAA regimens were applied for treating these patients. Sofosbuvir/Ledipasvir (SOF/LDV) led the highest pooled estimate SVR12 proportion, followed by Paritaprevir/Ritonavir/Ombitasivir/Dasabuvir (PrOD), Daclatasvir (DCV)/Simeprevir (SMV) ± Ribavirin (RBV), and SOF/SMV ± RBV, Asunaprevir (ASV)/DCV. There was a tendency for favoring a higher pooled SVR12 proportion in patients with METAVIR Stage F0‐F2 of 97% (95% CI: 0.93, 0.99) compared to 85% (95% CI: 0.79, 0.90) for stage F3‐F4 (P < 0.01). There was no significant difference between LT recipients treated with or without RBV (P = 0.23). Conclusions Direct‐acting antiviral treatment is highly effective and well‐tolerated in liver transplant recipients with recurrent GT1 HCV infection.
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Affiliation(s)
- Jiaye Liu
- Biomedical Research Center, Northwest Minzu University, Lanzhou, China.,Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Buyun Ma
- Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Wanlu Cao
- Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Meng Li
- Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Wichor M Bramer
- Department of Medical Library, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Maikel P Peppelenbosch
- Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Qiuwei Pan
- Biomedical Research Center, Northwest Minzu University, Lanzhou, China.,Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
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21
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O'Brien TR, Yang HI, Groover S, Jeng WJ. Genetic Factors That Affect Spontaneous Clearance of Hepatitis C or B Virus, Response to Treatment, and Disease Progression. Gastroenterology 2019; 156:400-417. [PMID: 30287169 DOI: 10.1053/j.gastro.2018.09.052] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Revised: 09/21/2018] [Accepted: 09/24/2018] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections can lead to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Over the past decade, studies of individuals infected with these viruses have established genetic associations with the probability of developing a chronic infection, risk of disease progression, and likelihood of treatment response. We review genetic and genomic methods that have been used to study risk of HBV and HCV infection and patient outcomes. For example, genome-wide association studies have linked a region containing the interferon lambda genes to spontaneous and treatment-induced clearance of HCV. We review the genetic variants associated with HCV and HBV infection, and how these variants affect specific expression or activities of their products. Further studies of these variants could provide insights into risk factors for and mechanisms of chronic infection and disease progression, as well as new strategies for treatment.
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Affiliation(s)
- Thomas R O'Brien
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Sarah Groover
- Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, Oklahoma
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Unit, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
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22
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Miuma S, Miyaaki H, Soyama A, Hidaka M, Takatsuki M, Shibata H, Taura N, Eguchi S, Nakao K. Utilization and efficacy of elbasvir/grazoprevir for treating hepatitis C virus infection after liver transplantation. Hepatol Res 2018; 48:1045-1054. [PMID: 29908044 DOI: 10.1111/hepr.13204] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 05/21/2018] [Accepted: 06/08/2018] [Indexed: 02/06/2023]
Abstract
AIM Recently, elbasvir/grazoprevir combination therapy (EBR/GZR) was reported to have excellent antiviral effects for chronic genotype 1 hepatitis C virus (HCV) infection. However, it has not been recommended for patients with post-liver transplant (LT) HCV re-infections because of a lack of evidence for effectiveness and drug-drug interactions. METHODS We report the usage of EBR/GZR in five post-LT HCV re-infected patients with the kinetics of renal function and tacrolimus trough levels during and after therapy. Furthermore, to evaluate the antiviral effects, we examined the HCV kinetics during and after therapy and compared this with other interferon-free therapy in post-LT patients (n = 19). RESULTS All patients treated with EBR/GZR therapy obtained rapid virologic response and sustained at 12 weeks post-treatment. There was no evidence of worsening estimated glomerular filtration rates. Three patients were given tacrolimus as immunosuppressive therapy and its trough levels were controllable with dosage adjustments. One patient developed grade 1 diarrhea 3 days after therapy induction. To evaluate the antiviral effects of EBR/GZR therapy for these patients, we compared them to the effects of daclatasvir/asunaprevir combination therapy (n = 8) and sofosbuvir/ledipasvir combination therapy (n = 11). The EBR/GZR combination was not inferior to other therapies in its early phase and late-phase antiviral effects. CONCLUSIONS Although further studies with a larger number of patients are required, we suggest that EBR/GZR therapy is an alternative therapy for patients with post-LT genotype 1 HCV re-infection.
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Affiliation(s)
- Satoshi Miuma
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Mitsuhisa Takatsuki
- Department of Surgery, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hidetaka Shibata
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Naota Taura
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
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Eckman MH, Woodle ES, Thakar CV, Paterno F, Sherman KE. Transplanting Hepatitis C Virus-Infected Versus Uninfected Kidneys Into Hepatitis C Virus-Infected Recipients: A Cost-Effectiveness Analysis. Ann Intern Med 2018; 169:214-223. [PMID: 29987322 DOI: 10.7326/m17-3088] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Direct-acting antiviral agents are now available to treat chronic hepatitis C virus (HCV) infection in patients with end-stage renal disease (ESRD). OBJECTIVE To examine whether it is more cost-effective to transplant HCV-infected or HCV-uninfected kidneys into HCV-infected patients. DESIGN Markov state-transition decision model. DATA SOURCES MEDLINE searches and bibliographies from relevant English-language articles. TARGET POPULATION HCV-infected patients with ESRD receiving hemodialysis in the United States. TIME HORIZON Lifetime. PERSPECTIVE Health care system. INTERVENTION Transplant of an HCV-infected kidney followed by HCV treatment versus transplant of an HCV-uninfected kidney preceded by HCV treatment. OUTCOME MEASURES Effectiveness, measured in quality-adjusted life-years (QALYs), and costs, measured in 2017 U.S. dollars. RESULTS OF BASE-CASE ANALYSIS Transplant of an HCV-infected kidney followed by HCV treatment was more effective and less costly than transplant of an HCV-uninfected kidney preceded by HCV treatment, largely because of longer wait times for uninfected kidneys. A typical 57.8-year-old patient receiving hemodialysis would gain an average of 0.50 QALY at a lifetime cost savings of $41 591. RESULTS OF SENSITIVITY ANALYSIS Transplant of an HCV-infected kidney followed by HCV treatment continued to be preferred in sensitivity analyses of many model parameters. Transplant of an HCV-uninfected kidney preceded by HCV treatment was not preferred unless the additional wait time for an uninfected kidney was less than 161 days. LIMITATION The study did not consider the benefit of decreased HCV transmission from treating HCV-infected patients. CONCLUSION Transplanting HCV-infected kidneys into HCV-infected patients increased quality-adjusted life expectancy and reduced costs compared with transplanting HCV-uninfected kidneys into HCV-infected patients. PRIMARY FUNDING SOURCE Merck Sharp & Dohme and the National Center for Advancing Translational Sciences.
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Affiliation(s)
- Mark H Eckman
- University of Cincinnati, Cincinnati, Ohio (M.H.E., E.S.W., C.V.T., F.P., K.E.S.)
| | - E Steve Woodle
- University of Cincinnati, Cincinnati, Ohio (M.H.E., E.S.W., C.V.T., F.P., K.E.S.)
| | - Charuhas V Thakar
- University of Cincinnati, Cincinnati, Ohio (M.H.E., E.S.W., C.V.T., F.P., K.E.S.)
| | - Flavio Paterno
- University of Cincinnati, Cincinnati, Ohio (M.H.E., E.S.W., C.V.T., F.P., K.E.S.)
| | - Kenneth E Sherman
- University of Cincinnati, Cincinnati, Ohio (M.H.E., E.S.W., C.V.T., F.P., K.E.S.)
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24
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Zhang H, Qiao L, Luo G. Characterization of apolipoprotein C1 in hepatitis C virus infection and morphogenesis. Virology 2018; 524:1-9. [PMID: 30130702 DOI: 10.1016/j.virol.2018.08.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 08/05/2018] [Accepted: 08/05/2018] [Indexed: 12/12/2022]
Abstract
Previous studies have shown that apolipoprotein C1 (apoC1)-specific antibodies precipitated hepatitis C virus (HCV) and neutralized HCV infectivity, suggesting that apoC1 is a HCV component. However, the importance of apoC1 in the HCV life cycle has not been experimentally examined. In the present study, we sought to determine the role of apoC1 in the HCV infection and morphogenesis by knocking out the apoC1 gene using the CRISPR/Cas9 system. Strikingly, apoC1 gene knockout markedly enhanced apoE expression. As a result, apoC1 gene knockout per se didn't significantly affect HCV infection or morphogenesis, probably ascribing to its redundant functions with apoE. However, knockout of apoC1 gene potentiated the impairment of HCV infection and/or morphogenesis by apoE-specific small interfering RNAs. Additionally, a recombinant apoC1 protein efficiently blocked HCV infection. Collectively, these findings suggest that apoC1 and apoE have redundant functions in the HCV infection and morphogenesis.
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Affiliation(s)
- Han Zhang
- Department of Microbiology, Peking University School of Basic Medical Sciences, Beijing 100191, China
| | - Luhua Qiao
- Department of Microbiology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, United States
| | - Guangxiang Luo
- Department of Microbiology, Peking University School of Basic Medical Sciences, Beijing 100191, China; Department of Microbiology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, United States.
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25
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Miuma S, Miyaaki H, Miyazoe Y, Suehiro T, Sasaki R, Shibata H, Taura N, Nakao K. Development of Duodenal Ulcers due to the Discontinuation of Proton Pump Inhibitors After the Induction of Sofosbuvir Plus Ledipasvir Therapy: A Report of Two Cases. Transplant Proc 2018; 50:222-225. [PMID: 29407313 DOI: 10.1016/j.transproceed.2017.12.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Revised: 10/17/2017] [Accepted: 12/05/2017] [Indexed: 12/13/2022]
Abstract
Sofosbuvir plus ledipasvir (SOF-LDV) combination therapy is a promising therapy for post-transplant hepatitis C virus (HCV) reinfection. It is known that gastric pH elevation induces lower absorption of ledipasvir; therefore, the use of proton pump inhibitors (PPIs) should be considered regarding dose reduction after SOF-LDV therapy induction. Here, we report two patients who developed duodenal ulcers due to the discontinuation of PPIs after the induction of SOF-LDV therapy for post-transplant HCV reinfection. The first patient was a 71-year-old man who had undergone living donor liver transplantation due to HCV-related liver cirrhosis. Lansoprazole, 30 mg daily, was discontinued upon SOF-LDV therapy induction. Seven days after SOF-LDV therapy induction, gastrointestinal endoscopy revealed the presence of a duodenal ulcer. The second patient was a 54-year-old man who had undergone living donor liver transplantation due to HCV-related end-stage liver disease. Similar to the first patient, rabeprazole sodium was discontinued upon the induction of SOF-LDV therapy. Eighteen days after SOF-LDV therapy induction, gastrointestinal endoscopy revealed the presence of a duodenal ulcer. In both cases, these duodenal ulcers improved after the resumption of the administration of PPIs, and a sustained virologic response at 12 weeks was achieved by SOF-LDV therapy with PPI use. Thus, PPI use should be continued consistently during SOF-LDV therapy for post-transplant HCV reinfection.
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Affiliation(s)
- S Miuma
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan.
| | - H Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Y Miyazoe
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - T Suehiro
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - R Sasaki
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - H Shibata
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - N Taura
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - K Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan
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26
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Wahid B, Waqar M, Saleem K, Shafi F, Rehman Z, Hanif I, Ahmad HM, Wasim M, Sajjad, Wahid K, Idrees M. Poor response to direct-acting antiviral therapy in HCV-infected elderly population: a real-life cohort study based on GeneXpert® technology. Future Virol 2018. [DOI: 10.2217/fvl-2017-0158] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Aim: This study aimed to determine the efficacy of direct-acting antiviral drugs in different ethnicities and elderly population of Pakistan. Methods: We used GeneXpert® technology to quantify HCV RNA and evaluated treatment response in different cohorts that included HCV patients classified on the basis of their age-group and ethnicity. Results: The findings of our study suggest that 76% of nonresponder patients were older than 55 years of age which shows that age is the predictor of treatment outcome of direct-acting antiviral drugs. In addition to this, no differences were observed in overall efficacy by ethnicity. Conclusion: Treatment-regimen sofosbuvir+ribavirin has a limited effect on older patients; therefore, practitioners and healthcare professionals need to reconsider treatment options for elderly populations.
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Affiliation(s)
- Braira Wahid
- Genome Centre for Molecular Based Diagnostics & Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan
- Centre for Applied Molecular Biology (CAMB), 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
| | - Muhammad Waqar
- Genome Centre for Molecular Based Diagnostics & Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan
- Centre for Applied Molecular Biology (CAMB), 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
| | - Komal Saleem
- Genome Centre for Molecular Based Diagnostics & Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan
- Centre for Applied Molecular Biology (CAMB), 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
| | - Faiza Shafi
- Genome Centre for Molecular Based Diagnostics & Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan
| | - Zobaria Rehman
- Genome Centre for Molecular Based Diagnostics & Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan
- Centre for Applied Molecular Biology (CAMB), 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
| | - Iqra Hanif
- Genome Centre for Molecular Based Diagnostics & Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan
| | - Hafiza Maleeha Ahmad
- Genome Centre for Molecular Based Diagnostics & Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan
| | - Muhammad Wasim
- Department of Medicine, Khyber Teaching Hospital, Peshawar, Pakistan
| | - Sajjad
- Genome Centre for Molecular Based Diagnostics & Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan
- Hazara University, Mansehra, Pakistan
| | - Khansa Wahid
- Lahore College for Women University, Jail Road, Lahore, Pakistan
| | - Muhammad Idrees
- Genome Centre for Molecular Based Diagnostics & Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan
- Centre for Applied Molecular Biology (CAMB), 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
- Hazara University, Mansehra, Pakistan
- Division of Molecular Virology & Diagnostics Center of Excellence in Molecular Biology (CEMB), 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
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27
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Hopcraft SE, Damania B. Tumour viruses and innate immunity. Philos Trans R Soc Lond B Biol Sci 2018; 372:rstb.2016.0267. [PMID: 28893934 DOI: 10.1098/rstb.2016.0267] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/12/2017] [Indexed: 12/13/2022] Open
Abstract
Host cells sense viral infection through pattern recognition receptors (PRRs), which detect pathogen-associated molecular patterns (PAMPs) and stimulate an innate immune response. PRRs are localized to several different cellular compartments and are stimulated by viral proteins and nucleic acids. PRR activation initiates signal transduction events that ultimately result in an inflammatory response. Human tumour viruses, which include Kaposi's sarcoma-associated herpesvirus, Epstein-Barr virus, human papillomavirus, hepatitis C virus, hepatitis B virus, human T-cell lymphotropic virus type 1 and Merkel cell polyomavirus, are detected by several different PRRs. These viruses engage in a variety of mechanisms to evade the innate immune response, including downregulating PRRs, inhibiting PRR signalling, and disrupting the activation of transcription factors critical for mediating the inflammatory response, among others. This review will describe tumour virus PAMPs and the PRRs responsible for detecting viral infection, PRR signalling pathways, and the mechanisms by which tumour viruses evade the host innate immune system.This article is part of the themed issue 'Human oncogenic viruses'.
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Affiliation(s)
- Sharon E Hopcraft
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Blossom Damania
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA .,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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28
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Wahid B, Rafique S, Saleem K, Ali A, Idrees M. An Increase in Expression of SOCS1 Gene with Increase in Hepatitis C Virus Viral Load. J Interferon Cytokine Res 2018; 38:122-128. [DOI: 10.1089/jir.2017.0129] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Affiliation(s)
- Braira Wahid
- PCR Section, Genome Centre for Molecular Based Diagnostics and Research Centre, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan
- Virology Lab, Centre for Applied Molecular Biology (CAMB), Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
| | - Shazia Rafique
- Division of Molecular Virology and Diagnostics Center of Excellence in Molecular Biology (CEMB), Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
| | - Komal Saleem
- PCR Section, Genome Centre for Molecular Based Diagnostics and Research Centre, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan
- Virology Lab, Centre for Applied Molecular Biology (CAMB), Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
| | - Amjad Ali
- Virology Lab, Centre for Applied Molecular Biology (CAMB), Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
| | - Muhammad Idrees
- PCR Section, Genome Centre for Molecular Based Diagnostics and Research Centre, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan
- Virology Lab, Centre for Applied Molecular Biology (CAMB), Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
- Division of Molecular Virology and Diagnostics Center of Excellence in Molecular Biology (CEMB), Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan
- Vice Chancellor Hazara University Mansehra, Pakistan
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Beneficial Effects of Monascus sp. KCCM 10093 Pigments and Derivatives: A Mini Review. Molecules 2018; 23:molecules23010098. [PMID: 29301350 PMCID: PMC6017178 DOI: 10.3390/molecules23010098] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 12/09/2017] [Accepted: 12/18/2017] [Indexed: 11/16/2022] Open
Abstract
The production of Monascus pigments and related byproducts, via microbial fermentation, has been broadly utilized as coloring by traditional food industries and as a natural textile dye. In addition to these traditional purposes, Monascus pigments have been recently favored for a variety of commercial and academic purposes. Pigments and derivatives formed during Monascus fermentation have pharmaceutical and clinical properties that can counteract common diseases, including obesity, type-2 diabetes, and cancer. Various research attempts have investigated the optimum conditions for this derived compound synthesis, as well as the still-unknown bio-functional effects. Recently, several studies were conducted using Monascus sp. KCCM 10093 and its derivatives. These experimental outcomes potentially reflect the bio-functional features of Monascus sp. KCCM 10093. However, no publication to date provides an overview of Monascus sp. KCCM 10093's unique metabolite products, functionalities, or biological pathways. In order to develop profitable commercial applications of Monascus sp. KCCM 10093, it is necessary not only to conduct continuous research, but also to systematically organize previous Monascus studies. The goals of this review are to investigate the current derivatives of Monascus sp. KCCM 10093 pigments-some of which have demonstrated newly-identified functionality-and the relevant uses of these molecules for pharmaceutical or nutraceutical purposes.
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30
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Pentagalloylglucose, a highly bioavailable polyphenolic compound present in Cortex moutan, efficiently blocks hepatitis C virus entry. Antiviral Res 2017; 147:19-28. [PMID: 28923507 DOI: 10.1016/j.antiviral.2017.09.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 08/07/2017] [Accepted: 09/13/2017] [Indexed: 01/19/2023]
Abstract
Approximately 142 million people worldwide are infected with hepatitis C virus (HCV). Although potent direct acting antivirals are available, high costs limit access to treatment. Chronic hepatitis C virus infection remains a major cause of orthotopic liver transplantation. Moreover, re-infection of the graft occurs regularly. Antivirals derived from natural sources might be an alternative and cost-effective option to complement therapy regimens for global control of hepatitis C virus infection. We tested the antiviral properties of a mixture of different Chinese herbs/roots named Zhi Bai Di Huang Wan (ZBDHW) and its individual components on HCV. One of the ZBDHW components, Penta-O-Galloyl-Glucose (PGG), was further analyzed for its mode of action in vitro, its antiviral activity in primary human hepatocytes as well as for its bioavailability and hepatotoxicity in mice. ZBDHW, its component Cortex Moutan and the compound PGG efficiently block entry of HCV of all major genotypes and also of the related flavivirus Zika virus. PGG does not disrupt HCV virion integrity and acts primarily during virus attachment. PGG shows an additive effect when combined with the well characterized HCV inhibitor Daclatasvir. Analysis of bioavailability in mice revealed plasma levels above tissue culture IC50 after a single intraperitoneal injection. In conclusion, PGG is a pangenotypic HCV entry inhibitor with high bioavailability. The low cost and wide availability of this compound make it a promising candidate for HCV combination therapies, and also emerging human pathogenic flaviviruses like ZIKV.
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Shrivastava S, Wilson E, Poonia B, Tang L, Osinusi A, Kohli A, Kottilil S. Augmentation of hepatitis C virus-specific immunity and sustained virologic response. J Viral Hepat 2017; 24:742-749. [PMID: 28267900 PMCID: PMC10836410 DOI: 10.1111/jvh.12702] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 02/12/2017] [Indexed: 12/23/2022]
Abstract
Treatment for chronic hepatitis C virus (HCV) infection has rapidly evolved into interferon-free directly acting antiviral regimens (DAA) that result in high sustained virologic response. DAAs primarily work by suppressing HCV replication and rely less on the immune system than interferon-based therapies. However, it is unclear whether the immune system recovers with suppression of HCV replication and contributes to HCV clearance with DAA therapy. We previously demonstrated HCV clearance is associated with increased HCV-specific immunity in CHCV-GT-1-infected patients during treatment with sofosbuvir (SOF)+ribavirin (RBV). Here, we aimed to analyse changes in HCV-specific immunological responses associated with viral clearance with combination DAA therapy of SOF+ledipasvir (LDV) for 12 weeks in CHCV-GT1 (N=14) patients who relapsed without augmentation of HCV-specific immunity during treatment with SOF+RBV. Phenotypic and functional changes within the T-cell compartment of PBMCs pre- and post-treatment were analysed. Retreatment of relapsers with LDV/SOF resulted in all patients attaining SVR12 . Suppression of HCV was associated with a decline in T-cell exhaustion markers (CD57; Tim3; PD1) along with augmented of HCV-specific T-cell IFN-gamma responses post-treatment. Addition of LDV to SOF was associated with augmentation of HCV-specific immunity and SVR in patients who previously failed SOF+RBV therapy without increased immunity. These findings demonstrate a novel effect of DAA in inducing host immune responses to aid HCV clearance and achieve SVR.
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Affiliation(s)
- S Shrivastava
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - E Wilson
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - B Poonia
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - L Tang
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - A Osinusi
- Gilead Sciences Inc., Foster City, CA, USA
| | - A Kohli
- Creighton University School of Medicine, St Joseph's Hospital, Phoenix, AZ, USA
| | - S Kottilil
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
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32
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Meijerink H, White RA, Løvlie A, de Blasio BF, Dalgard O, Amundsen EJ, Melum E, Kløvstad H. Modelling the burden of hepatitis C infection among people who inject drugs in Norway, 1973-2030. BMC Infect Dis 2017; 17:541. [PMID: 28774261 PMCID: PMC5543437 DOI: 10.1186/s12879-017-2631-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 07/25/2017] [Indexed: 02/08/2023] Open
Abstract
Background Lack of Hepatitis C virus (HCV) incidence data in (Norwegian) high-risk groups impedes the ability to make informed decisions on prevention measures. Thus we rely on modelling to estimate the incidence and burden of HCV infections. Methods We constructed a compartmental model for HCV infections in Norway among active and former people who inject drugs (PWIDs). We based yearly transition rates on literature. The model was fitted to absolute numbers of hepatitis C associated cirrhosis, hepatocellular carcinoma (HCC) and death from national data sources (2000–2013). We estimated the number (95%CI) of HCV infections, cirrhosis, HCC and death and disability adjusted life years (DALYs) due to HCV infections in Norway, 1973–2030. We assumed treatment rates in the projected period were similar to those in 2013. Results The estimated proportion of chronic HCV (including those with cirrhosis and HCC) among PWIDs was stable from 2000 (49%; 4441/9108) to 2013 (43%; 3667/8587). We estimated that the incidence of HCV among PWIDs was 381 new infections in 2015. The estimated number of people with cirrhosis, HCC, and liver transplant was predicted to increase until 2022 (1537 people). DALYs among active PWIDs estimated to peak in 2006 (3480 DALYs) and decrease to 1870 DALYs in 2030. Chronic HCV infection contributes most to the total burden of HCV infection, and peaks at 1917 DALYs (52%) in 2007. The burden of HCV related to PWID increased until 2006 with 81/100,000 DALYs inhabitants and decreased to 68/100,000 DALYs in 2015. Conclusion The burden of HCV associated with injecting drug use is considerable, with chronic HCV infection contributing most to the total burden. This model can be used to estimate the impact of different interventions on the HCV burden in Norway and to perform cost-benefit analyses of various public health measures. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2631-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hinta Meijerink
- Norwegian Institute of Public Health, Postboks 4404 Nydalen, 0403, Oslo, Norway.,European Programme for Intervention Epidemiology Training (EPIET), European Centre for Disease Prevention and Control, (ECDC), Stockholm, Sweden
| | - Richard A White
- Norwegian Institute of Public Health, Postboks 4404 Nydalen, 0403, Oslo, Norway
| | - Astrid Løvlie
- Norwegian Institute of Public Health, Postboks 4404 Nydalen, 0403, Oslo, Norway
| | - Birgitte Freiesleben de Blasio
- Norwegian Institute of Public Health, Postboks 4404 Nydalen, 0403, Oslo, Norway.,Department of Biostatistics, Oslo Centre for Biostatistics and Epidemiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Olav Dalgard
- Akershus University Hospital, Lørenskog, Norway.,Medical Faculty, Oslo University, Oslo, Norway
| | - Ellen J Amundsen
- Norwegian Institute of Public Health, Postboks 4404 Nydalen, 0403, Oslo, Norway
| | - Espen Melum
- Norwegian PSC Research Center, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Section of Gastroenterology, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Hilde Kløvstad
- Norwegian Institute of Public Health, Postboks 4404 Nydalen, 0403, Oslo, Norway.
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McComas CC, Palani A, Chang W, Holloway MK, Lesburg CA, Li P, Liverton N, Meinke PT, Olsen DB, Peng X, Soll RM, Ummat A, Wu J, Wu J, Zorn N, Ludmerer SW. Development of a New Structural Class of Broadly Acting HCV Non-Nucleoside Inhibitors Leading to the Discovery of MK-8876. ChemMedChem 2017; 12:1436-1448. [PMID: 28741898 DOI: 10.1002/cmdc.201700228] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 06/26/2017] [Indexed: 01/14/2023]
Abstract
Studies directed at developing a broadly acting non-nucleoside inhibitor of HCV NS5B led to the discovery of a novel structural class of 5-aryl benzofurans that simultaneously interact with both the palm I and palm II binding regions. An initial candidate was potent in vitro against HCV GT1a and GT1b replicons, and induced multi-log reductions in HCV viral load when orally dosed to chronic GT1 infected chimpanzees. However, in vitro potency losses against clinically relevant GT1a variants prompted a further effort to develop compounds with sustained potency across a broader array of HCV genotypes and mutants. Ultimately, a biology and medicinal chemistry collaboration led to the discovery of the development candidate MK-8876. MK-8876 demonstrated a pan-genotypic potency profile and maintained potency against clinically relevant mutants. It demonstrated moderate bioavailability in rats and dogs, but showed low plasma clearance characteristics consistent with once-daily dosing. Herein we describe the efforts which led to the discovery of MK-8876, which advanced into Phase 1 monotherapy studies for evaluation and characterization as a component of an all-oral direct-acting drug regimen for the treatment of chronic HCV infection.
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Affiliation(s)
- Casey C McComas
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | - Anandan Palani
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | | | - M Katharine Holloway
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | - Charles A Lesburg
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | - Peng Li
- WuXi AppTec, Shanghai, China
| | - Nigel Liverton
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | - Peter T Meinke
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | - David B Olsen
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | | | | | - Ajay Ummat
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | - Jie Wu
- WuXi AppTec, Shanghai, China
| | - Jin Wu
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | - Nicolas Zorn
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
| | - Steven W Ludmerer
- Merck & Co. Inc., Kenilworth, NJ, USA.,Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150, Lansdale, PA, 19446, USA
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Chen K, Lu P, Song R, Zhang J, Tao R, Wang Z, Zhang W, Gu M. Direct-acting antiviral agent efficacy and safety in renal transplant recipients with chronic hepatitis C virus infection: A PRISMA-compliant study. Medicine (Baltimore) 2017; 96:e7568. [PMID: 28746204 PMCID: PMC5627830 DOI: 10.1097/md.0000000000007568] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 06/13/2017] [Accepted: 06/25/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The efficacy and safety of direct-acting antivirals (DAAs) for treating hepatitis C virus (HCV)-infected renal transplant recipients (RTRs) has not been determined. METHODS We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials and assessed the quality of eligible studies using the Joanna Briggs Institute scale. DAA efficacy and safety were assessed using standard mean difference (SMD) with 95% confidence intervals (95%CIs). RESULTS Six studies (360 RTRs) were included. Two hundred thirty six RTRs (98.3%) achieved sustained virological response within 12 weeks; HCV infection was cleared in 239 RTRs after 24-week treatment. Liver function differed significantly pre- and posttreatment (alanine aminotransferase, SMD: 0.96, 95%CIs: 0.65, 1.26; aspartate aminotransferase, SMD: 0.89, 95%CIs: 0.60, 1.18); allograft function pre- and posttreatment was not statistically different (serum creatinine, SMD: -0.13, 95%CIs: -0.38, 0.12; estimated glomerular filtration rate, SMD: 0.20, 95%CIs: -0.11, 0.51). General symptoms (fatigue nausea dizziness or headache) were the most common adverse events (AEs) (39.3%). Severe AEs, that is, anemia, portal vein thrombosis, and streptococcus bacteraemia and pneumonia, were present in 1.1%, 0.6%, and 1.1% of RTRs, respectively. CONCLUSION Our findings suggest that DAAs are highly efficacious and safe for treating HCV-infected RTRs and without significant AE.
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Identification of a flavonoid isolated from plum (Prunus domestica) as a potent inhibitor of Hepatitis C virus entry. Sci Rep 2017. [PMID: 28638096 PMCID: PMC5479801 DOI: 10.1038/s41598-017-04358-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic liver diseases that often requires liver transplantation. The standard therapies are limited by severe side effects, resistance development, high expense and in a substantial proportion of cases, fail to clear the infection which bespeak the need for development of well-tolerated antivirals. Since most of the drug development strategies target the replication stage of viral lifecycle, the identification of entry inhibitors might be crucial especially in case of liver-transplant recipients. In the present study we have evaluated fruits which are known for their hepatoprotective effects in order to screen for entry inhibitors. We report the identification of a flavonoid, rutin, isolated from Prunus domestica as a new HCV entry inhibitor. Characterization and confirmation of the chemical structure was done by LC-ESI-MS, NMR and IR spectral analyses. Rutin significantly inhibited HCV-LP binding to hepatoma cells and inhibited cell-culture derived HCV (HCVcc) entry into hepatoma cells. Importantly, rutin was found to be non-toxic to hepatoma cells. Furthermore, rutin inhibits the early entry stage of HCV lifecycle possibly by directly acting on the viral particle. In conclusion, rutin is a promising candidate for development of anti-HCV therapeutics in the management of HCV infection.
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Gonzalez SA, Fierer DS, Talal AH. Medical and Behavioral Approaches to Engage People Who Inject Drugs Into Care for Hepatitis C Virus Infection. ADDICTIVE DISORDERS & THEIR TREATMENT 2017; 16:S1-S23. [PMID: 28701904 PMCID: PMC5491232 DOI: 10.1097/adt.0000000000000104] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Direct-acting antivirals for hepatitis C virus infection may revolutionize treatment among persons with substance use disorders. Despite persons with substance use disorders having the highest hepatitis C virus prevalence and incidence, the vast majority have not engaged into care for the infection. Previously, interferon-based treatments, with substantial side effects and the propensity to exacerbate mental health conditions, were major disincentives to pursuit of care for the infection. Direct-acting antivirals with viral eradication rates of >90%, significantly improved side effect profiles, and shorter treatment duration are dramatic improvements over prior treatment regimens that should promote widespread hepatitis C virus care among persons with substance use disorders. The major unmet need is strategies to promote persons with substance use disorders engagement into care for hepatitis C virus. Although physical integration of treatment for substance use and co-occurring conditions has been widely advocated, it has been difficult to achieve. Telemedicine offers an opportunity for virtual integration of behavioral and medical treatments that could be supplemented by conventional interventions such as hepatitis C virus education, case management, and peer navigation. Furthermore, harm reduction and strategies to reduce viral transmission are important to cease reinfection among persons with substance use disorders. Widespread prescription of therapy for hepatitis C virus infection to substance users will be required to achieve the ultimate goal of global virus elimination. Combinations of medical and behavioral interventions should be used to promote persons with substance use disorders engagement into and adherence with direct-acting antiviral-based treatment approaches. Ultimately, either physical or virtual colocation of hepatitis C virus and substance use treatment has the potential to improve adherence and consequently treatment efficacy.
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Affiliation(s)
- Stevan A. Gonzalez
- Division of Hepatology, Baylor Simmons Transplant Institute, Fort Worth, TX
| | | | - Andrew H. Talal
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Jacobs School of Medicine, State University of New York at Buffalo, Buffalo, NY
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Liao H, Tan P, Zhu Z, Yan X, Huang J. Sofosbuvir in combination with daclatasvir in liver transplant recipients with HCV infection: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2017; 41:262-271. [PMID: 28082137 DOI: 10.1016/j.clinre.2016.12.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2016] [Revised: 11/23/2016] [Accepted: 12/06/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND Studies focusing on the efficacy of SOF+DCV regimen on liver transplantation recipients with HCV infection are still limited. In the current study, we aimed to perform a systematic review and meta-analysis to evaluate the efficacy and tolerability of SOF+DCV regimen, with or without ribavirin, on post-LT setting. METHODS A systematic literature search of various databases as well as abstracts of major liver diseases conferences was performed. Studies with SVR data in HCV infected liver transplantation recipients treated with daclatasvir/sofosbuvir regimen were included. All statistical analyses were conducted by R version 3.3.1 (The R Foundation for Statistical Computing, Vienna, Austria). RESULTS Seven studies with a total of 379 LT recipients were included in this study. Most of these LT recipients had genotype 1 HCV infection. The overall rate of SVR12 reached 93.3% (95% CI: 83.3% to 99.4%). After excluding the study of Fontana et al., the SVR12 reached 96.8% and heterogeneity was lowered down (P=0.17). In three studies, patients treated with SOF+DCV (n=146) had a higher SVR12 rate than that of patients treated with SOF+DCV+RBV (n=83) (OR 0.33, 95% CI: 0.12 to 0.87; P=0.02). There was no difference in SVR12 between patients infected with HCV genotype 1 and genotype 3 (P=0.57) and no difference was found in SVR12 rate between 12-week therapy and 24-week therapy (P=0.82). The most common adverse effects (AEs) were: anemia 32% (n=64/202), infections 26% (n=38/149), neutropenia 23% (n=35/149), thrombocytopenia 21% (n=32/149) and renal failure 8% (n=12/149). CONCLUSION SOF+DCV±RBV regimen is of high efficacy and tolerability in LT recipients with HCV infection.
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Affiliation(s)
- Haotian Liao
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ping Tan
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zexin Zhu
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiaokai Yan
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jiwei Huang
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu 610041, China.
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38
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Katz SC, Bamboat ZM, Pillarisetty VG, DeMatteo RP. Liver immunology. BLUMGART'S SURGERY OF THE LIVER, BILIARY TRACT AND PANCREAS, 2-VOLUME SET 2017:173-187.e2. [DOI: 10.1016/b978-0-323-34062-5.00010-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Hedegaard DL, Tully DC, Rowe IA, Reynolds GM, Bean DJ, Hu K, Davis C, Wilhelm A, Ogilvie CB, Power KA, Tarr AW, Kelly D, Allen TM, Balfe P, McKeating JA. High resolution sequencing of hepatitis C virus reveals limited intra-hepatic compartmentalization in end-stage liver disease. J Hepatol 2017; 66:28-38. [PMID: 27531641 PMCID: PMC5558612 DOI: 10.1016/j.jhep.2016.07.048] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Revised: 07/22/2016] [Accepted: 07/29/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS The high replication and mutation rate of hepatitis C virus (HCV) results in a heterogeneous population of viral sequences in vivo. HCV replicates in the liver and infected hepatocytes occur as foci surrounded by uninfected cells that may promote compartmentalization of viral variants. Given recent reports showing interferon stimulated gene (ISG) expression in chronic hepatitis C, we hypothesized that local interferon responses may limit HCV replication and evolution. METHODS To investigate the spatial influence of liver architecture on viral replication we measured HCV RNA and ISG mRNA from each of the 8 Couinaud segments of the liver from 21 patients undergoing liver transplant. RESULTS HCV RNA and ISG mRNA levels were comparable across all sites from an individual liver but showed up to 500-fold difference between patients. Importantly, there was no association between ISG and HCV RNA expression across all sites in the liver or plasma. Deep sequencing of HCV RNA isolated from the 8 hepatic sites from two subjects showed a similar distribution of viral quasispecies across the liver and uniform sequence diversity. Single genome amplification of HCV E1E2-envelope clones from 6 selected patients at 2 hepatic sites supported these data and showed no evidence for HCV compartmentalization. CONCLUSIONS We found no differences between the hepatic and plasma viral quasispecies in all patients sampled. We conclude that in end-stage liver disease HCV RNA levels and the genetic pool of HCV envelope sequences are indistinguishable between distant sites in the liver and plasma, arguing against viral compartmentalization. LAY SUMMARY HCV is an RNA virus that exists as a quasispecies of closely related genomes that are under continuous selection by host innate and adaptive immune responses and antiviral drug therapy. The primary site of HCV replication is the liver and yet our understanding of the spatial distribution of viral variants within the liver is limited. High resolution sequencing of HCV and monitoring of innate immune responses at multiple sites across the liver identified a uniform pattern of diversity and argues against viral compartmentalization.
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Affiliation(s)
| | | | - Ian A. Rowe
- Centre for Human Virology, University of Birmingham, Birmingham, UK
| | - Gary M. Reynolds
- NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, UK
| | - David J. Bean
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Ke Hu
- Centre for Human Virology, University of Birmingham, Birmingham, UK
| | | | - Annika Wilhelm
- NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, UK
| | | | - Karen A. Power
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Alexander W. Tarr
- School of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
| | - Deirdre Kelly
- Liver Unit, Birmingham Childrens’ Hospital, Birmingham, UK
| | - Todd M. Allen
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Peter Balfe
- Centre for Human Virology, University of Birmingham, Birmingham, UK.
| | - Jane A. McKeating
- Centre for Human Virology, University of Birmingham, Birmingham, UK,NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, UK,Institute for Advanced Study, Technische Universität München, Lichtenbergstrasse 2a, D-85748 Garching, Germany
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Karam V, Sebagh M, Rifai K, Yilmaz F, Bhangui P, Danet C, Saliba F, Samuel D, Castaing D, Adam R, Feray C. Quality of life 10 years after liver transplantation: The impact of graft histology. World J Transplant 2016; 6:703-711. [PMID: 28058221 PMCID: PMC5175229 DOI: 10.5500/wjt.v6.i4.703] [Citation(s) in RCA: 7] [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: 05/30/2016] [Revised: 09/06/2016] [Accepted: 09/22/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To evaluate the relationship between the state of transplanted liver graft and the recipient quality of life (QOL) of histologically proven lesions in a 10-year post liver transplantation (LT) cohort of patients.
METHODS Seventy-two recipients with a functional first graft at 10 years post-LT underwent liver biopsy and completed a QOL questionnaire. Logistic regression analysis was used to explore associations between histological, clinical and QOL criteria.
RESULTS Ten years after LT, fibrosis was detected in 53% of patients, and affected the general health perception, while ductopenia, present in 36%, affected the well-being (P = 0.05). Hepatic steatosis (HS) was present in 33% of patients and was associated with the worst QOL score on multiple domains. When compared to patients without HS, patients with HS had significantly higher incidence of fibrosis (P = 0.03), hepatitis C virus (HCV) infection (P = 0.007), and more patients had retired from their job (P = 0.03). Recurrent or de novo HCV-associated fibrosis and patient retirement as objective variables, and abdominal pain or discomfort and joint aches or pains as subjective variables, emerged as independent determinants of HS.
CONCLUSION Long-term liver graft lesions, mainly HS presumably as a surrogate marker of HCV infection, may have a substantial impact on QOL 10 years after LT.
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Moore TO, Paradowski M, Ward SE. An atom-efficient and convergent approach to the preparation of NS5A inhibitors by C-H activation. Org Biomol Chem 2016; 14:3307-13. [PMID: 26936019 DOI: 10.1039/c6ob00340k] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
A novel approach of the convergent functionalisation of aryl dibromides to form NS5A type inhibitors using C-H activation is reported. The focus of investigation was to reduce the formation of homodimeric side product, as well as to investigate the scope of different aryl dibromides that were tolerated under the reaction conditions. The C-H activation methodology was found to give a viable synthetic route to NS5A inhibitors, with late stage functionalisation of the core portion of the molecule, albeit with some chemical functionalities not tolerated.
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Affiliation(s)
- Thomas O Moore
- Sussex Drug Discovery Centre, University of Sussex, Brighton, England BN1 9QJ, UK.
| | - Michael Paradowski
- Sussex Drug Discovery Centre, University of Sussex, Brighton, England BN1 9QJ, UK.
| | - Simon E Ward
- Sussex Drug Discovery Centre, University of Sussex, Brighton, England BN1 9QJ, UK.
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Noji S, Seki N, Maeba T, Sakai T, Watanabe E, Maeda K, Fukushima K, Noguchi T, Ogawa K, Toyonaga Y, Negoro T, Kawasaki H, Shiozaki M. Concise SAR Exploration Based on the "Head-to-Tail" Approach: Discovery of PI4KIIIα Inhibitors Bearing Diverse Scaffolds. ACS Med Chem Lett 2016; 7:919-923. [PMID: 27774129 DOI: 10.1021/acsmedchemlett.6b00232] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 08/03/2016] [Indexed: 12/31/2022] Open
Abstract
In typical kinase inhibitor programs, a hinge binder showing best potency with preferential specificity is initially selected, followed by fine-tuning of the accompanying substituents on its core module. A shortcoming of this approach is that the exclusive focus on a single chemotype can endanger all the analogues in the series if a critical shortcoming is revealed. Thus, an early evaluation of structure-activity relationships (SARs) can mitigate unforeseen outcomes within a series of multiple compounds, although there have been very few examples to follow such a policy. PI4KIIIα is one of four mammalian phosphatidylinositol-4 kinases and has recently drawn significant attention as an emerging target for hepatitis C virus (HCV) treatment. In this letter, a novel "head-to-tail" approach to discover a diverse set of PI4KIIIα inhibitors is reported. We believe this method will generate distinct core scaffolds, a rational strategy to circumvent potential risks in general kinase programs.
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Affiliation(s)
- Satoru Noji
- Chemical Research Laboratories, §Biological Pharmacological Research Laboratories, and ‡Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Noriyoshi Seki
- Chemical Research Laboratories, §Biological Pharmacological Research Laboratories, and ‡Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Takaki Maeba
- Chemical Research Laboratories, §Biological Pharmacological Research Laboratories, and ‡Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Takayuki Sakai
- Chemical Research Laboratories, §Biological Pharmacological Research Laboratories, and ‡Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Eiichi Watanabe
- Chemical Research Laboratories, §Biological Pharmacological Research Laboratories, and ‡Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Katsuya Maeda
- Chemical Research Laboratories, §Biological Pharmacological Research Laboratories, and ‡Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Kyoko Fukushima
- Chemical Research Laboratories, §Biological Pharmacological Research Laboratories, and ‡Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Toru Noguchi
- Chemical Research Laboratories, §Biological Pharmacological Research Laboratories, and ‡Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Kazuya Ogawa
- Chemical Research Laboratories, §Biological Pharmacological Research Laboratories, and ‡Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Yukiyo Toyonaga
- Chemical Research Laboratories, §Biological Pharmacological Research Laboratories, and ‡Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Tamotsu Negoro
- Chemical Research Laboratories, §Biological Pharmacological Research Laboratories, and ‡Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Hisashi Kawasaki
- Chemical Research Laboratories, §Biological Pharmacological Research Laboratories, and ‡Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
| | - Makoto Shiozaki
- Chemical Research Laboratories, §Biological Pharmacological Research Laboratories, and ‡Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
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Sun LQ, Mull E, Zheng B, D'Andrea S, Zhao Q, Wang AX, Sin N, Venables BL, Sit SY, Chen Y, Chen J, Cocuzza A, Bilder DM, Mathur A, Rampulla R, Chen BC, Palani T, Ganesan S, Arunachalam PN, Falk P, Levine S, Chen C, Friborg J, Yu F, Hernandez D, Sheaffer AK, Knipe JO, Han YH, Schartman R, Donoso M, Mosure K, Sinz MW, Zvyaga T, Rajamani R, Kish K, Tredup J, Klei HE, Gao Q, Ng A, Mueller L, Grasela DM, Adams S, Loy J, Levesque PC, Sun H, Shi H, Sun L, Warner W, Li D, Zhu J, Wang YK, Fang H, Cockett MI, Meanwell NA, McPhee F, Scola PM. Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing. J Med Chem 2016; 59:8042-60. [PMID: 27564532 DOI: 10.1021/acs.jmedchem.6b00821] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Arvind Mathur
- Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543, United States
| | - Richard Rampulla
- Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543, United States
| | - Bang-Chi Chen
- Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543, United States
| | - Theerthagiri Palani
- Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India
| | - Sivakumar Ganesan
- Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India
| | - Pirama Nayagam Arunachalam
- Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Qi Gao
- Department of Pharmaceutical Development, Bristol-Myers Squibb Research and Development , 1 Squibb Drive, New Brunswick, New Jersey 08903, United States
| | - Alicia Ng
- Department of Pharmaceutical Development, Bristol-Myers Squibb Research and Development , 1 Squibb Drive, New Brunswick, New Jersey 08903, United States
| | | | | | - Stephen Adams
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States
| | | | - Paul C Levesque
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States
| | - Huabin Sun
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States
| | - Hong Shi
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States
| | - Lucy Sun
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States
| | - William Warner
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States
| | - Danshi Li
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States
| | - Jialong Zhu
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States
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Seifert LL, Heinzow H, Kabar I, Christensen S, Hüsing A, Schmidt HHJ. Successful Anti-HCV Therapy of a Former Intravenous Drug User with Sofosbuvir and Daclatasvir in a Peritranspant Setting: A Case Report. AMERICAN JOURNAL OF CASE REPORTS 2016; 17:605-10. [PMID: 27554644 PMCID: PMC4999016 DOI: 10.12659/ajcr.895839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 04/22/2016] [Indexed: 02/02/2023]
Abstract
BACKGROUND Direct-acting antivirals (DAAs) represent a new hallmark in antiviral therapy of hepatitis C virus (HCV). DAAs have been shown to be safe and effective after liver transplantation (LT), but there is little information about their use in peritransplant settings. Former intravenous drug users represent an increasing group seeking HCV treatment. This case report demonstrates the successful peritransplant antiviral treatment of a former intravenous drug user who had been treated in a methadone maintenance program. CASE REPORT The patient was diagnosed with Child B cirrhosis for the first time in 2009. He had a Model for End-stage Liver Disease (MELD) score of 21 and started antiviral therapy with sofosbuvir (SOF) and daclatasvir (DCV) in March 2014. Due to hepatic decompensation, he received a LT in April 2014. Immunosuppression was performed with tacrolimus (TAC) and mycophenolate-mofetil (MMF), and boosted with prednisolone in the initial stage. Four weeks after his LT, the patient presented with an acute renal injury. The patient was discharged one week later after sufficient hydration, discontinuation of non-steroidal anti-phlogistics therapy, and adjustments to his immunosuppressive regimen. At the beginning of his therapy, the number of RNA copies was 13,000 IU/mL. He received 24 weeks of anti-HCV treatment with SOF and DCV; the antiviral treatment was successful and his LT was well tolerated. CONCLUSIONS Treatment of HCV is feasible in a peritransplant setting. The antiviral regimen we used did not seem to have any relevant interactions with the patient's immunosuppressive regimens. Still, the peritransplant setting is a very demanding environment for anti-HCV therapy, and further studies are needed.
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Affiliation(s)
- Leon Louis Seifert
- Department of Transplantation Medicine, University Hospital Münster, Münster, Germany
| | - Hauke Heinzow
- Department of Transplantation Medicine, University Hospital Münster, Münster, Germany
| | - Iyad Kabar
- Department of Transplantation Medicine, University Hospital Münster, Münster, Germany
| | - Stefan Christensen
- Center for Interdisciplinary Medicine (CIM) Infectious Diseases, Münster, Germany
| | - Anna Hüsing
- Department of Transplantation Medicine, University Hospital Münster, Münster, Germany
| | - Hartmut H.-J. Schmidt
- Department of Transplantation Medicine, University Hospital Münster, Münster, Germany
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Miyaaki H, Ichikawa T, Taura N, Miuma S, Honda T, Shibata H, Soyama A, Hidaka M, Takatsuki M, Eguchi S, Nakao K. Impact of Donor and Recipient Single Nucleotide Polymorphisms in Living Liver Donor Transplantation for Hepatitis C. Transplant Proc 2016; 47:2916-9. [PMID: 26707313 DOI: 10.1016/j.transproceed.2015.10.044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Revised: 09/29/2015] [Accepted: 10/20/2015] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Recently, several studies have shown that specific single nucleotide polymorphisms (SNPs) affect liver fibrosis progression in patients with hepatitis C virus (HCV) infection. In this study, we examined the impact of donor and recipient SNPs on the progression of fibrosis after liver transplantation for HCV infection. METHODS This cohort study enrolled 43 patients with HCV infection who underwent liver transplantation at our hospital. We evaluated 5 genotypes (rs4374383, rs2629751, rs9380516, rs8099917, and rs738409) that have been reported to be significant predictors of fibrosis in HCV infection using a Taqman assay. RESULTS Liver fibrosis (stage ≥ F1, New Inuyama classification) was detected at 1 year after liver transplantation in 30 cases (70%). The rs2629751 non-AA-genotype was found to be significantly associated with fibrosis progression at 1 year after liver transplantation (AA:GG or GA = 46%:88%, P < .05). The primary outcome was stage ≥F2 (portoportal septa) or liver-related mortality in 22 patients. The time to stage ≥F2 fibrosis or liver-related mortality was significantly different only in terms of the donor rs2629751 genotype (AA:GG or GA = 5.5 ± 0.6 years:3.6 ± 0.7 years, P = .025). CONCLUSIONS The rs2629751 genotype may be an important predictor of posttransplant outcome in HCV-infected patients. This result might be useful in donor selection for liver transplantation in HCV-infected patients and may guide therapeutic decisions regarding early antiviral treatment.
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Affiliation(s)
- H Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
| | - T Ichikawa
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - N Taura
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - S Miuma
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - T Honda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - H Shibata
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - A Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - M Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - M Takatsuki
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - S Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - K Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Karampitsakos T, Woolard T, Bouros D, Tzouvelekis A. Toll-like receptors in the pathogenesis of pulmonary fibrosis. Eur J Pharmacol 2016; 808:35-43. [PMID: 27364757 DOI: 10.1016/j.ejphar.2016.06.045] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 03/26/2016] [Accepted: 06/27/2016] [Indexed: 02/08/2023]
Abstract
Pulmonary fibrosis (PF) constitutes the end stage of a broad range of heterogeneous interstitial lung diseases, characterized by the destruction of the pulmonary parenchyma, deposition of extracellular matrix and dramatic changes in the phenotype of both fibroblasts and alveolar epithelial cells. More than 200 causes of pulmonary fibrosis have been identified so far, yet the most common form is idiopathic pulmonary fibrosis (IPF). IPF is a lethal lung disorder of unknown etiology with a gradually increasing worldwide incidence and a median survival of 3-5 years from the time of diagnosis. Despite intense research efforts, the pathogenesis remains elusive and no effective treatment is available. Accumulating body of evidence suggests an abnormal wound healing response followed by extracellular matrix deposition, destruction of lung architecture, ultimately leading to respiratory failure. The contribution of immune system in lung fibrogenesis had been largely underscored due to the absence of response to immunosuppressive agents; however, the premise that lung fibrosis has an immunologic background has been recently revived. Toll-like receptors (TLRs) are pattern recognition receptors (PRRs), which link innate and adaptive immune response and regulate wound healing. TLRs promote tissue repair or fibrosis in many disease settings including lung fibrosis, albeit with profound differences depending on the cellular microenvironment. This review summarizes the current state of knowledge regarding the mechanistic implications between TLRs and lung fibrosis and highlights the therapeutic potential of targeting TLR signaling at the ligand or receptor level.
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Affiliation(s)
- Theodoros Karampitsakos
- Academic Department of Pneumonology, Hospital for Diseases of the Chest, "Sotiria", Medical School, University of Athens, Messogion Avenue 152, Athens 11527, Greece
| | - Tony Woolard
- Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, P.O. Box 208057 New Haven, CT, USA
| | - Demosthenes Bouros
- Academic Department of Pneumonology, Hospital for Diseases of the Chest, "Sotiria", Medical School, University of Athens, Messogion Avenue 152, Athens 11527, Greece
| | - Argyris Tzouvelekis
- Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, P.O. Box 208057 New Haven, CT, USA.
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A Schisandra-Derived Compound Schizandronic Acid Inhibits Entry of Pan-HCV Genotypes into Human Hepatocytes. Sci Rep 2016; 6:27268. [PMID: 27252043 PMCID: PMC4890123 DOI: 10.1038/srep27268] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 05/13/2016] [Indexed: 01/06/2023] Open
Abstract
Despite recent progress in the development of hepatitis C virus (HCV) inhibitors, cost-effective antiviral drugs, especially among the patients receiving liver transplantations, are still awaited. Schisandra is a traditional medicinal herb used to treat a range of liver disorders including hepatitis for thousands of years in China. To isolate the bioactive compounds of schisandra for the treatment of HCV infection, we screened a schisandra-extracts library and identified a tetracyclic triterpenoid, schizandronic acid (SZA), as a novel HCV entry inhibitor. Our findings suggested that SZA potently inhibited pan-HCV genotype entry into hepatoma cells and primary human hepatocytes without interfering virus binding on cell surface or internalization. However, virion-cell fusion process was impaired in the presence of SZA, along with the increased host membrane fluidity. We also found that SZA inhibited the spread of HCV to the neighboring cells, and combinations of SZA with interferon or telaprevir resulted in additive synergistic effect against HCV. Additionally, SZA diminished the establishment of HCV infection in vivo. The SZA target is different from conventional direct-acting antiviral agents, therefore, SZA is a potential therapeutic compound for the development of effective HCV entry inhibitors, especially for patients who need to prevent HCV reinfection during the course of liver transplantations.
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48
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Van ND, Falk CS, Sandmann L, Vondran FWR, Helfritz F, Wedemeyer H, Manns MP, Ciesek S, von Hahn T. Modulation of HCV reinfection after orthotopic liver transplantation by fibroblast growth factor-2 and other non-interferon mediators. Gut 2016; 65:1015-23. [PMID: 25800783 PMCID: PMC4893125 DOI: 10.1136/gutjnl-2014-308003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 02/12/2015] [Indexed: 01/11/2023]
Abstract
OBJECTIVE In HCV infected individuals graft infection occurs shortly after orthotopic liver transplantation (OLT). We aimed to describe the composition of the inflammatory response at this time, how it affects the HCV replication cycle and identify novel proviral and antiviral factors. DESIGN We used a Luminex assay to quantify 50 inflammatory mediators in sera before and shortly after OLT. In vitro grown HCV based on the JFH-1 isolate were used to characterise the effects of patient sera and individual mediators on HCV. RESULTS Although the mediator composition is highly variable between individuals, sera drawn immediately post-OLT significantly enhance HCV infectivity compared with control sera from before OLT in about half of the cases. Among 27 non-interferon inflammatory mediators fibroblast growth factor (FGF)-2 stood out as it enhanced HCV RNA replication and release of infectious particles. The effect was concentration-dependent and detectable in dividing and non-dividing cells. Moreover, pharmacological inhibition of FGF-2 receptor signalling abrogated the enhancing effect of FGF-2 and inhibited HCV replication in the absence of serum FGF-2 suggesting that HCV replication is dependent on basal activation of the FGF-2 triggered signalling pathway. Finally, in individuals with chronic HCV infection with high viral load, serum FGF-2 was significantly higher compared with those with low viral load. CONCLUSIONS Although no single mediator may account for this effect, serum shortly post-OLT enhances HCV infection. FGF-2 is a novel endogenous driver of HCV replication and a potential therapeutic target.
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Affiliation(s)
- Nguyen Dinh Van
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany,Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany
| | - Christine S Falk
- Institute of Transplant Immunology, IFB-Tx, Medizinische Hochschule Hannover, Hannover, Germany
| | - Lisa Sandmann
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
| | - Florian W R Vondran
- German Center for Infection Research (DZIF), Hannover, Germany,Department of General, Visceral and Transplantation Surgery, Medizinische Hochschule Hannover, Hannover, Germany
| | - Fabian Helfritz
- German Center for Infection Research (DZIF), Hannover, Germany,Department of General, Visceral and Transplantation Surgery, Medizinische Hochschule Hannover, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany
| | - Sandra Ciesek
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany
| | - Thomas von Hahn
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany,German Center for Infection Research (DZIF), Hannover, Germany,Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany
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Miuma S, Ichikawa T, Miyaaki H, Haraguchi M, Tamada Y, Shibata H, Taura N, Soyama A, Hidaka M, Takatsuki M, Eguchi S, Nakao K. Efficacy and Tolerability of Pegylated Interferon and Ribavirin in Combination with Simeprevir to Treat Hepatitis C Virus Infections After Living Donor Liver Transplantation. J Interferon Cytokine Res 2016; 36:358-66. [DOI: 10.1089/jir.2015.0147] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Affiliation(s)
- Satoshi Miuma
- Department of Gastroenterology, Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Tatsuki Ichikawa
- Department of Gastroenterology, Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
- Department of Gastroenterology, Nagasaki Harbor Medical Center City Hospital, Nagasaki, Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology, Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Masafumi Haraguchi
- Department of Gastroenterology, Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Yoko Tamada
- Department of Gastroenterology, Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Hidetaka Shibata
- Department of Gastroenterology, Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Naota Taura
- Department of Gastroenterology, Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Akihiko Soyama
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Masaaki Hidaka
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Mitsuhisa Takatsuki
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Susumu Eguchi
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology, Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
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50
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Vieyres G, Welsch K, Gerold G, Gentzsch J, Kahl S, Vondran FWR, Kaderali L, Pietschmann T. ABHD5/CGI-58, the Chanarin-Dorfman Syndrome Protein, Mobilises Lipid Stores for Hepatitis C Virus Production. PLoS Pathog 2016; 12:e1005568. [PMID: 27124600 PMCID: PMC4849665 DOI: 10.1371/journal.ppat.1005568] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 03/22/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) particles closely mimic human very-low-density lipoproteins (VLDL) to evade humoral immunity and to facilitate cell entry. However, the principles that govern HCV association with VLDL components are poorly defined. Using an siRNA screen, we identified ABHD5 (α/β hydrolase domain containing protein 5, also known as CGI-58) as a new host factor promoting both virus assembly and release. ABHD5 associated with lipid droplets and triggered their hydrolysis. Importantly, ABHD5 Chanarin-Dorfman syndrome mutants responsible for a rare lipid storage disorder in humans were mislocalised, and unable to consume lipid droplets or support HCV production. Additional ABHD5 mutagenesis revealed a novel tribasic motif that does not influence subcellular localization but determines both ABHD5 lipolytic and proviral properties. These results indicate that HCV taps into the lipid droplet triglyceride reservoir usurping ABHD5 lipase cofactor function. They also suggest that the resulting lipid flux, normally devoted to VLDL synthesis, also participates in the assembly and release of the HCV lipo-viro-particle. Altogether, our study provides the first association between the Chanarin-Dorfman syndrome protein and an infectious disease and sheds light on the hepatic manifestations of this rare genetic disorder as well as on HCV morphogenesis. HCV replication is linked to the host lipid metabolism, and virions are secreted as lipo-viro-particles whose density, size and biochemical content resemble VLDL. HCV assembles close to lipid droplets and is released via the secretory pathway, but it remains unclear how it accesses the VLDL assembly pathway. In this study, we identified ABHD5 as a new host factor supporting HCV assembly and release. ABHD5 is a lipid droplet-associated lipase cofactor. In hepatocytes, ABHD5 was proposed to promote the recruitment of triglycerides from cytosolic towards luminal lipid droplets by mediating a cycle of phospholipid hydrolysis/re-esterification. Our data suggest that this ABHD5-dependent lipid transfer is not only required for VLDL maturation, but also for HCV assembly and virion release, indicating that lipid remodelling impacts on both assembly and virus transport. Finally, ABHD5 is associated with the Chanarin-Dorfman syndrome, a rare human genetic lipid metabolism disorder. We found that the Chanarin-Dorfman syndrome mutants were unable to support HCV assembly, pointing at a new host polymorphism that could determine susceptibility to HCV infection. Altogether, our results establish a new link between HCV, VLDL assembly and lipid remodeling pathways and open new possibilities to study the etiology of the liver manifestations of the Chanarin-Dorfman syndrome.
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Affiliation(s)
- Gabrielle Vieyres
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Kathrin Welsch
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Gisa Gerold
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Juliane Gentzsch
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Sina Kahl
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Florian W. R. Vondran
- German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Braunschweig, Germany
- ReMediES, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Lars Kaderali
- Institute for Bioinformatics, University Medicine Greifswald, Greifswald, Germany
| | - Thomas Pietschmann
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
- German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Braunschweig, Germany
- * E-mail:
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