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1
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Jutras G, Mehta N, Lai JC. Differential aging trends among candidates for liver transplant with and without HCC. Liver Transpl 2025; 31:716-726. [PMID: 39819830 PMCID: PMC12116243 DOI: 10.1097/lvt.0000000000000568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 12/18/2024] [Indexed: 01/19/2025]
Abstract
HCC has become a leading indication for liver transplant (LT), with HCC registrants increasing more than 6-fold in the past 2 decades, accompanied by a significant rise in older candidates. Given this trend and the influence of hepatitis C (HCV) treatments, updated data on aging and changing etiologies in older patients with HCC are needed. This study examines age trends, clinical characteristics, and transplant outcomes by comparing older (70+), younger patients with HCC, and patients without HCC. All adult candidates for LT (18+) in the UNOS/OPTN registry (2012-2022) were analyzed and categorized by HCC status and age (<70 or 70+). Regression coefficients compared HCC and non-HCC registrants and recipients by age group. The aging trend among LT registrants was more pronounced in patients with HCC. From 2012 to 2022, the mean age of HCC registrants rose from 58.7 to 62.9, with those aged 70+ increasing from 4.2% to 15.0%. Non-HCC registrants saw minimal change, with a stable mean age of 53 years and a modest rise in those 70+ from 2.1% to 4.7%. HCV prevalence among patients with HCC decreased from 37.5% to 27.4%, while patients without HCC dropped from 14.8% to 5%. Posttransplant outcomes for older HCC recipients remained favorable, with 1-year and 5-year survival rates of 91% and 71%, respectively, comparable to older patients without HCC (87% and 69%). Among over 132,000 LT registrants from 2012 to 2022, the age of HCC candidates increased, with a growing proportion aged 70 and older, while the age and proportion of older adults among non-HCC registrants remained stable. This demographic shift underscores the importance of enhanced frailty assessments to improve outcomes for older patients with HCC.
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Affiliation(s)
- Gabrielle Jutras
- Department of Medicine, Division of Gastroenterology and Hepatology, University of California, San Francisco, California, USA
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2
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Chanan EL, Wagener G, Whitlock EL, Berger JC, McAdams-DeMarco MA, Yeh JS, Nunnally ME. Perioperative Considerations in Older Kidney and Liver Transplant Recipients: A Review. Transplantation 2024; 108:e346-e356. [PMID: 38557579 PMCID: PMC11442682 DOI: 10.1097/tp.0000000000005000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
With the growth of the older adult population, the number of older adults waitlisted for and undergoing kidney and liver transplantation has increased. Transplantation is an important and definitive treatment for this population. We present a contemporary review of the unique preoperative, intraoperative, and postoperative issues that patients older than 65 y face when they undergo kidney or liver transplantation. We focus on geriatric syndromes that are common in older patients listed for kidney or liver transplantation including frailty, sarcopenia, and cognitive dysfunction; discuss important considerations for older transplant recipients, which may impact preoperative risk stratification; and describe unique challenges in intraoperative and postoperative management for older patients. Intraoperative challenges in the older adult include using evidence-based best anesthetic practices, maintaining adequate perfusion pressure, and using minimally invasive surgical techniques. Postoperative concerns include controlling acute postoperative pain; preventing cardiovascular complications and delirium; optimizing immunosuppression; preventing perioperative kidney injury; and avoiding nephrotoxicity and rehabilitation. Future studies are needed throughout the perioperative period to identify interventions that will improve patients' preoperative physiologic status, prevent postoperative medical complications, and improve medical and patient-centered outcomes in this vulnerable patient population.
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Affiliation(s)
- Emily L Chanan
- Department of Anesthesiology, Perioperative Care and Pain Medicine, NYU Grossman School of Medicine, New York, NY
| | - Gebhard Wagener
- Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY
| | - Elizabeth L Whitlock
- Department of Anesthesia & Perioperative Care, University of California, San Francisco, San Francisco, CA
| | - Jonathan C Berger
- Department of Surgery, NYU Grossman School of Medicine, New York, NY
| | - Mara A McAdams-DeMarco
- Department of Surgery, NYU Grossman School of Medicine, New York, NY
- Department of Population Health, NYU Grossman School of Medicine, New York, NY
| | - Joseph S Yeh
- Department of Anesthesiology, Perioperative Care and Pain Medicine, NYU Grossman School of Medicine, New York, NY
| | - Mark E Nunnally
- Department of Anesthesiology, Perioperative Care and Pain Medicine, NYU Grossman School of Medicine, New York, NY
- Department of Surgery, NYU Grossman School of Medicine, New York, NY
- Department of Neurology, NYU Grossman School of Medicine, New York, NY
- Department of Medicine, NYU Grossman School of Medicine, New York, NY
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3
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Lyu CA, Shen Y, Zhang P. Zooming in and out: Exploring RNA Viral Infections with Multiscale Microscopic Methods. Viruses 2024; 16:1504. [PMID: 39339980 PMCID: PMC11437419 DOI: 10.3390/v16091504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 09/19/2024] [Accepted: 09/22/2024] [Indexed: 09/30/2024] Open
Abstract
RNA viruses, being submicroscopic organisms, have intriguing biological makeups and substantially impact human health. Microscopic methods have been utilized for studying RNA viruses at a variety of scales. In order of observation scale from large to small, fluorescence microscopy, cryo-soft X-ray tomography (cryo-SXT), serial cryo-focused ion beam/scanning electron microscopy (cryo-FIB/SEM) volume imaging, cryo-electron tomography (cryo-ET), and cryo-electron microscopy (cryo-EM) single-particle analysis (SPA) have been employed, enabling researchers to explore the intricate world of RNA viruses, their ultrastructure, dynamics, and interactions with host cells. These methods evolve to be combined to achieve a wide resolution range from atomic to sub-nano resolutions, making correlative microscopy an emerging trend. The developments in microscopic methods provide multi-fold and spatial information, advancing our understanding of viral infections and providing critical tools for developing novel antiviral strategies and rapid responses to emerging viral threats.
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Affiliation(s)
- Cheng-An Lyu
- Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK;
- Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX3 7BN, UK
| | - Yao Shen
- Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK;
| | - Peijun Zhang
- Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK;
- Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX3 7BN, UK
- Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK
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Lerosey L, Ksiasek E, Abrahamowicz M, Antoine C, Dharancy S, Dumortier J, Doussot A, Di Martino V, Houssel-Debry P, Conti F, Francoz C, Pageaux GP, Salame E, Faitot F, Coilly A, Hardwigsen J, Decaens T, Chermak F, Muscari F, Anty R, Duvoux C, Abergel A, Minello A, Mouillot T, Binquet C, Latournerie M. Recipient age influences survival after liver transplant: Results of the French national cohort 2007-2017. Liver Int 2024; 44:1396-1408. [PMID: 38451069 DOI: 10.1111/liv.15867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 01/11/2024] [Accepted: 01/31/2024] [Indexed: 03/08/2024]
Abstract
BACKGROUND In recent years, age at liver transplantation (LT) has markedly increased. In the context of organ shortage, we investigated the impact of recipient age on post-transplantation mortality. METHODS All adult patients who received a first LT between 2007 and 2017 were included in this cross-sectional study. Recipients' characteristics at the time of listing, donor and surgery data, post-operative complications and follow-up of vital status were retrieved from the national transplantation database. The impact of age on 5-year overall mortality post-LT was estimated using a flexible multivariable parametric model which was also used to estimate the association between age and 10-year net survival, accounting for expected age- and sex-related mortality. RESULTS Among the 7610 patients, 21.4% were aged 60-65 years, and 15.7% over 65. With increasing age, comorbidities increased but severity of liver disease decreased. Older recipient age was associated with decreased observed survival at 5 years after LT (p < .001), with a significant effect particularly during the first 2 years. The linear increase in the risk of death associated with age does not allow any definition of an age's threshold for LT (p = .832). Other covariates associated with an increased risk of 5-year death were dialysis and mechanical ventilation at transplant, transfusion during LT, hepatocellular carcinoma and donor age. Ten-year flexible net survival analysis confirmed these results. CONCLUSION Although there was a selection process for older recipients, increasing age at LT was associated with an increased risk of death, particularly in the first years after LT.
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Affiliation(s)
- Lea Lerosey
- Service d'Hépato-gastro-entérologie, CHU Dijon-Bourgogne, Dijon, France
| | - Elea Ksiasek
- CHU Dijon Bourgogne, INSERM, Université de Bourgogne, CIC 1432, Module Épidémiologie Clinique, Dijon, France
| | - Michal Abrahamowicz
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada
| | - Corinne Antoine
- Agence de Biomédecine, Direction Prélèvement Greffe Organes-Tissus, Saint-Denis, France
| | - Sébastien Dharancy
- Service des maladies de l'appareil digestif, CHRU de Lille, Lille, France
- Université Lille 2 and Inserm U795, Lille, France
| | - Jérôme Dumortier
- Service d'Hépa-gastroentérologie, Hôpital Édouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Alexandre Doussot
- Service de Chirurgie Hépato-biliaire, Hôpital Jean Minjoz, Besançon, France
| | | | | | - Filomena Conti
- Service d'Hépatologie, Hôpital Pitié-Salpêtrière, Assistance Publique des Hôpitaux de Paris, Paris, France
| | - Claire Francoz
- Service d'hépatologie, Hôpital Beaujon, Assistance Publique des Hôpitaux de Paris, Paris, France
| | | | - Ephrem Salame
- Service de chirurgie digestive et transplantation hépatique, CHU Tours, Tours, France
| | | | - Audrey Coilly
- Service d'Hépatologie, Hôpital Paul Brousse, Assistance Publique des Hôpitaux de Paris, Paris, France
| | - Jean Hardwigsen
- Service de chirurgie digestive et transplantation hépatique, CHU Marseille, Marseille, France
| | - Thomas Decaens
- Service d'hépato-gastroentérologie, CHU Grenoble, Grenoble, France
| | - Faiza Chermak
- Service d'Hépato-gastro-entérologie, CHU Bordeaux, Bordeaux, France
| | - Fabrice Muscari
- Service Chirurgie Hépato-Bilio-Pancréatique et Transplantation, CHU Toulouse, Toulouse, France
| | | | | | - Armand Abergel
- Hépatologie, CHU de Clermont Ferrand, Clermont-Ferrand, France
| | - Anne Minello
- Service d'Hépato-gastro-entérologie, CHU Dijon-Bourgogne, Dijon, France
| | - Thomas Mouillot
- Service d'Hépato-gastro-entérologie, CHU Dijon-Bourgogne, Dijon, France
| | - Christine Binquet
- CHU Dijon Bourgogne, INSERM, Université de Bourgogne, CIC 1432, Module Épidémiologie Clinique, Dijon, France
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Gómez-Gavara C, Lim C, Adam R, Zieniewicz K, Karam V, Mirza D, Heneghan M, Pirenne J, Cherqui D, Oniscu G, Watson C, Schneeberger S, Boudjema K, Fondevila C, Pratschke J, Salloum C, Esposito F, Esono D, Lahat E, Feray C, Azoulay D. The impact of advanced patient age in liver transplantation: a European Liver Transplant Registry propensity-score matching study. HPB (Oxford) 2022; 24:974-985. [PMID: 34872865 DOI: 10.1016/j.hpb.2021.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 11/05/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND The futility of liver transplantation in elderly recipients remains under debate in the HCV eradication era. METHODS The aim was to assess the effect of older age on outcome after liver transplantation. We used the ELTR to study the relationship between recipient age and post-transplant outcome. Young and elderly recipients were compared using a PSM method. RESULTS A total of 10,172 cases were analysed. Recipient age >65 years was identified as an independent risk factor associated with reduced patient survival (HR:1.42 95%CI:1.23-1.65,p < 0.001). After PSM, 2124 patients were matched, and the same association was found between elderly recipients and patient survival and graft survival (p < 0.001). As hepatocellular carcinoma and alcoholic cirrhosis were independent prognostic factors for patient and graft survival a propensity score-matching was performed for each. Patient and graft survival were significantly worse (p < 0.05) in the alcoholic cirrhosis elderly group. However, patient and graft survival in the hepatocellular carcinoma cohort were similar (p > 0.05) between groups. CONCLUSION Liver transplantation is an acceptable and safe curative option for elderly transplant candidates, with worse long-term outcomes compare to young candidates. The underlying liver disease for liver transplantation has a significant impact on the selection of elderly patients.
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Affiliation(s)
- Concepción Gómez-Gavara
- Department of Hepatobiliary and Pancreatic Surgery and Liver Transplantation, Vall D´Hebrón Hospital, Barcelona, Spain
| | - Chetana Lim
- Department of Hepatobiliary and Pancreatic Surgery and Liver Transplantation, Pitié-Salpêtrière Hospital, Paris, France
| | - René Adam
- Department of Hepatobiliary and Pancreatic Surgery and Liver Transplantation, Paul Brousse Hospital, Villejuif, France
| | - Krzysztof Zieniewicz
- Department of General and Liver Surgery, Medical University of Warsaw, Banacha, Poland
| | - Vincent Karam
- Department of Hepatobiliary and Pancreatic Surgery and Liver Transplantation, Paul Brousse Hospital, Villejuif, France
| | - Darius Mirza
- HPB Surgery, University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK
| | | | - Jacques Pirenne
- Abdominal Transplant Surgery, Transplantation Research Group, KU, Leuven, Belgium
| | - Daniel Cherqui
- Department of Hepatobiliary and Pancreatic Surgery and Liver Transplantation, Paul Brousse Hospital, Villejuif, France
| | - Gabriel Oniscu
- Scottish Liver Transplant Unit, Edinburgh Transplant Centre, Edinburgh, United Kingdom
| | - Christopher Watson
- Department of Surgery, Addenbrooke´s Hospital, Cambridge, United Kingdom
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Karim Boudjema
- Department of Hepatobiliary and Digestive Surgery, Pontchaillou University Hospital, 2 Rue Henri le Guilloux, 35000, Rennes, France
| | - Constantino Fondevila
- General & Digestive Surgery, Institut Clínic de Malalties Digestives I Metabòliques, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| | - Johann Pratschke
- Department of Surgery, Campus Mitte/Campus Virchow, Charité University Hospital, Berlin, Germany
| | - Chady Salloum
- Department of Hepatobiliary and Pancreatic Surgery and Liver Transplantation, Paul Brousse Hospital, Villejuif, France
| | - Francesco Esposito
- Department of Digestive Surgery, Grand Hôpital de L'Est Francilien, Meaux, France
| | - Daniel Esono
- Department of Information and Communications Technologies, Universitat Pompeu Fabra, Barcelona, Spain
| | - Eylon Lahat
- Department of Hepatobiliary and Pancreatic Surgery and Transplantation, Sheba Medical Center, Faculty of Medicine Tel Aviv University, Israel
| | - Cyrille Feray
- Department of Hepatobiliary and Pancreatic Surgery and Liver Transplantation, Paul Brousse Hospital, Villejuif, France
| | - Daniel Azoulay
- Department of Hepatobiliary and Pancreatic Surgery and Transplantation, Sheba Medical Center, Faculty of Medicine Tel Aviv University, Israel; Department of Hepatobiliary and Pancreatic Surgery and Liver Transplantation, Paul Brousse Hospital, Villejuif, France.
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6
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Akdur A, Karakaya E, Ayvazoglu Soy HE, Yarbug Karakayalı F, Moray G, Haberal M. Clinical Outcomes of Liver Transplantation for Patients Over 60 Years Old: A Single-Center Experience. EXP CLIN TRANSPLANT 2022; 20:31-38. [PMID: 35384805 DOI: 10.6002/ect.mesot2021.o14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Although advanced age is no longer considered an absolute contraindication for liver transplant, transplant in elderly patients with comorbid diseases remains debatable because of high risks with surgery. Here, we report patient outcomes in this population. MATERIALS AND METHODS We retrospectively reviewed medical records of 276 liver transplant recipients, grouped by age. Group 1 (≤59 years old) consisted of 247 recipients, and group 2 (≥60 years old) consisted of 29 recipients. Reviewed data included age, sex, cause of liver disease, presence of hepatocellular carcinoma, Child-Pugh and Model for End-Stage Liver Disease scores, survival, and posttransplant complications. RESULTS In both groups, most patients (n = 108) required liver transplant for hepatitis B virus. Mean age was 40 ± 12.3 and 63 ± 2.3 years in groups 1 and 2, respectively, with more men than women in both group 1 (71.7% vs 28.3%) and group 2 (75.9% vs 24.1%). No significant differences were shown between groups for patient characteristics, except group 1 had significantly higher Model for End-Stage Liver Disease score. Group 1 mean survival time was 10.2 ± 0.6 years, with patient survival rates at 1, 5, 10, and 15 years of 65.5%, 53%, 46.3%, and 40%, respectively. In group 2, respective results were 10.6 ± 1.3 years and 75.9%, 68.6%, 61%, and 48.8% (no significant difference vs group 1). CONCLUSIONS Liver transplant recipients >60 years of age had survival rates, acute rejection rates, and complications similar to younger recipients. Liver transplant should not be withheld from older recipients on the basis of age alone. However, comprehensive screening for comorbidities should be performed.
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Affiliation(s)
- Aydıncan Akdur
- From the Department of General Surgery, Division of Transplantation, Baskent University, Ankara, Turkey
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Garriga D, Chichón FJ, Calisto BM, Ferrero DS, Gastaminza P, Pereiro E, Pérez-Berna AJ. Imaging of Virus-Infected Cells with Soft X-ray Tomography. Viruses 2021; 13:2109. [PMID: 34834916 PMCID: PMC8618346 DOI: 10.3390/v13112109] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 02/07/2023] Open
Abstract
Viruses are obligate parasites that depend on a host cell for replication and survival. Consequently, to fully understand the viral processes involved in infection and replication, it is fundamental to study them in the cellular context. Often, viral infections induce significant changes in the subcellular organization of the host cell due to the formation of viral factories, alteration of cell cytoskeleton and/or budding of newly formed particles. Accurate 3D mapping of organelle reorganization in infected cells can thus provide valuable information for both basic virus research and antiviral drug development. Among the available techniques for 3D cell imaging, cryo-soft X-ray tomography stands out for its large depth of view (allowing for 10 µm thick biological samples to be imaged without further thinning), its resolution (about 50 nm for tomographies, sufficient to detect viral particles), the minimal requirements for sample manipulation (can be used on frozen, unfixed and unstained whole cells) and the potential to be combined with other techniques (i.e., correlative fluorescence microscopy). In this review we describe the fundamentals of cryo-soft X-ray tomography, its sample requirements, its advantages and its limitations. To highlight the potential of this technique, examples of virus research performed at BL09-MISTRAL beamline in ALBA synchrotron are also presented.
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Affiliation(s)
- Damià Garriga
- ALBA Synchrotron Light Source, 08290 Cerdanyola del Vallès, Spain; (D.G.); (B.M.C.); (E.P.)
| | - Francisco Javier Chichón
- Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; (F.J.C.); (P.G.)
| | - Bárbara M. Calisto
- ALBA Synchrotron Light Source, 08290 Cerdanyola del Vallès, Spain; (D.G.); (B.M.C.); (E.P.)
| | - Diego S. Ferrero
- Institut de Biologia Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Parc Científic de Barcelona, 08028 Barcelona, Spain;
| | - Pablo Gastaminza
- Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; (F.J.C.); (P.G.)
| | - Eva Pereiro
- ALBA Synchrotron Light Source, 08290 Cerdanyola del Vallès, Spain; (D.G.); (B.M.C.); (E.P.)
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Pietrosi G, Russelli G, Barbera F, Curcio G, Tuzzolino F, Gallo A, Volpes R, Vizzini G, Conaldi PG. Direct-acting antivirals ability to clear intestinal HCV-RNA in liver transplant patients. Transpl Infect Dis 2020; 22:e13345. [PMID: 32495971 PMCID: PMC7685120 DOI: 10.1111/tid.13345] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 02/21/2020] [Accepted: 05/24/2020] [Indexed: 12/11/2022]
Abstract
The hepatitis C virus mainly infects the liver but is also able to infect and replicate in other body compartments by creating an extra-hepatic reservoir that may influence the persistence of the infection after transplantation. It is unknown whether antiviral drugs affect the viral extra-hepatic sites. We evaluated the ability of pegylated/interferon + ribavirin and sofosbuvir + ribavirin to clear the virus from the gastrointestinal mucosa of liver-transplanted patients with HCV recurrence after transplantation. A total of 51 liver-transplanted patients, 30 treated with pegylated/interferon + ribavirin (ERA1) and 21 treated with sofosbuvir + ribavirin (ERA2), were enrolled, and blood serum and gastrointestinal tissues analyzed for the presence of HCV-RNA. In the ERA1 group, the 46.6% of patients had a sustained viral response to antiviral treatment, and gastrointestinal biopsies were positive for HCV in 73.3% of cases, 54.5% of responders, and 45.5% of non-responders. In the ERA2 group, the 66.6% had a sustained viral response, and gastrointestinal HCV-RNA was present in the 14.3% of patients, all relapsers. Sofosbuvir + ribavirin cleared the intestinal HCV in 85.7% of patients with recurrent HCV infection, while pegylated/interferon + ribavirin cleared it in 26.6% of treated patients, demonstrating the better effectiveness of new direct antiviral agents in clearing HCV intestinal reservoir.
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Affiliation(s)
- Giada Pietrosi
- Hepatology Unit, Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS ISMETT, Palermo, Italy
| | | | | | - Gabriele Curcio
- Endoscopy Service, Department of Diagnostic and Therapeutic Services, IRCCS ISMETT, Palermo, Italy
| | | | - Alessia Gallo
- Department of Research, IRCCS ISMETT, Palermo, Italy
| | - Riccardo Volpes
- Hepatology Unit, Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS ISMETT, Palermo, Italy
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Morales MK, Lambing T, Husson J. Review: Evaluation and Management of the HIV/HCV Co-Infected Kidney or Liver Transplant Candidate. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2020. [DOI: 10.1007/s40506-020-00220-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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10
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Tenner L, Melhado TV, Bobadilla R, Turner BJ, Morgan R. The Cost of Cure: Barriers to Access for Hepatitis C Virus Treatment in South Texas. J Oncol Pract 2019; 15:61-63. [PMID: 30668219 DOI: 10.1200/jop.18.00525] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
Affiliation(s)
- Laura Tenner
- Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, San Antonio, TX.,Joe R. and Teresa Lozano Long School of Medicine, UT Health San Antonio, San Antonio, TX
| | - Trisha V Melhado
- Joe R. and Teresa Lozano Long School of Medicine, UT Health San Antonio, San Antonio, TX
| | - Raudel Bobadilla
- Joe R. and Teresa Lozano Long School of Medicine, UT Health San Antonio, San Antonio, TX
| | - Barbara J Turner
- Joe R. and Teresa Lozano Long School of Medicine, UT Health San Antonio, San Antonio, TX
| | - Robert Morgan
- School of Public Health, University of Texas Health Science Center at Houston, Houston, TX
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11
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Shoreibah M, Romano J, Sims OT, Guo Y, Jones D, Venkata K, Kommineni V, Orr J, Fitzmorris P, Massoud OI. Effect of Hepatitis C Treatment on Renal Function in Liver Transplant Patients. J Clin Transl Hepatol 2018; 6:391-395. [PMID: 30637216 PMCID: PMC6328736 DOI: 10.14218/jcth.2018.00026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 06/17/2018] [Accepted: 06/23/2018] [Indexed: 12/13/2022] Open
Abstract
Background and Aims: Hepatitis C Virus (HCV) is uniformly recurrent after liver transplant (LT) and recurrence is associated with an increased risk of mortality. Immunosuppressive medications increase the risk of chronic kidney disease, and the presence of chronic kidney disease presents a challenge for HCV treatment in LT recipients. The aim of this study was to assess changes in glomerular filtration rates (GFRs) of LT recipients receiving HCV treatment. Methods: This is a retrospective study of LT patients who received HCV treatment between 2015 and 2016 (n = 60). The outcomes of interest were differences in serum creatinine levels and in GFR, measured at treatment initiation and at 24 weeks after treatment. The average age of the patients was 59 years-old, and 17% were cirrhotic and 67% were treatment-experienced. All patients received sofosbuvir/ledipasvir without ribavirin. Results: All patients achieved sustained virologic response at 12 weeks after treatment (SVR12). At baseline, 55% of patients had GFR <60 mL/min per 1.73 m2. Among those patients, GFR did not change in 18%, 33% had improved GFR, and 48% had worsened GFR. Up to 45% of the patients had a GFR >60 mL/min per 1.73 m2. Among those patients, GFR did not change in 81%, and 19% had worsened GFR. In the entire cohort, 65% of patients had improved or stable GFR and 35% had worsened GFR. The average change in serum creatinine between baseline and 24 weeks was 0.10 (p = 0.18). Conclusions: This study showed improved or unchanged GFR in 65% and worsened GFR in 35% of LT recipients who achieved SVR12. Worsening of GFR was more frequently encountered in those with impaired renal function at baseline. Caution should be used when treating HCV in LT recipients, especially those with baseline status of renal impairment.
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Affiliation(s)
- Mohamed Shoreibah
- Division of Gastroenterology & Hepatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - John Romano
- Department of Internal Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Omar T. Sims
- Department of Social Work, College of Arts and Sciences, University of Alabama at Birmingham, Birmingham, AL, USA
- Department of Health Behavior, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA
- Center for AIDS Research, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Yuqi Guo
- School of Social Work, University of Alabama, Tuscaloosa, AL, USA
| | - DeAnn Jones
- Department of Pharmacology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Krishna Venkata
- Department of Internal Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Vishnu Kommineni
- Department of Internal Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jordan Orr
- Division of Gastroenterology and Hepatology, Department of Medicine, Vanderbilt University, Nashville, TN, USA
| | - Paul Fitzmorris
- Division of Gastroenterology & Hepatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Omar I. Massoud
- Division of Gastroenterology & Hepatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
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12
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Salam KA, Wang RY, Grandinetti T, De Giorgi V, Alter HJ, Allison RD. Binding of Free and Immune Complex-Associated Hepatitis C Virus to Erythrocytes Is Mediated by the Complement System. Hepatology 2018; 68:2118-2129. [PMID: 29742812 PMCID: PMC6226377 DOI: 10.1002/hep.30087] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 04/26/2018] [Accepted: 05/04/2018] [Indexed: 12/20/2022]
Abstract
Erythrocytes bind circulating immune complexes (ICs) and facilitate IC clearance from the circulation. Chronic hepatitis C virus (HCV) infection is associated with IC-related disorders. In this study, we investigated the kinetics and mechanism of HCV and HCV-IC binding to and dissociation from erythrocytes. Cell culture-produced HCV was mixed with erythrocytes from healthy blood donors, and erythrocyte-associated virus particles were quantified. Purified complement proteins, complement-depleted serum, and complement receptor antibodies were used to investigate complement-mediated HCV-erythrocyte binding. Purified HCV-specific immunoglobulin G (IgG) from a chronic HCV-infected patient was used to study complement-mediated HCV-IC/erythrocyte binding. Binding of HCV to erythrocytes increased 200- to 1,000-fold after adding complement active human serum in the absence of antibody. Opsonization of free HCV occurred within 10 minutes, and peak binding to erythrocytes was observed at 20-30 minutes. Complement protein C1 was required for binding, whereas C2, C3, and C4 significantly enhanced binding. Complement receptor 1 (CR1, CD35) antibodies blocked the binding of HCV to erythrocytes isolated from chronically infected HCV patients and healthy blood donors. HCV-ICs significantly enhanced complement-mediated binding to erythrocytes compared to unbound HCV. Dissociation of complement-opsonized HCV from erythrocytes depended on the presence of Factor I. HCV released by Factor I bound preferentially to CD19+ B cells compared to other leukocytes. Conclusion: These results demonstrate that complement mediates the binding of free and IC-associated HCV to CR1 on erythrocytes and provide a mechanistic rationale for investigating the differential phenotypic expression of HCV-IC-related disease.
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Affiliation(s)
- Kazi Abdus Salam
- Infectious Diseases Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA,Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi-6205, Bangladesh
| | - Richard Y. Wang
- Infectious Diseases Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Teresa Grandinetti
- Infectious Diseases Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Valeria De Giorgi
- Infectious Diseases Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Harvey J. Alter
- Infectious Diseases Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Robert D. Allison
- Infectious Diseases Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
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13
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Haugen CE, Holscher CM, Garonzik-Wang J, Pozo M, Warsame F, McAdams-DeMarco M, Segev DL. National Trends in Liver Transplantation in Older Adults. J Am Geriatr Soc 2018; 66:2321-2326. [PMID: 30325004 PMCID: PMC6289760 DOI: 10.1111/jgs.15583] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 07/27/2018] [Accepted: 07/31/2018] [Indexed: 12/29/2022]
Abstract
OBJECTIVES To explore trends in liver transplantation (LT) and outcomes for older recipients for evaluation, counseling, and appropriate referral of this vulnerable group of older adults. DESIGN Prospective national cohort study. SETTING Scientific Registry of Transplant Recipients (January 1, 2003-December 31, 2016). PARTICIPANTS Older (aged ≥ 65) deceased donor liver-only transplant recipients (n=8,627). MEASUREMENTS We evaluated temporal changes in recipient, donor, and transplant characteristics and post-LT length of stay (LOS), acute rejection, graft loss, and mortality using logistic regression and Cox proportional hazards. RESULTS LT in older adults almost quadrupled, from 263 in 2003 (9.5% of total LTs that year) to 1,144 in 2016 (20.7% of total LTs). Recent recipients were more likely to be female and African American and have a higher body mass index and Model for End-Stage Liver Disease score. Hepatitis C, nonalcoholic steatohepatitis, and hepatocellular carcinoma were the most common indications for LT in recent recipients. Odds of LOS longer than 2 weeks decreased 34% from 2003-06 to 2013-16 (adjusted odds ratio (aOR)=0.66, 95% confidence interval (CI)=0.57-0.76, P < .001), 1-year acute rejection decreased 30% (aOR=0.70, 95% CI=0.56-0.88, P = .002), all-cause graft loss decreased 54% (adjusted hazard ratio (aHR)=0.46, 95% CI=0.40-0.52, P < .001), and mortality decreased 57% (aHR=0.43, 95% CI=0.38-0.49, P < .001). CONCLUSION Despite the substantial increase in the number of older adults undergoing LT and the severity of their condition, LOS, rejection, graft loss, and mortality have significantly decreased over time. These trends can help guide appropriate LT referral and counseling in older adults with end-stage liver disease. J Am Geriatr Soc 66:2321-2326, 2018.
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Affiliation(s)
- Christine E Haugen
- Department of Surgery, School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Courtenay M Holscher
- Department of Surgery, School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | | | - Marcos Pozo
- Department of Surgery, School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Fatima Warsame
- Department of Surgery, School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Mara McAdams-DeMarco
- Department of Surgery, School of Medicine, Johns Hopkins University, Baltimore, Maryland
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
| | - Dorry L Segev
- Department of Surgery, School of Medicine, Johns Hopkins University, Baltimore, Maryland
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
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14
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Younossi Z, Papatheodoridis G, Cacoub P, Negro F, Wedemeyer H, Henry L, Hatzakis A. The comprehensive outcomes of hepatitis C virus infection: A multi-faceted chronic disease. J Viral Hepat 2018; 25 Suppl 3:6-14. [PMID: 30398294 DOI: 10.1111/jvh.13005] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 08/16/2018] [Indexed: 02/06/2023]
Abstract
Treatment of hepatitis C virus (HCV) infection has been revolutionized with the introduction of pangenotypic, interferon- and ribavirin-free regimens associated with high cure rates and a low side effect profile. Additionally, there is evidence that HCV cure reduces HCV complications, improves patient-reported outcomes and is cost-saving in most western countries in the long term. This is a review of the comprehensive burden of HCV and the value of eliminating HCV infection. With the introduction of the interferon-free all-oral, once a day pill treatment regimen for the cure of HCV, the potential to eliminate HCV by 2030 has become a possibility for some regions of the world. Nevertheless, there are barriers to screening, linkage to care, and treatment in many countries that must be overcome in order to reach this goal. In conclusion, globally, work must continue to ensure national policies are in place to support screening, linkage to care and affordable treatment in order to eliminate HCV.
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Affiliation(s)
- Zobair Younossi
- Department of Medicine, Inova Fairfax Hospital, Falls Church, Virginia.,Beatty Center for Integrated Research, Inova Health System, Falls Church, Virginia
| | - Georgios Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens Laiko, Athens, Greece
| | - Patrice Cacoub
- Department of Internal Medicine and Clinical Immunology, AP HP Hôpital La Pitié-Salpêtrière, Paris, France.,CNRS UMR 7087, INSERM UMR S-959, DHU I2B, Sorbonne Université, Paris, France
| | | | | | - Linda Henry
- Center for Outcomes Research in Liver Disease, Washington D.C
| | - Angelos Hatzakis
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School of National and Kapodistrian University of Athens, Athens, Greece.,Hepatitis B and C Public Policy Association, L-2453 , Luxembourg
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15
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Terrault NA, Pageaux GP. A changing landscape of liver transplantation: King HCV is dethroned, ALD and NAFLD take over! J Hepatol 2018; 69:767-768. [PMID: 30104027 DOI: 10.1016/j.jhep.2018.07.020] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Accepted: 07/22/2018] [Indexed: 12/04/2022]
Affiliation(s)
- Norah A Terrault
- Gastroenterology/Hepatology, University of California San Francisco, CA, USA.
| | - Georges-Philippe Pageaux
- Hepatology and Liver Transplantation Unit, CHU Saint Eloi, Montpellier University, 34295 Montpellier, France.
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16
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Asrani SK, Kouznetsova M, Ogola G, Taylor T, Masica A, Pope B, Trotter J, Kamath P, Kanwal F. Increasing Health Care Burden of Chronic Liver Disease Compared With Other Chronic Diseases, 2004-2013. Gastroenterology 2018; 155:719-729.e4. [PMID: 29802851 DOI: 10.1053/j.gastro.2018.05.032] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Revised: 05/09/2018] [Accepted: 05/18/2018] [Indexed: 01/16/2023]
Abstract
BACKGROUND & AIMS Chronic liver disease (CLD) is a common and expensive condition, and studies of CLD-related hospitalizations have underestimated the true burden of disease. We analyzed data from a large, diverse health care system to compare time trends in CLD-related hospitalizations with those in congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD). METHODS We collected data from a large health care system in Texas on hospitalizations related to CLD (n = 27,783), CHF (n = 60,415), and COPD (n = 34,199) from January 1, 2004 through December 31, 2013. We calculated annual hospitalization rates (per 100,000) and compared hospital course, inpatient mortality, ancillary services, and readmissions. RESULTS Compared with patients with CHF (median age, 71 years) or COPD (median age, 69 years), patients with CLD were significantly younger (median age, 57 years) (P < .01 vs CHF and COPD). Higher proportions of patients with CLD were uninsured (11.7% vs 5.4% for CHF and 5.4% for COPD, P < .01) and Hispanic (17% for CLD vs 9.3% for CHF and 5.0% for COPD, P < .01). A lower proportion of patients with CLD had Medicare (41.5% vs 68.6% with CHF and 70.1% with COPD, P < .01). From 2004 through 2013, the rate of CLD-related hospitalization increased by 92% (from 1295/100,000 to 2490/100,000), compared with 6.7% for CHF (from 3843/100,000 to 4103/100,000) and 48.8% for COPD (from 1775/100,000 to 2642/100,000). During this time period, CLD-related hospitalizations covered by Medicare increased from 31.8% to 41.5%, whereas hospitalizations covered by Medicare did not change for CHF (remained at 70%) or COPD (remained at 70%). Patients with CLD had longer hospital stays (7.3 days vs 6.2 days for CHF and 5.9 days for COPD, P < .01). A higher proportion of patients with CLD died or were discharged to hospice (14.2% vs 11.5% of patients with CHF and 9.3% of patients with COPD, P < .01), and a smaller proportion had access to postacute care (13.2% vs 23.2% of patients with CHF and 27.4% of patients with COPD, P < .01). A higher proportion of patients with CLD were readmitted to the hospital within 30 days (25% vs 21.9% of patients with CHF and 20.6% with COPD, P < .01). CONCLUSIONS Patients with CLD, compared with selected other chronic diseases, had increasing rates of hospitalization, longer hospital stays, more readmissions, and, despite these adverse outcomes, less access to postacute care. Disease management models for CLD are greatly needed to manage the anticipated increase in hospitalizations for CLD.
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Affiliation(s)
- Sumeet K Asrani
- Baylor University Medical Center, Baylor Scott and White, Dallas, Texas.
| | - Maria Kouznetsova
- Center for Clinical Effectiveness, Baylor Scott and White, Dallas, Texas
| | - Gerald Ogola
- Center for Clinical Effectiveness, Baylor Scott and White, Dallas, Texas
| | | | - Andrew Masica
- Center for Clinical Effectiveness, Baylor Scott and White, Dallas, Texas
| | - Brandon Pope
- Center for Clinical Effectiveness, Baylor Scott and White, Dallas, Texas
| | - James Trotter
- Baylor University Medical Center, Baylor Scott and White, Dallas, Texas
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17
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Beig J, Orr D, Harrison B, Gane E. Hepatitis C Virus Eradication with New Interferon-Free Treatment Improves Metabolic Profile in Hepatitis C Virus-Related Liver Transplant Recipients. Liver Transpl 2018; 24:1031-1039. [PMID: 29577581 DOI: 10.1002/lt.25060] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 04/22/2018] [Accepted: 05/20/2018] [Indexed: 12/15/2022]
Abstract
Interferon (IFN)-free, direct-acting antiviral (DAA) therapy agents provide a safe and efficacious treatment for liver transplant recipients with recurrent hepatitis C virus (HCV) infection. The aim of this study is to evaluate the impact of HCV eradication on the metabolic factors in liver transplant recipients. We completed a retrospective single-center study on HCV-related liver transplant recipients treated with IFN-free DAAs including both treatment-naive and treatment-experienced patients. IFN-free DAAs impact on the metabolic profile were assessed at baseline and sustained virological response (SVR) between 24 and 48 weeks. In total, 91 liver transplant recipients with recurrent HCV infection received IFN-free DAA treatment, 62 patients had IFN-based treatment failure, and 29 were treatment-naïve, of whom 87 (96%) achieved SVR. Eradication of recurrent HCV infection was associated with reduction in the treatment of diabetes and hypertension by 38% and 22% from the baseline respectively. Hemoglobin A1c (HbA1c) levels declined from mean 35.5 ± 4.3 mmol/mol to 33.3 ±3.6 mmol/mol at 44 weeks posttreatment (P = 0.03). Total cholesterol levels increased from 3.8 ± 0.9 mmol/L to 4.9 ± 0.9 mmol/L at 41 weeks posttreatment (P < 0.0001), reflecting a significant increase in serum low-density lipoprotein (LDL) levels (2.0 ± 0.8 to 2.9 ± 0.8; P < 0.0001). Estimated glomerular filtration rate (eGFR) levels increased from 64.9 ± 20 mL/minute to 69.6 ± 20 mL/minute at 24 weeks posttreatment (P = 0.0004). Glucose, lipid profile, and eGFR changes were independent of weight changes and immunosuppression dosage and trough levels. In conclusion, eradication of recurrent HCV infection by DAA therapy has beneficial impacts on glucose metabolism and renal profile and reverses the hypolipidemic effect of HCV in liver transplant recipients. These extrahepatic effects of DAA therapy need to be validated by larger prospective studies.
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Affiliation(s)
- Junaid Beig
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | - David Orr
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | - Barry Harrison
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | - Edward Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
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18
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Kwong A, Kim WR, Mannalithara A, Heo NY, Udompap P, Kim D. Decreasing mortality and disease severity in hepatitis C patients awaiting liver transplantation in the United States. Liver Transpl 2018; 24:735-743. [PMID: 29125676 PMCID: PMC5945341 DOI: 10.1002/lt.24973] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 08/16/2017] [Accepted: 10/13/2017] [Indexed: 12/13/2022]
Abstract
Hepatitis C virus (HCV) infection has been the leading indication for liver transplantation (LT) in the United States. Since 2013, interferon-free antiviral therapy has led to sustained virological response in many LT candidates. We compared the wait-list mortality of HCV patients with that of patients with other chronic liver diseases. Data for primary LT candidates were obtained from the Organ Procurement and Transplantation Network database. Adult wait-list registrants were divided into 3 cohorts: cohort 1 included patients on the waiting list as of January 1, 2004; cohort 2 as of January 1, 2009; and cohort 3 as of January 1, 2014. The primary outcome was wait-list mortality, and the secondary outcome was the rate of change in Model for End-Stage Liver Disease (MELD). Multivariate Cox proportional hazards analysis was performed to evaluate 12-month wait-list mortality. The cohorts included 7627 LT candidates with HCV and 13,748 patients without HCV. Compared with cohort 2, HCV patients in cohort 3 had a 21% lower risk of death (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.67-0.93). Among patients with non-HCV liver disease, no difference in mortality was seen between cohorts 2 and 3 (HR, 0.97; 95% CI, 0.86-1.09). Among HCV patients, the mean rate of change in MELD decreased from 2.35 per year for cohort 2 to 1.90 per year for cohort 3, compared with 1.90 and 1.66 in cohorts 2 and 3, respectively, among non-HCV patients. In this population-based study, wait-list mortality and progression of disease severity decreased in recent HCV patients for whom direct-acting antiviral agents were available. Liver Transplantation 24 735-743 2018 AASLD.
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Affiliation(s)
- Allison Kwong
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, United States
| | - W. Ray Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, United States
| | - Ajitha Mannalithara
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, United States
| | - Nae-Yun Heo
- Department of Medicine, Inje University Haeundae Paik Hospital, Busan, Korea
| | - Prowpanga Udompap
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, United States
| | - Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, United States
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19
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Dirchwolf M, Marciano S, Giunta DH, Posadas-Martínez ML, Biggins SW, Ruf AE. Trends in liver transplantation for hepatitis C in a country with reduced access to direct-acting antiviral agents. Clin Transplant 2018; 32:e13230. [PMID: 29485711 DOI: 10.1111/ctr.13230] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/19/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV)-related cirrhosis is a leading indication for liver transplantation (LT) worldwide. Access to effective HCV treatment is inequitable globally. We aimed to analyze whether the introduction of effective HCV treatment caused an impact in LT trends in a middle-income country. METHODS Cross-sectional analysis of all adult patients who were listed/received a LT in Argentina for HCV, alcohol-related liver disease (ALD), or autoimmune hepatitis/primary biliary cirrhosis (AIH/PBC) from 2007 to 2017. Joinpoint regression analysis was used to identify changes in the cumulative incidence rates in waiting list (WL) registration, WL mortality, and LT. RESULTS Liver transplantation WL for HCV increased significantly between 2007 and 2014, with an annual percentage change (APC) +7.8%, P = .01, followed by a downward slope from 2014 to 2017 with an APC -9.8%, P = .1. There were no significant changes in WL mortality. LT trends remained stable. LT for HCV without MELD exception points for HCC decreased (APC -6.6%, P = .01), whereas LT for HCV with HCC exception points increased (APC +11.1, P = .01) during the study period. CONCLUSION Waiting list and LT for HCV without HCC decreased, whereas LT for HCV and HCC increased; this may be related to selective antiviral treatment access for patients with advanced fibrosis.
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Affiliation(s)
| | - Sebastián Marciano
- Liver Unit, Hospital Italiano, Buenos Aires, Argentina.,Department of Research, Hospital Italiano, Buenos Aires, Argentina
| | - Diego H Giunta
- Department of Research, Hospital Italiano, Buenos Aires, Argentina
| | | | | | - Andrés E Ruf
- Liver Unit, Hospital Privado de Rosario, Rosario, Argentina.,Fundación para la Docencia e Investigación de las Enfermedades del Hígado (FUNDIEH), Buenos Aires, Argentina
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20
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Biomarkers development for early detection of cancer: Reducing the burden of cancer in the ageing society. THE EUROBIOTECH JOURNAL 2018. [DOI: 10.2478/ebtj-2018-0005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Abstract
The ageing process in the European society will become one of the key driving forces of change over the next decades. The specific demands of older generations constitute a key market of the future, and the pressure to improve and expand health services increases, especially as far as chronic diseases, such as cancer. Availability of cost effective cancer early detection protocols, based on predictive biomarkers, will improve patients management reducing consequently the high costs associated to treating patients when the disease is at an advanced stage.
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21
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Saxena V, Terrault NA. Recurrent Primary Disease After Liver Transplantation. ZAKIM AND BOYER'S HEPATOLOGY 2018:784-815.e14. [DOI: 10.1016/b978-0-323-37591-7.00053-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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22
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Dultz G, Graubard BI, Martin P, Welker MW, Vermehren J, Zeuzem S, McGlynn KA, Welzel TM. Liver transplantation for chronic hepatitis C virus infection in the United States 2002-2014: An analysis of the UNOS/OPTN registry. PLoS One 2017; 12:e0186898. [PMID: 29088255 PMCID: PMC5663425 DOI: 10.1371/journal.pone.0186898] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 09/20/2017] [Indexed: 12/19/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a leading cause for orthotopic liver transplantation (OLT) in the U.S. We investigated characteristics of HCV-infected patients registered for OLT, and explored factors associated with mortality. Data were obtained from the United Network for Organ Sharing and Organ Procurement and Transplantation network (UNOS/OPTN) registry. Analyses included 41,157 HCV-mono-infected patients ≥18 years of age listed for cadaveric OLT between February 2002 and June 2014. Characteristics associated with pre- and post-transplant survival and time trends over the study period were determined by logistic and Cox proportional hazard regression analyses and Poisson regressions. Most patients were white (69.1%) and male (70.8%). At waitlist registration, mean age was 54.6 years and mean MELD was 16. HCC was recorded in 26.9% of the records. A total of 51.2% of the patients received an OLT, 21.0% died or were too sick; 15.6% were delisted and 10.4% were still waiting. Factors associated with increased waitlist mortality were older age, female gender, blood type 0, diabetes, no HCC and transplant region (p<0.001). OLT recipient characteristics associated with increased risk for post OLT mortality were female gender, age, diabetes, race (p<0,0001), and allocation MELD (p = 0.005). Donor characteristics associated with waitlist mortality included age, ethnicity (p<0.0001) and diabetes (p<0.03). Waitlist registrations and OLTs for HCC significantly increased from 14.4% to 37.3% and 27.8% to 38.5%, respectively (p<0.0001). Pre- and post-transplant survival depended on a variety of patient-, donor-, and allocation- characteristics of which most remain relevant in the DAA-era. Still, intensified HCV screening strategies and timely and effective treatment of HCV are highly relevant to reduce the burden of HCV-related OLTs in the U.S.
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Affiliation(s)
- Georg Dultz
- University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Barry I. Graubard
- Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America
| | - Paul Martin
- Hepatology Division, University of Miami, Miami, FL, United States of America
| | | | | | - Stefan Zeuzem
- University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Katherine A. McGlynn
- HREB, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America
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23
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The impact of the recipient and donor interferon lambda-3 polymorphism on the course of HCV infection following liver transplantation. Clin Exp Hepatol 2017; 3:152-158. [PMID: 29062905 PMCID: PMC5649482 DOI: 10.5114/ceh.2017.68401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Accepted: 05/02/2017] [Indexed: 11/23/2022] Open
Abstract
Aim of the study Aim of the study was to assess the impact of the recipient and donor interferon lambda-3 (IFNL3) single-nucleotide polymorphisms (SNPs) rs12979860 and rs8099917 on the course of hepatitis C virus (HCV) reinfection following liver transplantation. Material and methods The study involved 141 subjects after liver transplantation for HCV-induced cirrhosis, performed between 2000 and 2015. It assessed the impact of both SNPs on the outcomes of interferon/ribavirin (IFN/RBV) treatment following transplantation, HCV viral load, laboratory test results, histological lesions in the liver graft, the risk of acute rejection, and the development of hepatocellular carcinoma (HCC) in patient’s own liver. Results In the case of rs12979860, SVR was achieved in 58.8% of recipients with the CC genotype, and only 12% of recipients with the TT genotype (p = 0.016). Recipients with the rs12979860 CC variant had lower viral load and lower alanine transaminase (ALT) activity than recipients with a non-CC variant. Opposite effects were demonstrated in the analysis of the donors’ genotype. Recipients with the unfavorable variants (rs12979860 TT and rs8099917 GG) had a lower risk of graft rejection and tended to have a higher risk of developing HCC in their own liver. Conclusions The IFNL3 rs12979860 polymorphism may be considered a predictor for IFN/RBV effectiveness following liver transplantation. The course of HCV reinfection following liver transplantation may be more aggressive if an unfavorable variant in the recipient coexists with a promising variant in the donor. Particularly careful monitoring for HCC in recipients with unfavorable IFNL3 variants is warranted.
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Rising Rates of Hepatocellular Carcinoma Leading to Liver Transplantation in Baby Boomer Generation with Chronic Hepatitis C, Alcohol Liver Disease, and Nonalcoholic Steatohepatitis-Related Liver Disease. Diseases 2017; 5:diseases5040020. [PMID: 28954412 PMCID: PMC5750531 DOI: 10.3390/diseases5040020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 09/24/2017] [Accepted: 09/25/2017] [Indexed: 12/23/2022] Open
Abstract
We aim to study the impact of the baby boomer (BB) generation, a birth-specific cohort (born 1945–1965) on hepatocellular carcinoma (HCC)-related liver transplantation (LT) in patients with chronic hepatitis C virus (HCV), alcoholic liver disease (ALD), and non-alcoholic steatohepatitis (NASH). We performed a retrospective analysis using the United Network for Organ Sharing (UNOS)/Organ Procurement Transplant Network (OPTN) database from 2003 to 2014 to compare HCC-related liver transplant surgery trends between two cohorts—the BB and non-BB—with a secondary diagnosis of HCV, ALD, or NASH. From 2003–2014, there were a total of 8313 liver transplant recipients for the indication of HCC secondary to HCV, ALD, or NASH. Of the total, 6658 (80.1%) HCC-related liver transplant recipients were BB. The number of liver transplant surgeries for the indication of HCC increased significantly in NASH (+1327%), HCV (+382%), and ALD (+286%) during the study period. The proportion of BB who underwent LT for HCC was the highest in HCV (84.7%), followed by NASH (70.3%) and ALD (64.7%). The recommendations for birth-cohort specific HCV screening stemmed from a greater understanding of the high prevalence of chronic HCV and HCV-related HCC within BB. The rising number of HCC-related LT among BB with ALD and NASH suggests the need for increased awareness and improved preventative screening/surveillance measures within NASH and ALD cohorts as well.
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25
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Sharma P, Goodrich NP, Schaubel DE, Smith AR, Merion RM. National assessment of early hospitalization after liver transplantation: Risk factors and association with patient survival. Liver Transpl 2017; 23:1143-1152. [PMID: 28688150 PMCID: PMC5568939 DOI: 10.1002/lt.24813] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 06/21/2017] [Accepted: 06/26/2017] [Indexed: 12/24/2022]
Abstract
Hospitalization is known to occur frequently in the first 6 months following liver transplantation (LT). Using a novel data linkage between the Scientific Registry of Transplant Recipients and Centers for Medicare and Medicaid Services, our study has 2 objectives: (1) to determine risk factors for "early" hospitalization (ie, within 6 months of LT); and (2) to quantify the importance of hospitalization history in the first 6 months with respect to subsequent patient survival (ie, survival, conditional on surviving 6 months post-LT). The study population consisted of patients aged ≥18 years who underwent deceased donor LT between January 1, 2003 and December 31, 2010, with Medicare as primary or secondary insurance and were discharged alive from the index LT hospitalization (n = 7220). The early hospitalization rate was 2.76 per patient-year and was significantly associated with many recipient factors (eg, recipient age, hepatitis C, diabetes, poor renal function including dialysis, and recipient of transjugular intrahepatic portosystemic shunt procedure before LT), as well as donor race and donation after cardiac death. Conditional on surviving 6 months after LT, the covariate-adjusted death rate increased by 22% for each additional hospitalization occurring in the first 6 months (hazard ratio, 1.22; P < 0.001). In conclusion, several LT recipient factors are significantly associated with early hospitalization. Moreover, a patient's hospitalization profile during follow-up months 0-6 is a very strong predictor of survival thereafter. Efforts and resources should be devoted toward identifying LT recipients at risk for early hospitalization and modifying the actionable risk factors such as hepatitis C, diabetes, and body mass index to improve resource utilization and overall outcomes. Liver Transplantation 23 1143-1152 2017 AASLD.
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Affiliation(s)
- Pratima Sharma
- Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan
| | | | - Douglas E Schaubel
- Department of Biostatistics, University of Michigan, Ann Arbor, Michigan
| | - Abigail R Smith
- Arbor Research Collaborative for Health, Ann Arbor, Michigan
| | - Robert M Merion
- Arbor Research Collaborative for Health, Ann Arbor, Michigan,Department of Surgery, University of Michigan, Ann Arbor, Michigan
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26
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Russelli G, Pizzillo P, Iannolo G, Barbera F, Tuzzolino F, Liotta R, Traina M, Vizzini G, Gridelli B, Badami E, Conaldi PG. HCV replication in gastrointestinal mucosa: Potential extra-hepatic viral reservoir and possible role in HCV infection recurrence after liver transplantation. PLoS One 2017; 12:e0181683. [PMID: 28750044 PMCID: PMC5531480 DOI: 10.1371/journal.pone.0181683] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Accepted: 07/04/2017] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Hepatitis C virus (HCV) predominantly infects hepatocytes, although it is known that receptors for viral entry are distributed on a wide array of target cells. Chronic HCV infection is indeed characterized by multiple non-liver manifestations, suggesting a more complex HCV tropism extended to extrahepatic tissues and remains to be fully elucidated. In this study, we investigated the gastrointestinal mucosa (GIM) as a potential extrahepatic viral replication site and its contribution to HCV recurrence. METHODS We analyzed GIM biopsies from a cohort of 76 patients, 11 of which were HCV-negative and 65 HCV-positive. Of these, 54 biopsies were from liver-transplanted patients. In 29 cases, we were able to investigate gastrointestinal biopsies from the same patient before and after transplant. To evaluate the presence of HCV, we looked for viral antigens and genome RNA, whilst to assess viral replicative activity, we searched for the replicative intermediate minus-strand RNA. We studied the genetic diversity and the phylogenetic relationship of HCV quasispecies from plasma, liver and gastrointestinal mucosa of HCV-liver-transplanted patients in order to assess HCV compartmentalization and possible contribution of gastrointestinal variants to liver re-infection after transplantation. RESULTS Here we show that HCV infects and replicates in the cells of the GIM and that the favorite hosts were mostly enteroendocrine cells. Interestingly, we observed compartmentalization of the HCV quasispecies present in the gastrointestinal mucosa compared to other tissues of the same patient. Moreover, the phylogenetic analysis revealed a high similarity between HCV variants detected in gastrointestinal mucosa and those present in the re-infected graft. CONCLUSIONS Our results demonstrated that the gastrointestinal mucosa might be considered as an extrahepatic reservoir of HCV and that could contribute to viral recurrence. Moreover, the finding that HCV infects and replicates in neuroendocrine cells opens new perspectives on the role of these cells in the natural history of HCV infection.
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Affiliation(s)
- Giovanna Russelli
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Paola Pizzillo
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy
| | - Gioacchin Iannolo
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy
| | - Floriana Barbera
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | | | - Rosa Liotta
- Pathology Service, Department of Diagnostic and Therapeutic Services, IRCCS-ISMETT, Palermo, Italy
| | - Mario Traina
- Endoscopy Service, Department of Diagnostic and Therapeutic Services, IRCCS-ISMETT, Palermo, Italy
| | - Giovanni Vizzini
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT, Palermo, Italy
| | - Bruno Gridelli
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT, Palermo, Italy
| | | | - Pier Giulio Conaldi
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy
- Fondazione Ri.MED, Palermo, Italy
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27
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Moreno GA, Wang A, Sánchez González Y, Díaz Espinosa O, Vania DK, Edlin BR, Brookmeyer R. Value of Comprehensive HCV Treatment among Vulnerable, High-Risk Populations. VALUE IN HEALTH : THE JOURNAL OF THE INTERNATIONAL SOCIETY FOR PHARMACOECONOMICS AND OUTCOMES RESEARCH 2017; 20:736-744. [PMID: 28577690 DOI: 10.1016/j.jval.2017.01.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 01/23/2017] [Accepted: 01/27/2017] [Indexed: 06/07/2023]
Abstract
OBJECTIVES The objective of this study was to explore the trade-offs society and payers make when expanding treatment access to patients with chronic hepatitis C virus (HCV) infection in early stages of disease as well as to vulnerable, high-risk populations, such as people who inject drugs (PWID) and HIV-infected men who have sex with men (MSM-HIV). METHODS A discrete time Markov model simulated HCV progression and treatment over 20 years. Population cohorts were defined by behaviors that influence the risk of HCV exposure: PWID, MSM-HIV, an overlap cohort of individuals who are both PWID and MSM-HIV, and all other adults. Six different treatment scenarios were modeled, with varying degrees of access to treatment at different fibrosis stages and to different risk cohorts. Benefits were measured as quality-adjusted life-years and a $150,000/quality-adjusted life-year valuation was used to assess social benefits. RESULTS Compared with limiting treatment to METAVIR fibrosis stages F3 or F4 and excluding PWID, expanding treatment to patients in all fibrosis stages and including PWID reduces cumulative new infections by 55% over a 20-year horizon and reduces the prevalence of HCV by 93%. We find that treating all HCV-infected individuals is cost saving and net social benefits are over $500 billion greater compared with limiting treatment. Including PWID in treatment access saves 12,900 to 41,200 lives. CONCLUSIONS Increased access to treatment brings substantial value to society and over the long-term reduces costs for payers, as the benefits accrued from long-term reduction in prevalent and incident cases, mortality, and medical costs outweigh the cost of treatment.
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Affiliation(s)
| | | | | | | | | | - Brian R Edlin
- Weill Cornell Medical College, Cornell University, New York City, NY, USA
| | - Ronald Brookmeyer
- Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA, USA
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28
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Abstract
AIM To compare age-related morbidity and mortality after transjugular intrahepatic portosystemic shunts (TIPS). METHODS We performed a retrospective chart review of patients who underwent TIPS at the University of California Los Angeles Medical Center between 2008 to 2014. Elderly patients (65 y and older) were matched with nonelderly patients (controls, below 65 y) by model for end-stage liver disease (MELD) score (±3), indication for TIPS (refractory ascites vs. variceal bleeding), serum sodium level (±5), in a ratio of 1:1. Endpoints measures were hospital stay post-TIPS, rifaximin, or lactulose use, TIPS failure at 30 days, readmission at 90 days, MELD at 90 days, and mortality at 90 days. RESULTS A total of 30 patient matches were included in this study: 30 control and 30 elderly patients. The median [interquartile (IQR)] MELD scores for controls and elderly were 11 (9, 13.8) for the controls and 11.5 (9, 14.8) for elderly patients (P=0.139). There were no significant differences in serum sodium and indication for TIPS. Thirty and 90-day follow-up laboratory test results were also similar between elderly and control patients. Event-free survival at 90 days was similar between controls and elderly patients [odds ratio (OR), 0.86; 95% confidence interval (CI), 0.3-2.5; P>0.05]. There was a trend toward greater hospitalization (OR, 1.76; 95% CI, 0.52-5.95; P=0.546) and mortality (OR, 3.3; 95% CI, 0.3-14.01; P=0.182). CONCLUSIONS The results of this study suggest event-free survival is similar between nonelderly and elderly patients. Although statistically significant, there is a tendency toward greater mortality and hospitalization in the elderly.
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29
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van Tilborg M, Maan R, van der Meer AJ, de Knegt RJ. Interferon-free antiviral therapy for chronic hepatitis C among patients in the liver transplant setting. Best Pract Res Clin Gastroenterol 2017. [PMID: 28624110 DOI: 10.1016/j.bpg.2017.04.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C (HCV) infection remains a major public health problem with many infected individuals worldwide. The revolutionary discovery of highly effective direct-acting antivirals (DAAs) makes chronic HCV infection a curable disease, even in patients with advanced liver disease. Liver function may improve shortly after initiation of antiviral therapy in patients on the waiting list and could even obviate the need for transplantation. However, whether these short term benefits also result in a favorable prognosis on the long-term remains to be seen and this fuels the discussion whether DAAs should be used prior to liver transplantation in all patients. Following liver transplantation, DAA treatment is also highly effective so that postponing antiviral treatment to the post-transplant setting may be better for certain patients. Furthermore, the discussion whether HCV positive organ donors should be used now viral eradication is achieved in almost all patients has regained interest.
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Affiliation(s)
| | - Raoel Maan
- Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | | | - Robert J de Knegt
- Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
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30
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Bowring MG, Kucirka LM, Massie AB, Luo X, Cameron A, Sulkowski M, Rakestraw K, Gurakar A, Kuo I, Segev DL, Durand CM. Changes in Utilization and Discard of Hepatitis C-Infected Donor Livers in the Recent Era. Am J Transplant 2017; 17:519-527. [PMID: 27456927 PMCID: PMC5266634 DOI: 10.1111/ajt.13976] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 07/12/2016] [Indexed: 01/25/2023]
Abstract
The impact of interferon (IFN)-free direct-acting antiviral (DAA) hepatitis C virus (HCV) treatments on utilization and outcomes associated with HCV-positive deceased donor liver transplantation (DDLT) is largely unknown. Using the Scientific Registry of Transplant Recipients, we identified 25 566 HCV-positive DDLT recipients from 2005 to 2015 and compared practices according to the introduction of DAA therapies using modified Poisson regression. The proportion of HCV-positive recipients who received HCV-positive livers increased from 6.9% in 2010 to 16.9% in 2015. HCV-positive recipients were 61% more likely to receive an HCV-positive liver after 2010 (early DAA/IFN era) (aRR:1.45 1.611.79 , p < 0.001) and almost three times more likely to receive one after 2013 (IFN-free DAA era) (aRR:2.58 2.853.16 , p < 0.001). Compared to HCV-negative livers, HCV-positive livers were 3 times more likely to be discarded from 2005 to 2010 (aRR:2.69 2.993.34 , p < 0.001), 2.2 times more likely after 2010 (aRR:1.80 2.162.58 , p < 0.001) and 1.7 times more likely after 2013 (aRR:1.37 1.682.04 , p < 0.001). Donor HCV status was not associated with increased risk of all-cause graft loss (p = 0.1), and this did not change over time (p = 0.8). Use of HCV-positive livers has increased dramatically, coinciding with the advent of DAAs. However, the discard rate remains nearly double that of HCV-negative livers. Further optimization of HCV-positive liver utilization is necessary to improve access for all candidates.
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Affiliation(s)
- Mary G Bowring
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Lauren M Kucirka
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore MD
| | - Allan B Massie
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore MD
| | - Xun Luo
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Andrew Cameron
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Mark Sulkowski
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Katie Rakestraw
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ahmet Gurakar
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Irene Kuo
- Department of Epidemiology and Biostatistics, George Washington University School of Public Health, Washington, DC
| | - Dorry L Segev
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore MD,Scientific Registry of Transplant Recipients, Minneapolis, MN
| | - Christine M Durand
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD,Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
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31
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Van Nuys K, Brookmeyer R, Chou JW, Dreyfus D, Dieterich D, Goldman DP. Broad Hepatitis C Treatment Scenarios Return Substantial Health Gains, But Capacity Is A Concern. Health Aff (Millwood) 2017; 34:1666-74. [PMID: 26438742 DOI: 10.1377/hlthaff.2014.1193] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Treatment of hepatitis C virus, the most common chronic viral infection in the United States, has historically suffered from challenges including serious side effects, low efficacy, and ongoing transmission and reinfection. Recent innovations have produced breakthrough therapies that are effective in more than 90 percent of patients. These treatments could dramatically reduce the virus's prevalence but are costly. To quantify the benefit of these treatments to society, including the value of reduced transmission, we estimated the effects of several hepatitis C treatment strategies on cost and population health. Treating patients at all disease stages could generate $610-$1,221 billion in additional quality-adjusted life-years, plus an additional $139 billion in saved medical expenditures over fifty years, and minimize the disease burden, but up-front treatment costs would exceed $150 billion. An intermediate scenario--treating 5 percent of the infected population annually, regardless of patients' disease stages--would also return substantial benefits and would be much more affordable under current financing schemes.
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Affiliation(s)
- Karen Van Nuys
- Karen Van Nuys is a senior research economist at Precision Health Economics, in Los Angeles, California
| | - Ronald Brookmeyer
- Ronald Brookmeyer is a professor of biostatistics at the University of California, Los Angeles
| | - Jacquelyn W Chou
- Jacquelyn W. Chou is an associate director and research scientist at Precision Health Economics
| | - David Dreyfus
- David Dreyfus is a data scientist at Arete Analytics, in Andover, Massachusetts
| | - Douglas Dieterich
- Douglas Dieterich is a professor of medicine in the Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai, in New York City
| | - Dana P Goldman
- Dana P. Goldman is the Leonard D. Schaeffer Chair and director of the Schaeffer Center for Health Policy and Economics at the University of Southern California, in Los Angeles
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32
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Donovan RJ, Choi C, Ali A, Heuman DM, Fuchs M, Bavry AA, Jovin IS. Perioperative Cardiovascular Evaluation for Orthotopic Liver Transplantation. Dig Dis Sci 2017; 62:26-34. [PMID: 27830409 DOI: 10.1007/s10620-016-4371-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 11/01/2016] [Indexed: 01/01/2023]
Abstract
Patients with advanced liver disease have a high prevalence of cardiovascular risk factors, but many of them are asymptomatic. Cardiovascular risk stratification prior to liver transplant can be done by dobutamine stress echocardiography, stress myocardial perfusion imaging, cardiac computer tomography, and coronary angiography, but there are no clear recommendations regarding what method should be used and who should be screened. Because of this and because of inherent risk profile in this population, the variations in practice are significant. Careful screening and rigorous management of cardiovascular risk factors are important to ensure optimal cardiovascular outcomes in the immediate post-transplantation period and in the long term as well.
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Affiliation(s)
- Robert J Donovan
- Department of Medicine, Virginia Commonwealth University, McGuire VAMC, Richmond, VA, USA
| | - Calvin Choi
- Department of Medicine, Randall VAMC, University of Florida, Gainesville, FL, USA
| | - Asghar Ali
- Department of Medicine, Virginia Commonwealth University, McGuire VAMC, Richmond, VA, USA.
| | - Douglas M Heuman
- Department of Medicine, Virginia Commonwealth University, McGuire VAMC, Richmond, VA, USA
| | - Michael Fuchs
- Department of Medicine, Virginia Commonwealth University, McGuire VAMC, Richmond, VA, USA
| | - Anthony A Bavry
- Department of Medicine, Randall VAMC, University of Florida, Gainesville, FL, USA
| | - Ion S Jovin
- Department of Medicine, Virginia Commonwealth University, McGuire VAMC, Richmond, VA, USA
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33
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Fayek SA, Quintini C, Chavin KD, Marsh CL. The Current State of Liver Transplantation in the United States: Perspective From American Society of Transplant Surgeons (ASTS) Scientific Studies Committee and Endorsed by ASTS Council. Am J Transplant 2016; 16:3093-3104. [PMID: 27545282 DOI: 10.1111/ajt.14017] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Revised: 08/09/2016] [Accepted: 08/09/2016] [Indexed: 01/25/2023]
Abstract
This article is a review of the salient points and a future prospective based on the 2014 Organ Procurement and Transplantation Network (OPTN)/Scientific Registry of Transplant Recipients (SRTR) liver donation and transplantation data report recently published by the American Journal of Transplantation. Emphasis of our commentary and interpretation is placed on data relating to waitlist dynamics, organ utilization rates, the impact of recent advances in the treatment of hepatitis C, and the increases in end-stage renal disease among liver transplant candidates. Finally, we share our vision on potential areas of innovation that are likely to significantly improve the field of liver transplantation in the near future.
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Affiliation(s)
- S A Fayek
- Transplant Surgery, Fort Worth Transplant Institute at Plaza Medical Center, Fort Worth, TX
| | - C Quintini
- Liver Transplantation and HPB Surgery, Cleveland Clinic Foundation, Cleveland, OH
| | - K D Chavin
- Transplant Surgery, Medical University of South Carolina, Charleston, SC.
| | - C L Marsh
- Scripps Center for Organ Transplantation, Scripps Clinic & Green Hospital, La Jolla, CA
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34
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Lutchman G, Nguyen NH, Chang CY, Ahmed A, Daugherty T, Garcia G, Kumari R, Gupta S, Doshi D, Nguyen MH. Effectiveness and tolerability of simeprevir and sofosbuvir in nontransplant and post-liver transplant patients with hepatitis C genotype 1. Aliment Pharmacol Ther 2016; 44:738-46. [PMID: 27506182 DOI: 10.1111/apt.13761] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 06/16/2016] [Accepted: 07/21/2016] [Indexed: 12/23/2022]
Abstract
BACKGROUND Hepatitis C virus genotype 1a (HCV-1a), prior treatment, cirrhosis and post-transplant status are historically associated with poor treatment responses. The new oral direct-acting agents appear to be effective and safe in these patients. AIMS To evaluate the effectiveness and tolerability of simeprevir and sofosbuvir in a diverse real-life cohort of patients, including difficult-to-treat patients. METHODS We conducted a retrospective cohort study in 198 consecutive patients with hepatitis C genotype 1 (148 nontransplant, 50 post transplant), who were treated with simeprevir and sofosbuvir for 12 weeks between December 2013 and December 2014. Primary outcome was sustained virological response with undetectable HCV RNA 12 weeks after completion of therapy (SVR12). Risk factors evaluated for lack of SVR12 included HCV 1a (vs. 1b), prior treatment (vs. none), and cirrhosis (vs. no cirrhosis). RESULTS SVR12 rates were similar in non- and post-transplant settings, 82% and 88%, respectively. There were no significant differences in adverse events in patients regardless of cirrhosis or transplant status. On multivariate analysis also inclusive of gender and liver transplant status, negative predictors of SVR12 were having at least 2 or 3 risk factors (OR 0.30, 95% CI 0.10-0.87, P = 0.027 or 0.29, 95% CI 0.09-0.85, P = 0.025, respectively). CONCLUSION Simeprevir and sofosbuvir combination is a safe and effective regimen for the treatment of non- and post-transplant patients with traditional risk factors for poor treatment response, unless more than 2 difficult-to-treat risk factors are present.
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Affiliation(s)
- G Lutchman
- Gastroenterology and Hepatology, Liver Transplant Program, Stanford University Medical Center, Palo Alto, CA, USA
| | - N H Nguyen
- School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - C Y Chang
- Gastroenterology and Hepatology, Liver Transplant Program, Stanford University Medical Center, Palo Alto, CA, USA
| | - A Ahmed
- Gastroenterology and Hepatology, Liver Transplant Program, Stanford University Medical Center, Palo Alto, CA, USA
| | - T Daugherty
- Gastroenterology and Hepatology, Liver Transplant Program, Stanford University Medical Center, Palo Alto, CA, USA
| | - G Garcia
- Gastroenterology and Hepatology, Liver Transplant Program, Stanford University Medical Center, Palo Alto, CA, USA
| | - R Kumari
- Gastroenterology and Hepatology, Liver Transplant Program, Stanford University Medical Center, Palo Alto, CA, USA
| | - S Gupta
- Medical Affairs, Janssen Scientific Affairs, Titusville, NJ, USA
| | - D Doshi
- Health Economics & Outcomes Research, Janssen Scientific Affairs, Titusville, NJ, USA
| | - M H Nguyen
- Gastroenterology and Hepatology, Liver Transplant Program, Stanford University Medical Center, Palo Alto, CA, USA
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35
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Benítez-Gutiérrez L, de Mendoza C, Baños I, Duca A, Arias A, Treviño A, Requena S, Citores MJ, Cuervas-Mons V. Drug-Induced Lung Injury in a Liver Transplant Patient Treated With Sofosbuvir. Transplant Proc 2016; 48:2515-2518. [PMID: 27742338 DOI: 10.1016/j.transproceed.2016.08.026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
New direct-acting antivirals (DAAs) have dramatically improved sustained virologic response (SVR) rates in patients treated for chronic hepatitis C. Although the safety of these agents has been very good in registration trials, unexpected side effects have been reported after much broader use of DAAs on marketing. We retrospectively examined all liver transplant recipients with chronic hepatitis C that received sofosbuvir-based regimens at our clinic. A total of 24 liver transplant recipients with recurrent chronic hepatitis C had received sofosbuvir up to April 2015. Regimens were as follows: sofosbuvir+simeprevir (8), SOF+ledipasvir (6), sofosbuvir+daclatasvir (5) and sofosbuvir+ribavirin (5). Overall, treatment was very well tolerated with only mild adverse events in 42% of patients. However, a 52-year-old woman developed severe respiratory failure within 10 days after beginning sofosbuvir+daclatasvir. High-resolution computerized tomography showed areas of diffused ground-glass opacities in both lungs, suggesting drug-induced lung injury. The bronchoalveolar lavage showed marked signs of acute inflammation without recovering any infectious agent. The patient was treated with high-dose corticosteroids and steadily recovered. DAA therapy was not discontinued, but sofosbuvir was replaced by simeprevir. She reached sustained virologic response after completing 24 weeks of DAA therapy. Given the close temporal association, radiologic and bronchoalveolar lavage findings, and negative work-up for infectious agents, we postulated that sofosbuvir was the most likely explanation for drug-induced lung injury in our patient.
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Affiliation(s)
- L Benítez-Gutiérrez
- Internal Medicine Department and Liver Transplantation Unit, Puerta de Hierro University Hospital, Majadahonda, Spain; Internal Medicine Laboratory, Puerta de Hierro Research Institute, Majadahonda, Spain.
| | - C de Mendoza
- Internal Medicine Department and Liver Transplantation Unit, Puerta de Hierro University Hospital, Majadahonda, Spain; Internal Medicine Laboratory, Puerta de Hierro Research Institute, Majadahonda, Spain
| | - I Baños
- Internal Medicine Department and Liver Transplantation Unit, Puerta de Hierro University Hospital, Majadahonda, Spain
| | - A Duca
- Internal Medicine Department and Liver Transplantation Unit, Puerta de Hierro University Hospital, Majadahonda, Spain
| | - A Arias
- Internal Medicine Department and Liver Transplantation Unit, Puerta de Hierro University Hospital, Majadahonda, Spain
| | - A Treviño
- Internal Medicine Department and Liver Transplantation Unit, Puerta de Hierro University Hospital, Majadahonda, Spain; Internal Medicine Laboratory, Puerta de Hierro Research Institute, Majadahonda, Spain
| | - S Requena
- Internal Medicine Department and Liver Transplantation Unit, Puerta de Hierro University Hospital, Majadahonda, Spain; Internal Medicine Laboratory, Puerta de Hierro Research Institute, Majadahonda, Spain
| | - M J Citores
- Internal Medicine Department and Liver Transplantation Unit, Puerta de Hierro University Hospital, Majadahonda, Spain; Internal Medicine Laboratory, Puerta de Hierro Research Institute, Majadahonda, Spain
| | - V Cuervas-Mons
- Internal Medicine Department and Liver Transplantation Unit, Puerta de Hierro University Hospital, Majadahonda, Spain; Department of Medicine, Autonomous University, Madrid, Spain
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Pérez-Berná AJ, Rodríguez MJ, Chichón FJ, Friesland MF, Sorrentino A, Carrascosa JL, Pereiro E, Gastaminza P. Structural Changes In Cells Imaged by Soft X-ray Cryo-Tomography During Hepatitis C Virus Infection. ACS NANO 2016; 10:6597-611. [PMID: 27328170 DOI: 10.1021/acsnano.6b01374] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2023]
Abstract
Chronic hepatitis C virus (HCV) infection causes severe liver disease in millions of humans worldwide. Pathogenesis of HCV infection is strongly driven by a deficient immune response of the host, although intersection of different aspects of the virus life cycle with cellular homeostasis is emerging as an important player in the pathogenesis and progression of the disease. Cryo soft X-ray tomography (cryo-SXT) was performed to investigate the ultrastructural alterations induced by the interference of HCV replication with cellular homeostasis. Native, whole cell, three-dimensional (3D) maps were obtained in HCV replicon-harboring cells and in a surrogate model of HCV infection. Tomograms from HCV-replicating cells show blind-ended endoplasmic reticulum tubules with pseudospherical extrusions and marked alterations of mitochondrial morphology that correlated spatially with the presence of endoplasmic reticulum alterations, suggesting a short-range influence of the viral machinery on mitochondrial homeostasis. Both mitochondrial and endoplasmic reticulum alterations could be reverted by a combination of sofosbuvir/daclatasvir, which are clinically approved direct-acting antivirals for the treatment of chronic HCV infection. In addition to providing structural insight into cellular aspects of HCV pathogenesis, our study illustrates how cryo-SXT is a powerful 3D wide-field imaging tool for the assessment and understanding of complex cellular processes in a setting of near-native whole hydrated cells. Our results also constitute a proof of concept for the use of cryo-SXT as a platform that enables determining the potential impact of candidate compounds on the ultrastructure of the cell that may assist drug development at a preclinical level.
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Affiliation(s)
- Ana Joaquina Pérez-Berná
- MISTRAL Beamline Experiments Division, ALBA Synchrotron Light Source , Cerdanyola del Vallès, 08290 Barcelona, Spain
| | | | | | | | - Andrea Sorrentino
- MISTRAL Beamline Experiments Division, ALBA Synchrotron Light Source , Cerdanyola del Vallès, 08290 Barcelona, Spain
| | | | - Eva Pereiro
- MISTRAL Beamline Experiments Division, ALBA Synchrotron Light Source , Cerdanyola del Vallès, 08290 Barcelona, Spain
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EXP CLIN TRANSPLANTExp Clin Transplant 2016; 14. [DOI: 10.6002/ect.2015.0284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Bunchorntavakul C, Reddy KR. Treat chronic hepatitis C virus infection in decompensated cirrhosis - pre- or post-liver transplantation? the ironic conundrum in the era of effective and well-tolerated therapy. J Viral Hepat 2016; 23:408-18. [PMID: 27018088 DOI: 10.1111/jvh.12534] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 03/01/2016] [Indexed: 12/12/2022]
Abstract
The management of hepatitis C virus (HCV) infection in patients with decompensated cirrhosis has evolved dramatically over the past few years mainly due to the availability of all-oral antiviral regimens. The currently approved all-oral direct-acting antivirals (DAA) containing sofosbuvir, ledipasvir, daclatasvir and ribavirin, in various combinations, have shown to be safe and effective in patients with decompensated cirrhosis with sustained virological response (SVR) rates nearly comparable to those with well-compensated liver disease. Unique issues yet remain such as the challenges with renal insufficiency, tolerability of ribavirin and risk of further hepatic decompensation with a protease inhibitor-based regimen. While most patients who achieve SVR have demonstrated improvement in hepatic synthetic function over the short course of follow, the long-term beneficial effects are unknown. Further, the baseline predictors of improvement in hepatic function have not been well delineated and thus have left us in a quandary as to what we might expect with successful therapy and thus we are at a loss to well educate our patients. The major concern, in potential liver transplant candidates, is of unintended 'harm' by achieving SVR but without improvement in hepatic function to an extent where the patients might function well. As HCV therapies are as effective in liver transplant recipients, there is a growing sentiment in some of the transplant quarters that those with decompensated liver disease and awaiting liver transplant be treated for HCV after liver transplant. This strategy would thus eliminate any concern of leaving a patient in 'no person's' land by treating HCV successfully pretransplant but not to the point of functional normalcy, while also would maintain the risk of HCC. Yet a contrarian view would be that not all patients have access to liver transplantation (LT), cannot bear the cost, have comorbidities or contraindications to LT. While the debate continues, it is essential that we develop robust predictors of improvement in liver function so that we can carefully select our patients for therapy in the context of liver transplantation.
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Affiliation(s)
- C Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Bangkok, Thailand
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA
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Gao Y, Ren H, Meng F, Li J, Cheung E, Li H, Zhao J, Liu H, Liu Z, Zhang M. Pathological Roles of Interleukin-22 in the Development of Recurrent Hepatitis C after Liver Transplantation. PLoS One 2016; 11:e0154419. [PMID: 27123854 PMCID: PMC4849629 DOI: 10.1371/journal.pone.0154419] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 04/13/2016] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE The aim of this study was to longitudinally evaluate and analyze the role of interleukin-22-producing CD4 positive cells (IL-22) in the pathogenesis of Hepatitis C Virus recurrence after Orthotopic Liver Transplantation (HCV-OLT). METHODS 15 HCV-OLT, 15 age- and gender- matched non-HCV post-OLT (OLT) and 15 hepatitis C virus infected (HCV) patients were enrolled into our study from the liver transplantation and research center at Beijing 302 Hospital. We determined the frequencies of IL-22 using flow cytometry and expression of IL-22 mRNA using PCR in peripheral blood and liver tissue. We also divided HCV-OLT patients into rapid fibrosis progression (RFP) and slow fibrosis progression (SFP), examined IL-22 cells and analyzed the correlations between IL-22 frequencies and liver injury, fibrosis and clinical parameters. Moreover, we investigated the role of IL-22 in Human Hepatic Stellate Cells (HSCs). RESULTS The levels of serum IL-22, frequencies of IL-22 producing cells in peripheral blood mononuclear cells, and expression of IL-22 mRNA and protein in the liver in the HCV-OLT group were significantly higher than that in the HCV and OLT groups. Furthermore, eight (53.3%) patients developed RFP after two years; another three patients were diagnosed liver cirrhosis. The frequencies of IL-22 were much higher in RFP compared with SFP, while no significant difference existed between OLT and SFP. Intrahepatic IL-22 positive cells were located in fibrotic areas and significantly correlated with α-smooth muscle actin (α-SMA) and fibrosis staging scores, not with grading scores and HCRVNA. In vitro, IL-22 administration prevented HSCs apoptosis, promoted HSCs proliferation and activation, up-regulated the expression of HSC-sourced growth factors including α-SMA, TGF-β and TIMP-1, and increased the production of liver fibrosis markers including laminin, hyaluronic acid and collagen type IV. CONCLUSION Peripheral and intrahepatic IL-22 is up-regulated and plays a pathological role in exacerbating liver fibrosis by activating HSCs in HCV-OLT patients, which may predict RFP and serve as an attractive target for anti-fibrotic therapy.
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Affiliation(s)
- Yinjie Gao
- Liver Transplantation and Research Center, 302 Military Hospital, Beijing, China
- Department of Infectious Diseases, Medical School of Chinese PLA, Beijing, China
| | - Hui Ren
- Liver Transplantation and Research Center, 302 Military Hospital, Beijing, China
| | - Fanping Meng
- Liver Cirrhosis and Research Center, 302 Military Hospital, Beijing, China
| | - Jin Li
- Liver Transplantation and Research Center, 302 Military Hospital, Beijing, China
| | - Eddie Cheung
- California Pacific Medical Center, San Francisco, California, United States of America
- University of California at Davis school of medicine, Sacramento, California, United States of America
| | - Hanwei Li
- Liver Cirrhosis and Research Center, 302 Military Hospital, Beijing, China
| | - Jingmin Zhao
- Department of Pathology and Hepatology, 302 Military Hospital, Beijing, China
| | - Hongling Liu
- Liver Transplantation and Research Center, 302 Military Hospital, Beijing, China
| | - Zhenwen Liu
- Liver Transplantation and Research Center, 302 Military Hospital, Beijing, China
| | - Min Zhang
- Liver Transplantation and Research Center, 302 Military Hospital, Beijing, China
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Saab S, Park SH, Mizokami M, Omata M, Mangia A, Eggleton E, Zhu Y, Knox SJ, Pang P, Subramanian M, Kowdley K, Afdhal NH. Safety and efficacy of ledipasvir/sofosbuvir for the treatment of genotype 1 hepatitis C in subjects aged 65 years or older. Hepatology 2016; 63:1112-9. [PMID: 26704693 DOI: 10.1002/hep.28425] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Revised: 12/17/2015] [Accepted: 12/21/2015] [Indexed: 12/12/2022]
Abstract
UNLABELLED Elderly subjects have been historically underrepresented in clinical trials involving antiviral hepatitis C therapies. The aim of this analysis was to retrospectively evaluate the safety and efficacy of ledipasvir/sofosbuvir (LDV/SOF) by age groups of <65 years versus ≥65 years among subjects enrolled in phase 3 trials. Four open-label phase 3 clinical trials evaluated the safety and efficacy of LDV/SOF with or without ribavirin (RBV) for the treatment of genotype 1 chronic hepatitis C virus. Sustained virological response at 12 weeks, treatment-emergent adverse events (AEs), and graded laboratory abnormalities were analyzed according to age group. Of the 2293 subjects enrolled in four phase 3 trials, 264 (12%) were ≥65 years of age, of whom 24 were aged ≥75 years. Sustained virological response at 12 weeks was achieved by 97% (1965/2029) of subjects aged <65 years and 98% (258/264) of subjects aged ≥65 years. The most common AEs in both LDV/SOF groups that occurred in ≥10% of subjects were headache and fatigue. The rate of study discontinuation due to AEs was similar in the two age cohorts. The use of RBV in 1042 (45%) subjects increased the number of AEs, treatment-related AEs, and AEs leading to study drug modification/interruption, particularly among elderly subjects. CONCLUSIONS LDV/SOF with or without RBV was highly effective for treatment of genotype 1 chronic hepatitis C virusin subjects aged 65 and older. Addition of RBV did not increase sustained virological response at 12 weeks rates but led to higher rates of AEs, especially in elderly subjects.
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Affiliation(s)
- Sammy Saab
- University of California Los Angeles, Los Angeles, CA
| | - Sarah H Park
- University of California Los Angeles, Los Angeles, CA
| | | | - Masao Omata
- Yamanashi Prefectural Hospital Organization, Yamanashi, Japan
| | - Alessandra Mangia
- Liver Unit, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
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Saab S, Gonzalez YS, Huber C, Wang A, Juday T. Cost-effectiveness of Ombitasvir/Paritaprevir/Ritonavir, Dasabuvir+Ribavirin for US Post-Liver Transplant Recurrent Genotype 1 HCV. Liver Int 2016; 36:515-21. [PMID: 26610059 DOI: 10.1111/liv.13033] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 11/17/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Orthotopic liver transplant patients with recurrent hepatitis C (HCV) historically have had limited treatment options. Ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin (3D+R) was approved by the FDA in December 2014 for liver transplant recipients with recurrent genotype 1 HCV, in whom it is effective and well-tolerated. METHODS Using a two-phase Markov model, we analysed the cost-effectiveness of 3D+R in liver transplant recipients, the only HCV treatment with FDA approval in this population. As a sensitivity analysis, we also considered the cost-effectiveness of pegylated interferon plus ribavirin, the only other therapy with data from Phase III trials in this population. Patients were given one of three options: 3D+R for 24 weeks, pegylated interferon and ribavirin for 48 weeks (PR48) or no treatment (NT). Patients were then followed through subsequent disease progression until death. Outcome measures analysed were: lifetime risks of liver morbidity and mortality, treatment costs, non-treatment medical expenditures, and quality-adjusted life years. RESULTS Treatment with 3D+R was associated with a significantly lower lifetime risk of liver-related morbidity and mortality than treatment with PR48 or NT. 3D+R also was associated with a higher gain in quality-adjusted life years (11.3 compared to 8.25 with NT) and lower discounted overall costs ($423,585 compared to $724,757 with NT). CONCLUSIONS The use of 3D+R for liver transplant recipients with recurrent HCV is an outcome-improving and cost-effective regimen for this population with limited treatment options and large unmet need.
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Affiliation(s)
- Sammy Saab
- Pfleger Liver Institute, University of California, Los Angeles, California, USA
| | | | - Caroline Huber
- Precision Health Economics, Los Angeles, California, USA
| | - Alice Wang
- AbbVie Inc., North Chicago, Illinois, USA
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The changing ‘face’ of wait-listed patients in the USA. Curr Opin Organ Transplant 2016; 21:89-90. [DOI: 10.1097/mot.0000000000000300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Su F, Yu L, Berry K, Liou IW, Landis CS, Rayhill SC, Reyes JD, Ioannou GN. Aging of Liver Transplant Registrants and Recipients: Trends and Impact on Waitlist Outcomes, Post-Transplantation Outcomes, and Transplant-Related Survival Benefit. Gastroenterology 2016; 150:441-53.e6; quiz e16. [PMID: 26522262 DOI: 10.1053/j.gastro.2015.10.043] [Citation(s) in RCA: 151] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 09/30/2015] [Accepted: 10/21/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Epidemiologic factors have generated increased demand for liver transplantation among older patients. We aimed to describe trends in age among liver transplant registrants and recipients and the effect of age on waitlist and post-transplantation outcomes and on transplant-related survival benefit. METHODS We obtained data from the United Network for Organ Sharing on adults who were listed for liver transplantation (N = 122,606) or underwent liver transplantation (N = 60,820) from 2002 to 2014 in the United States. Competing risks analysis was used to model waitlist outcomes and Cox proportional hazards analysis to model post-transplantation survival. These models were also used to estimate 5-year transplant-related survival benefit for different age groups, calculated as the difference between waitlist and post-transplantation life expectancy. RESULTS Between 2002 and 2014, the mean age of liver transplant registrants increased from 51.2 to 55.7 years, with a more prominent increase in hepatitis C virus-positive (50.9-57.9 years) than hepatitis C virus-negative (51.3-54.3 years) registrants. The proportion of registrants aged ≥60 years increased from 19% to 41%. In hepatitis C virus-negative patients, aging trends were driven by increasing proportions of patients with hepatocellular carcinoma or nonalcoholic steatohepatitis. Among transplant registrants, increasing age was associated with increasing mortality before transplantation and decreasing likelihood of transplantation. Among transplant recipients, increasing age was associated with increasing post-transplantation mortality. There was little difference in 5-year transplant-related survival benefit between different age groups who had the same Model for End-Stage Liver Disease score. CONCLUSIONS Dramatic aging of liver transplant registrants and recipients occurred from 2002 to 2014, driven by aging of the hepatitis C virus-positive cohort and increased prevalence of nonalcoholic steatohepatitis and hepatocellular carcinoma. Increasing age does not affect transplant-related survival benefit substantially because age diminishes both post-transplantation survival and waitlist survival approximately equally.
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Affiliation(s)
- Feng Su
- Division of Internal Medicine, Department of Medicine, University of Washington, Seattle, Washington
| | - Lei Yu
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington
| | - Kristin Berry
- Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, Washington
| | - Iris W Liou
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington
| | - Charles S Landis
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington
| | - Stephen C Rayhill
- Division of Transplant Surgery, Department of Surgery, University of Washington, Seattle, Washington
| | - Jorge D Reyes
- Division of Transplant Surgery, Department of Surgery, University of Washington, Seattle, Washington
| | - George N Ioannou
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington.
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Oliver M, Ortiz CC, Ortiz J. Challenging hepatitis C-infected liver transplant patients. Hepat Med 2016; 8:1-8. [PMID: 26889091 PMCID: PMC4723095 DOI: 10.2147/hmer.s96110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Caring for liver transplant patients suffering from chronic hepatitis C virus (HCV) infection is a challenging task for transplant surgeons and primary physicians alike. HCV is the leading cause of liver transplantation in the USA and comes with a myriad of complications that increase morbidity and mortality. This review focuses on patient follow-up, spanning from before the liver transplant occurs to the patient's long-term health. Pretransplant, both donor and recipient variables, must be carefully chosen to ensure optimal surgical success. Risk factors must be identified and HCV viral load must be reduced to a minimum. In addition to standard transplant complications, HCV patients suffer from additional problems, such as fibrosing cholestatic hepatitis and widespread viremia. Physicians must focus on the balance of immunosuppressive and antiviral medications, while considering possible side effects from these potent drugs. Over the years following surgery, physicians must identify any signs of failing liver health, as HCV-positive patients have an increased risk for cirrhosis and certain life-threatening malignancies.
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Affiliation(s)
| | | | - Jorge Ortiz
- Department of Transplant Surgery, University of Toledo Medical Center, Toledo, OH, USA
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Khachatoorian R, French SW. Chaperones in hepatitis C virus infection. World J Hepatol 2016; 8:9-35. [PMID: 26783419 PMCID: PMC4705456 DOI: 10.4254/wjh.v8.i1.9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 10/01/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
Abstract
The hepatitis C virus (HCV) infects approximately 3% of the world population or more than 185 million people worldwide. Each year, an estimated 350000-500000 deaths occur worldwide due to HCV-associated diseases including cirrhosis and hepatocellular carcinoma. HCV is the most common indication for liver transplantation in patients with cirrhosis worldwide. HCV is an enveloped RNA virus classified in the genus Hepacivirus in the Flaviviridae family. The HCV viral life cycle in a cell can be divided into six phases: (1) binding and internalization; (2) cytoplasmic release and uncoating; (3) viral polyprotein translation and processing; (4) RNA genome replication; (5) encapsidation (packaging) and assembly; and (6) virus morphogenesis (maturation) and secretion. Many host factors are involved in the HCV life cycle. Chaperones are an important group of host cytoprotective molecules that coordinate numerous cellular processes including protein folding, multimeric protein assembly, protein trafficking, and protein degradation. All phases of the viral life cycle require chaperone activity and the interaction of viral proteins with chaperones. This review will present our current knowledge and understanding of the role of chaperones in the HCV life cycle. Analysis of chaperones in HCV infection will provide further insights into viral/host interactions and potential therapeutic targets for both HCV and other viruses.
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Suraweera D, Sundaram V, Saab S. Treatment of Hepatitis C Virus Infection in Liver Transplant Recipients. Gastroenterol Hepatol (N Y) 2016; 12:23-30. [PMID: 27330501 PMCID: PMC4865783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Chronic hepatitis C virus (HCV) infection is the leading cause of liver transplantation in adults. Although the recurrence of HCV infection after liver transplantation is nearly universal, the recent advances in direct-acting antiviral (DAA) agents have revolutionized the management of HCV infection in the posttransplant setting. A number of these agents have been evaluated in recent clinical trials and have shown high sustained virologic response rates, shorter durations of treatment, and decreased adverse events when compared with the previous treatment of pegylated interferon and ribavirin. This article will review the current literature on the efficacy, tolerability, and potential drug interactions of various DAA agents in patients with recurrent HCV infection posttransplant.
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Affiliation(s)
- Duminda Suraweera
- Dr Suraweera is a resident in the Department of Medicine at Olive-View Medical Center in Sylmar, California. Dr Sundaram is an assistant professor of medicine at Cedars-Sinai Medical Center in Los Angeles, California. Dr Saab is a professor of medicine and surgery at the University of California at Los Angeles in Los Angeles, California
| | - Vinay Sundaram
- Dr Suraweera is a resident in the Department of Medicine at Olive-View Medical Center in Sylmar, California. Dr Sundaram is an assistant professor of medicine at Cedars-Sinai Medical Center in Los Angeles, California. Dr Saab is a professor of medicine and surgery at the University of California at Los Angeles in Los Angeles, California
| | - Sammy Saab
- Dr Suraweera is a resident in the Department of Medicine at Olive-View Medical Center in Sylmar, California. Dr Sundaram is an assistant professor of medicine at Cedars-Sinai Medical Center in Los Angeles, California. Dr Saab is a professor of medicine and surgery at the University of California at Los Angeles in Los Angeles, California
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Wedd JP, Nordstrom E, Nydam T, Durham J, Zimmerman M, Johnson T, Thomas Purcell W, Biggins SW. Hepatocellular carcinoma in patients listed for liver transplantation: Current and future allocation policy and management strategies for the individual patient. Liver Transpl 2015; 21:1543-52. [PMID: 26457885 DOI: 10.1002/lt.24356] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 09/10/2015] [Accepted: 09/14/2015] [Indexed: 12/12/2022]
Abstract
Liver transplantation can provide definitive cure for patients with cirrhosis and hepatocellular carcinoma (HCC) when used appropriately. Advances in the management of HCC have allowed improved control of HCC while waiting for liver transplantation and new approaches to candidate selection particularly with regard to tumor burden and downstaging protocols. Additionally, there have been recent changes in allocation policy related to HCC in the U.S. that cap the HCC MELD exception at 34 points and implement a 6-month delay in a HCC MELD exception. This review examines the U.S. liver transplant allocation policy related to HCC, comprehensively details locoregional therapy options in HCC patients awaiting liver transplantation, and considers the impact of an increasing burden of HCC on future liver graft allocation policy.
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Affiliation(s)
- Joel P Wedd
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Eric Nordstrom
- Division of Gastroenterology and Hepatology, University of Colorado, Aurora, CO
| | - Trevor Nydam
- Department of Surgery, University of Colorado, Aurora, CO
| | - Janette Durham
- Department of Interventional Radiology, Anschutz Medical Campus, University of Colorado, Aurora, CO
| | | | - Thor Johnson
- Department of Interventional Radiology, Anschutz Medical Campus, University of Colorado, Aurora, CO
| | - W Thomas Purcell
- Division of Medical Oncology, University of Colorado, Aurora, CO
| | - Scott W Biggins
- Division of Gastroenterology and Hepatology, University of Colorado, Aurora, CO
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48
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Abstract
The management of hepatitis C virus (HCV) infection in special populations is challenging. The efficacy and safety data of the currently approved all-oral direct-acting antiviral combinations, including sofosbuvir, ledipasvir, daclatasvir, paritaprevir/ritonavir/ombitasvir plus dasabuvir (3D), and ribavirin, is compelling for use in special HCV populations, as has recently been recommended by expert guidelines. The treatment regimens and sustained virological response rates for special populations are nearly similar to those of the general HCV population. Sofosbuvir is not recommended in patients with severe renal impairment, and simeprevir and 3D regimen are not recommended for those with decompensated liver disease.
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Bambha KM. Implications of an aging liver transplant waiting list: Survival benefit should be based upon "mile-age" and performance. Liver Transpl 2015; 21:1459-61. [PMID: 26476094 DOI: 10.1002/lt.24357] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 10/15/2015] [Indexed: 02/07/2023]
Affiliation(s)
- Kiran M Bambha
- Division of Gastroenterology and Hepatology, Anschutz Medical Campus, University of Colorado, Denver, Aurora, CO
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50
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Ofosu A, Durand CM, Saberi B, Alqahtani S, Ucbilek E, Belden M, Cameron AM, Gurakar A. Implications of Treating Hepatitis C Virus Infection Among Patients Awaiting Cadaveric Liver Transplant: A Single-Center Experience. EXP CLIN TRANSPLANT 2015; 13 Suppl 3:7-10. [PMID: 26640901 DOI: 10.6002/ect.tdtd2015.l16] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES We examined hepatitis C virus positivity among the donors in our center to investigate whether hepatitis C treatment affected liver transplant Model for End-Stage Liver Disease. MATERIALS AND METHODS We retrospectively reviewed all deceased-donor liver transplants performed between January 2013 and December 2014 at our center, with the primary indication of hepatitis C virus. Baseline demographic and laboratory characteristics of recipients and donors were collected. Statistical analyses were done with P values ≤ .05 considered significant. RESULTS Seventy-five liver transplants were performed, and 62 of them were hepatitis C virus RNA-positive at the time of liver transplant donor offer. In 2013, during the Pre-Direct Antiviral Agents era, 14 of 33 hepatitis C virus RNA-positive recipients (42%) were matched to hepatitis C virus-positive donors. During the Direct Antiviral Agents era in 2014, this ratio was 38% (11/29) (P = .72). The mean Model for End-Stage Liver Disease at transplant of the 62 hepatitis C virus RNA-positive recipients was 29, whereas the mean Model for End-Stage Liver Disease of 13 hepatitis C virus RNA-negative recipients was 31. This was not statistically significant (P = .25). CONCLUSIONS Although hepatitis C virus treatment before liver transplant is an attractive option to eliminate the risk of complications because of recurrent hepatitis C virus after liver transplant, its potential effect on limiting the donor pool for the recipient must also be considered. In our observation, 40% of our donor pool consists of hepatitis C virus-positive donors. Further multiregional studies are warranted to verify this observation and to see the potential effect of direct antiviral agent treatment into waiting times and the Model for End-Stage Liver Disease at organ allocation.
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Affiliation(s)
- Andrew Ofosu
- From the Johns Hopkins University School of Medicine, Division of Gastroenterology, Baltimore, MD, United States
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